Veronica Hackethal, MD

When the COVID-19 pandemic first hit, cancer screening in the United States came to an abrupt halt. That experience, coupled with the financial fallout of the pandemic, has led some doctors to reassess business as usual.

In particular, a trio has taken aim at skin cancer screening – arguing that it should stop – in a ‘sounding board’ commentary published online Jan. 7 in the New England Journal of Medicine.

“The COVID-19 pandemic has functionally stopped skin cancer screening; what is important is not to restart it,” wrote the authors, led by H. Gilbert Welch, MD, MPH, at Brigham and Women’s Hospital, Boston, Massachusetts. Dr. Welch has often raised questions about cancer screening and highlighted the issue of overdiagnosis.

In this latest essay, Dr. Welch teamed up with pathologist Benjamin Mazer, MD, Yale University, New Haven, Conn., who writes commentaries for this news organization, and dermatologist Adewole S. Adamson, MD, University of Texas, Austin, to argue that screening for skin cancer has led to an overdiagnosis of melanoma.

However, two melanoma experts pointed out flaws in some of their arguments, and said the issue is more nuanced than they present.


 

Arguing that melanoma is overdiagnosed

The incidence of melanoma is six times as high as it was 40 years ago, making it the third most common cancer in the United States, the investigators pointed out. However, while case rates have skyrocketed, death rates from melanoma have remained about the same, which points to overdiagnosis.

They described a cycle of increased diagnostic scrutiny that is driving overdiagnosis of melanoma. This includes heightened awareness (perhaps overly) among patients, widespread skin screenings, lower clinical thresholds for biopsy, and lower thresholds among pathologists for diagnosis of melanoma. Fear of missing cancer, legal concerns, and financial incentives may all contribute.

“We view the rise in the incidence of melanoma as a sentinel event, a warning that an epidemic of inspection, surveillance, and biopsy of pigmented skin lesions is permeating through the general population,” they wrote.

Furthermore, overdiagnosis could contribute to unnecessary intervention.

Between 2004 and 2017, rates of biopsy among fee-for-service Medicare recipients almost doubled (from 5% to 8%), according to coding trends data cited in the article. Overdiagnosis and unnecessary intervention could cause psychological, financial, and physical harm to the patient, and the authors argued for interrupting the cycle.

“The most important step to break the cycle of melanoma overdiagnosis is to stop population-wide screening for skin cancer,” they wrote.

The U.S. Preventive Services Task Force currently states that there is insufficient evidence to weigh the balances versus the harms of skin cancer screening, leaving it open to interpretation.

“[T]he increase in melanoma diagnoses by a factor of 6, with at least an order of magnitude more persons undergoing a biopsy and no apparent effect on mortality, is more than enough to recommend against population-wide screening,” Dr. Welch and colleagues concluded.

But the issue may be more nuanced, argued a melanoma expert.

“Everyone agrees that screening high-risk groups has the greatest chance of reducing cancer mortality. In melanoma, the strongest risk factor is the number of moles and presence of clinically atypical moles,” David Polsky, MD, PhD, commented in an interview. Dr. Polsky is a professor of dermatologic oncology at the Perlmutter Cancer Center at New York University Langone Health.

However, population-based studies have shown that at least half of melanoma patients are not considered high risk based on the appearance of the mole, he explained.

“Studies to identify genetic risk factors for melanoma have not yet progressed to the point where these can be tested in the clinic. We clearly have a knowledge gap that needs to be addressed,” he said.

Moreover, it’s not easy to predict which early melanomas will metastasize, said dermatologist Jennifer Stein, MD, PhD, who specializes in treating patients at high risk for melanoma at NYU Langone.

“This paper suggests that it may not be important to detect and treat melanoma in situ, and that the increase in diagnosis of melanoma in situ has led to more harms than good,” she said. “There is evidence that most melanomas do originate as in situ lesions. Unfortunately, we cannot predict which ones will become more aggressive. For this reason, we treat melanoma in situ.”
 

Taking issue with some of the arguments

Both Dr. Polsky and Dr. Stein took issue with several of the arguments put forward by Dr. Welch and colleagues.

For instance, Dr. Welch and colleagues cited research suggesting that UV light is a weak risk factor for melanoma, but Dr. Polsky disagreed. “There are many lines of evidence ranging from epidemiological, clinical, and biological studies that prove the causative association between ultraviolet light and melanoma, while acknowledging that other factors, such as genetic predisposition, play an important role,” he said. “Since ultraviolet light in the form of outdoor sunburns or indoor tanning exposure are modifiable risk factors, it is important that we continue with our current public messaging on their causal role in the development of melanoma.”

Furthermore, the 2012 study that the authors cited to support their argument that pathologists today are more likely to diagnose melanoma than in years past is flawed, according to Dr. Stein. The study was very small and included just nine contemporary pathologists. Unlike in real life, pathologists in the study could not diagnose lesions as “atypical,” and may have erred on the side of caution by calling them malignant.

“There were multiple limitations to this study that were acknowledged by its authors, who stated that it was a hypothesis-generating study and may not be generalizable,” Dr. Stein said.

In addition, Dr. Polsky took issue with the suggestion that awareness about melanoma among the general public is overly heightened.

“Reducing melanoma awareness would not be wise,” he said. “Studies have shown that awareness of melanoma is associated with the diagnosis of earlier-stage lesions that can be cured by simple skin surgery, without the need for more costly interventions utilized for more advanced melanomas.”

Dr. Mazer reported receiving travel compensation from Hillcrest Healthcare Systems, and is a commentator for this new organization. Dr. Welch has written three books on the subjects of overdiagnosis and testing for cancer. Dr. Adamson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When the COVID-19 pandemic first hit, cancer screening in the United States came to an abrupt halt. That experience, coupled with the financial fallout of the pandemic, has led some doctors to reassess business as usual.

In particular, a trio has taken aim at skin cancer screening – arguing that it should stop – in a ‘sounding board’ commentary published online Jan. 7 in the New England Journal of Medicine.

“The COVID-19 pandemic has functionally stopped skin cancer screening; what is important is not to restart it,” wrote the authors, led by H. Gilbert Welch, MD, MPH, at Brigham and Women’s Hospital, Boston, Massachusetts. Dr. Welch has often raised questions about cancer screening and highlighted the issue of overdiagnosis.

In this latest essay, Dr. Welch teamed up with pathologist Benjamin Mazer, MD, Yale University, New Haven, Conn., who writes commentaries for this news organization, and dermatologist Adewole S. Adamson, MD, University of Texas, Austin, to argue that screening for skin cancer has led to an overdiagnosis of melanoma.

However, two melanoma experts pointed out flaws in some of their arguments, and said the issue is more nuanced than they present.


 

Arguing that melanoma is overdiagnosed

The incidence of melanoma is six times as high as it was 40 years ago, making it the third most common cancer in the United States, the investigators pointed out. However, while case rates have skyrocketed, death rates from melanoma have remained about the same, which points to overdiagnosis.

They described a cycle of increased diagnostic scrutiny that is driving overdiagnosis of melanoma. This includes heightened awareness (perhaps overly) among patients, widespread skin screenings, lower clinical thresholds for biopsy, and lower thresholds among pathologists for diagnosis of melanoma. Fear of missing cancer, legal concerns, and financial incentives may all contribute.

“We view the rise in the incidence of melanoma as a sentinel event, a warning that an epidemic of inspection, surveillance, and biopsy of pigmented skin lesions is permeating through the general population,” they wrote.

Furthermore, overdiagnosis could contribute to unnecessary intervention.

Between 2004 and 2017, rates of biopsy among fee-for-service Medicare recipients almost doubled (from 5% to 8%), according to coding trends data cited in the article. Overdiagnosis and unnecessary intervention could cause psychological, financial, and physical harm to the patient, and the authors argued for interrupting the cycle.

“The most important step to break the cycle of melanoma overdiagnosis is to stop population-wide screening for skin cancer,” they wrote.

The U.S. Preventive Services Task Force currently states that there is insufficient evidence to weigh the balances versus the harms of skin cancer screening, leaving it open to interpretation.

“[T]he increase in melanoma diagnoses by a factor of 6, with at least an order of magnitude more persons undergoing a biopsy and no apparent effect on mortality, is more than enough to recommend against population-wide screening,” Dr. Welch and colleagues concluded.

But the issue may be more nuanced, argued a melanoma expert.

“Everyone agrees that screening high-risk groups has the greatest chance of reducing cancer mortality. In melanoma, the strongest risk factor is the number of moles and presence of clinically atypical moles,” David Polsky, MD, PhD, commented in an interview. Dr. Polsky is a professor of dermatologic oncology at the Perlmutter Cancer Center at New York University Langone Health.

However, population-based studies have shown that at least half of melanoma patients are not considered high risk based on the appearance of the mole, he explained.

“Studies to identify genetic risk factors for melanoma have not yet progressed to the point where these can be tested in the clinic. We clearly have a knowledge gap that needs to be addressed,” he said.

Moreover, it’s not easy to predict which early melanomas will metastasize, said dermatologist Jennifer Stein, MD, PhD, who specializes in treating patients at high risk for melanoma at NYU Langone.

“This paper suggests that it may not be important to detect and treat melanoma in situ, and that the increase in diagnosis of melanoma in situ has led to more harms than good,” she said. “There is evidence that most melanomas do originate as in situ lesions. Unfortunately, we cannot predict which ones will become more aggressive. For this reason, we treat melanoma in situ.”
 

Taking issue with some of the arguments

Both Dr. Polsky and Dr. Stein took issue with several of the arguments put forward by Dr. Welch and colleagues.

For instance, Dr. Welch and colleagues cited research suggesting that UV light is a weak risk factor for melanoma, but Dr. Polsky disagreed. “There are many lines of evidence ranging from epidemiological, clinical, and biological studies that prove the causative association between ultraviolet light and melanoma, while acknowledging that other factors, such as genetic predisposition, play an important role,” he said. “Since ultraviolet light in the form of outdoor sunburns or indoor tanning exposure are modifiable risk factors, it is important that we continue with our current public messaging on their causal role in the development of melanoma.”

Furthermore, the 2012 study that the authors cited to support their argument that pathologists today are more likely to diagnose melanoma than in years past is flawed, according to Dr. Stein. The study was very small and included just nine contemporary pathologists. Unlike in real life, pathologists in the study could not diagnose lesions as “atypical,” and may have erred on the side of caution by calling them malignant.

“There were multiple limitations to this study that were acknowledged by its authors, who stated that it was a hypothesis-generating study and may not be generalizable,” Dr. Stein said.

In addition, Dr. Polsky took issue with the suggestion that awareness about melanoma among the general public is overly heightened.

“Reducing melanoma awareness would not be wise,” he said. “Studies have shown that awareness of melanoma is associated with the diagnosis of earlier-stage lesions that can be cured by simple skin surgery, without the need for more costly interventions utilized for more advanced melanomas.”

Dr. Mazer reported receiving travel compensation from Hillcrest Healthcare Systems, and is a commentator for this new organization. Dr. Welch has written three books on the subjects of overdiagnosis and testing for cancer. Dr. Adamson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

When the COVID-19 pandemic first hit, cancer screening in the United States came to an abrupt halt. That experience, coupled with the financial fallout of the pandemic, has led some doctors to reassess business as usual.

In particular, a trio has taken aim at skin cancer screening – arguing that it should stop – in a ‘sounding board’ commentary published online Jan. 7 in the New England Journal of Medicine.

“The COVID-19 pandemic has functionally stopped skin cancer screening; what is important is not to restart it,” wrote the authors, led by H. Gilbert Welch, MD, MPH, at Brigham and Women’s Hospital, Boston, Massachusetts. Dr. Welch has often raised questions about cancer screening and highlighted the issue of overdiagnosis.

In this latest essay, Dr. Welch teamed up with pathologist Benjamin Mazer, MD, Yale University, New Haven, Conn., who writes commentaries for this news organization, and dermatologist Adewole S. Adamson, MD, University of Texas, Austin, to argue that screening for skin cancer has led to an overdiagnosis of melanoma.

However, two melanoma experts pointed out flaws in some of their arguments, and said the issue is more nuanced than they present.


 

Arguing that melanoma is overdiagnosed

The incidence of melanoma is six times as high as it was 40 years ago, making it the third most common cancer in the United States, the investigators pointed out. However, while case rates have skyrocketed, death rates from melanoma have remained about the same, which points to overdiagnosis.

They described a cycle of increased diagnostic scrutiny that is driving overdiagnosis of melanoma. This includes heightened awareness (perhaps overly) among patients, widespread skin screenings, lower clinical thresholds for biopsy, and lower thresholds among pathologists for diagnosis of melanoma. Fear of missing cancer, legal concerns, and financial incentives may all contribute.

“We view the rise in the incidence of melanoma as a sentinel event, a warning that an epidemic of inspection, surveillance, and biopsy of pigmented skin lesions is permeating through the general population,” they wrote.

Furthermore, overdiagnosis could contribute to unnecessary intervention.

Between 2004 and 2017, rates of biopsy among fee-for-service Medicare recipients almost doubled (from 5% to 8%), according to coding trends data cited in the article. Overdiagnosis and unnecessary intervention could cause psychological, financial, and physical harm to the patient, and the authors argued for interrupting the cycle.

“The most important step to break the cycle of melanoma overdiagnosis is to stop population-wide screening for skin cancer,” they wrote.

The U.S. Preventive Services Task Force currently states that there is insufficient evidence to weigh the balances versus the harms of skin cancer screening, leaving it open to interpretation.

“[T]he increase in melanoma diagnoses by a factor of 6, with at least an order of magnitude more persons undergoing a biopsy and no apparent effect on mortality, is more than enough to recommend against population-wide screening,” Dr. Welch and colleagues concluded.

But the issue may be more nuanced, argued a melanoma expert.

“Everyone agrees that screening high-risk groups has the greatest chance of reducing cancer mortality. In melanoma, the strongest risk factor is the number of moles and presence of clinically atypical moles,” David Polsky, MD, PhD, commented in an interview. Dr. Polsky is a professor of dermatologic oncology at the Perlmutter Cancer Center at New York University Langone Health.

However, population-based studies have shown that at least half of melanoma patients are not considered high risk based on the appearance of the mole, he explained.

“Studies to identify genetic risk factors for melanoma have not yet progressed to the point where these can be tested in the clinic. We clearly have a knowledge gap that needs to be addressed,” he said.

Moreover, it’s not easy to predict which early melanomas will metastasize, said dermatologist Jennifer Stein, MD, PhD, who specializes in treating patients at high risk for melanoma at NYU Langone.

“This paper suggests that it may not be important to detect and treat melanoma in situ, and that the increase in diagnosis of melanoma in situ has led to more harms than good,” she said. “There is evidence that most melanomas do originate as in situ lesions. Unfortunately, we cannot predict which ones will become more aggressive. For this reason, we treat melanoma in situ.”
 

Taking issue with some of the arguments

Both Dr. Polsky and Dr. Stein took issue with several of the arguments put forward by Dr. Welch and colleagues.

For instance, Dr. Welch and colleagues cited research suggesting that UV light is a weak risk factor for melanoma, but Dr. Polsky disagreed. “There are many lines of evidence ranging from epidemiological, clinical, and biological studies that prove the causative association between ultraviolet light and melanoma, while acknowledging that other factors, such as genetic predisposition, play an important role,” he said. “Since ultraviolet light in the form of outdoor sunburns or indoor tanning exposure are modifiable risk factors, it is important that we continue with our current public messaging on their causal role in the development of melanoma.”

Furthermore, the 2012 study that the authors cited to support their argument that pathologists today are more likely to diagnose melanoma than in years past is flawed, according to Dr. Stein. The study was very small and included just nine contemporary pathologists. Unlike in real life, pathologists in the study could not diagnose lesions as “atypical,” and may have erred on the side of caution by calling them malignant.

“There were multiple limitations to this study that were acknowledged by its authors, who stated that it was a hypothesis-generating study and may not be generalizable,” Dr. Stein said.

In addition, Dr. Polsky took issue with the suggestion that awareness about melanoma among the general public is overly heightened.

“Reducing melanoma awareness would not be wise,” he said. “Studies have shown that awareness of melanoma is associated with the diagnosis of earlier-stage lesions that can be cured by simple skin surgery, without the need for more costly interventions utilized for more advanced melanomas.”

Dr. Mazer reported receiving travel compensation from Hillcrest Healthcare Systems, and is a commentator for this new organization. Dr. Welch has written three books on the subjects of overdiagnosis and testing for cancer. Dr. Adamson disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

A new, large study has confirmed that different types of hormone replacement therapy (HRT) are associated with an increased risk for breast cancer and has provided additional information on factors associated with that increased risk.

The study was published online on October 28 in The BMJ.

“The study confirms increased risk of breast cancer in patients taking HRT but shows that the magnitude of risk depends on a number of factors,” first author Yana Vinogradova, PhD, said in an interview. Dr. Vinogradova is a medical statistician at the University of Nottingham (England).

The study also suggests the risk may be lower than was estimated in a large meta-analysis of 24 trials that was published in 2019 in The Lancet. In that study, researchers suggested the risk for breast cancer with HRT was higher and persisted longer than had been thought.

This conclusion from the meta-analysis was widely reported in the lay press and led to the UK Medicine and Healthcare Products Regulatory Agency issuing a safety alert for HRT regarding breast cancer. Experts in the field questioned the alert and said it caused undue anxiety. The European Medicines Agency also issued a safety alert because of the study.

This new study was begun before publication of the meta-analysis. Although the results are broadly similar in suggesting increased risk for breast cancer with HRT use, findings from the new study suggest the risk is lower than had been estimated in the meta-analysis and that the risk diminishes more rapidly after stopping HRT than was suggested by the meta-analysis.

“The publicity surrounding publication of the meta-analysis highlighted unexpectedly high risks and led to a heightened level of concern in some quarters,” Dr. Vinogradova commented. “Our study, based on general population data, has not confirmed any such findings. In general, it showed lower levels of risk and clarified the variability of magnitude within them.”

Dr. Vinogradova said the discrepancy could be related to the fact that the studies were designed differently. The meta-analysis relied on results from 24 studies that were conducted around the world at different periods and included women of different ages and backgrounds. The studies in the meta-analysis used different methods, including questionnaires that relied on women’s memories and therefore could have been biased, she said.

In contrast, the new study analyzed EMR data collected prospectively by general practices in the United Kingdom. The data came from the QResearch and from the Clinical Practice Research Datalink (CPRD) databases, the two largest primary care databases in the United Kingdom, which were linked to hospital, mortality, and cancer registries.

Because this study used a “consistent design” and “consistent data sources,” these new results “are likely to be more accurate and reliable for assessing risks among HRT users,” Dr. Vinogradova commented.

This study used an observational design, so it cannot prove that HRT causes breast cancer. These results may better represent women in the general U.K. population, compared with the earlier meta-analysis, she added.

Commenting on the new study, Michael Jones, PhD, senior staff scientist in genetics and epidemiology at the Institute of Cancer Research, London, also emphasized that it was large and its data came from general practitioner medical records, “so the strong statistical associations are unlikely to be due to chance.

“The results of this study generally confirm what has been seen before and is well established – that the use of combined estrogen plus progestogen HRT is associated with increased risk of breast cancer, and this risk increases with duration of use. But reassuringly, after stopping HRT, the raised risk of breast cancer mostly returns to that seen in nonusers of HRT,” he said.

“It’s important to note that no one study should be considered in isolation,” he added. “Even though some risks were found to be slightly smaller than those reported in another meta-analysis of the worldwide epidemiological evidence recently published in 2019, women considering use of HRT should still follow advice given to them by their [general practitioners].”
 

Study details

In the study, researchers evaluated all types of HRT commonly prescribed in the United Kingdom over the past 20 years, including topical estrogen, vaginal pessaries, and creams. They grouped HRT use by recent (within the past 5 years) and past (5 or more years ago) and HRT duration as short term (less than 5 years) and long term (5 years or longer). Results were adjusted for a range of factors that could affect breast cancer risk, including lifestyle, smoking, alcohol consumption, other medical conditions, family history, and use of other prescribed drugs.

The analysis included 98,611 women aged 50-79 years who were first diagnosed with breast cancer between 1998 and 2019. These women were matched by age and general practice to 457,498 women who were not diagnosed with breast cancer over these years. HRT use was reported in 34% (33,703) of women with breast cancer and in 31% (134,391) of women without breast cancer.

Overall, the risk for breast cancer was increased with use of most HRT drugs (adjusted odds ratio, 1.21; 95% confidence, 1.19-1.23), compared with not using HRT drugs. The highest risk was tied to combined estrogen/progestogen HRT (adjusted OR, 1.26; 95% CI, 1.24-1.29). The lowest risk was tied to estrogen-only HRT (adjusted OR, 1.06; 95% CI, 1.03-1.10). Estrogen cream and vaginal estrogen were not associated with increased breast cancer risk.

In general, breast cancer risk was higher among recent HRT users and those receiving long-term therapy. HRT-associated breast cancer risk increased with age and declined after discontinuing treatment. Therapy of less than 1 year was not associated with increased breast cancer risk.

Women who had recently been receiving long-term combined estrogen/progestogen HRT had a 79% increased risk for breast cancer (adjusted OR, 1.79; 95% CI, 1.73-1.85), compared with never-users. Among recent long-term users of combined HRT, breast cancer risk was highest for norethisterone (adjusted OR, 1.88; 95% CI, 1.79-1.99) and lowest for dydrogesterone (adjusted OR, 1.24; 95% CI, 1.03-1.48). Women who had recently been receiving long-term estrogen-only HRT had a 15% increased risk for breast cancer compared to never-users (adjusted OR, 1.15; 95% CI, 1.09-1.21).

Among women who discontinued HRT 5 or more years ago, risk for breast cancer was no longer increased for long-term estrogen-only therapy and short-term estrogen/progestogen therapy. However, breast cancer risk remained elevated 5 years after discontinuing long-term estrogen/progestogen (adjusted OR, 1.16; 95% CI, 1.11-1.21).

HRT-associated risk for breast cancer increased with age across all durations of therapy.

Compared with never-use, recent long-term estrogen-only therapy was associated with zero extra breast cancer cases per 10,000 women-years among women aged 50-59 years and eight extra cases per 10,000 women-years among women aged 70-79.

Recent long-term estrogen/progestogen use was associated with 15 extra breast cancer cases among women aged 50-59 and 36 extra cases among women aged 70-79 per 10,000 women-years.

Past long-term estrogen/progestogen use was associated with zero extra breast cancer cases among women aged 50-59 and eight extra cases among women aged 70-79 per 10,000 women-years.

Summarizing, Dr. Vinogradova said the increased risk for breast cancer with HRT appears to be “relatively small, particularly for younger women and for any women who use HRT only for a restricted period.”

Decisions about whether to use HRT and which type to use should depend on symptom severity, patient factors, and suitability of other treatment options, she commented.

“Particularly for those women who our study has shown to be most at risk, these decisions should be made through discussions between the patient and her doctor,” she concluded. “We hope that the new and more detailed information provided by our study will facilitate such prescribing decisions.”

The study was partially funded by the School for Primary Care Research of the National Institute for Health Research, by Cancer Research UK, and by the Cancer Research UK Oxford Center. Dr. Vinogradova has disclosed no relevant financial relationships. Senior author Julia Hippisley-Cox is an unpaid director of QResearch and was a paid director of ClinRisk until 2019. The other authors have disclosed no relevant financial relationships.
 

A version of this story originally appeared on Medscape.com.

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

When the first reports emerged of “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of experience reigning in “cytokine release syndrome” (CRS) in patients treated with chimeric antigen receptor (CAR) therapies for advanced blood cancers.

There was hope that drugs used to quell CRS in patients with cancer would be effective in patients with severe COVID. But the promise of a quick fix with oncology medications has yet to be fully realized.

Part of the problem is that the two conditions, while analogous, are “not the same,” said Nirali Shah, MD, head of the hematologic malignancies section in the pediatric oncology branch at the National Cancer Institute.

“You have to understand the underlying pathophysiology, what triggers the inflammation,” Dr. Shah said.

CAR T–related CRS is caused by activated T cells in patients with cancer who often do not have an infection, she explained. In contrast, cytokine storm in COVID-19 is triggered by a viral pathogen that can drive “out of control” inflammation. These differences may explain why drugs work in the first instance, but not in the second, she added. Drugs that inhibit interleukin-6 (such as tocilizumab, sarilumab, and siltuximab) are used with great success to dampen down the CRS in patients receiving CAR therapy for blood cancers. And although trials of these agents in patients with COVID are still ongoing, initial results are disappointing.

The first global, phase 3 randomized controlled trial of tocilizumab in severe COVID-19 failed to meet its primary endpoint of improved clinical status, and it did not meet its secondary endpoint of improved mortality at week 4.

In its recent recommendations, the National Institutes of Health noted a lack of data to support the efficacy of IL-6 inhibitors in COVID-19, and recommended against their use, except as part of a clinical trial.
 

Trimming the tree vs. cutting it down

As researchers have begun to decode the immune process underlying severe COVID-19, they have turned to other cancer drugs to tame cytokine storm.

Louis Staudt, MD, PhD, and Wyndham Wilson, MD, PhD, both at the NCI, think that cytokine storm in COVID-19 is driven by macrophages, which trigger release of multiple cytokines.

For years, the pair have been studying lymphoid tumors. Dr. Staudt is chief of the lymphoid malignancies branch at the NCI, and Wilson is head of the lymphoma therapeutics section. In past work, Dr. Staudt discovered that inhibiting an enzyme called bruton tyrosine kinase (BTK) dampens macrophage function.

When the pandemic began, Dr. Staudt and Dr. Wilson realized that singling out just one cytokine like IL-6 may not be enough. They thought that a more effective approach may be to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit multiple cytokines at the same time.

Dr. Staudt likens the immune response to a tree, with the macrophages composing the tree trunk and the limbs made up of individual cytokines.

“Targeting macrophages is getting at the trunk of the problem,” he said. “You’re only cutting off the limbs with tocilizumab.”

In just 3 days, Dr. Staudt and Dr. Wilson went from concept to approval to launching a prospective, observational study. The study took place at five centers in the US, and included 19 patients hospitalized with COVID-19; the results were published in Science Immunology. Over a treatment course of 14 days, the majority of patients treated off-label with acalabrutinib improved, some within 24 hours. Eight of 11 patients on supplemental oxygen were discharged on room air. Four of eight patients on ventilators were extubated, with two of these discharged on room air. Two patients on ventilators died. No discernible toxicity was noted.

Analyses also showed increased BTK activity and elevated IL-6 levels in monocytes – precursors of macrophages – in patients with severe COVID-19, compared with healthy volunteers.

“We showed that the target of acalabrutinib was active in the immune cells of patients with severe COVID-19,” Dr. Staudt said. “So we have the target. We have the drug to hit the target. And we have an apparent clinical benefit.”

Those three things were compelling enough to launch the CALAVI phase 2 trial, an open-label, randomized, controlled trial, sponsored by AstraZeneca and the NCI, that is being conducted in the United States and internationally. It is testing acalabrutinib with best supportive care versus BSC alone in people hospitalized with COVID-19. The trial is scheduled to be completed on Nov. 26.

Preliminary insights from this trial are expected soon. “These are not insights that we will likely publish, but they are important insights that will lead to the launch of a definitive double-blind, randomized, phase 3 trial, which we hope to launch in the next month or so,” Dr. Wilson said.
 

Targeting inflammation and infection simultaneously

Other scientists are investigating inhibitors of Janus kinase (JAK), a family of enzymes that play a key role in orchestrating immune responses, particularly cytokines. Interest in JAK inhibition to control hyperinflammation in cancer goes back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant]).

“It wasn’t a huge leap for those of us with a lot of understanding of JAK inhibitors to propose taking them into the clinic to treat patients with COVID-19,” commented John Mascarenhas, MD, the leader of clinical investigation in the myeloproliferative disorders program at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Mascarenhas is also principal investigator of the PRE-VENT trial, which is comparing the investigational JAK2 inhibitor pacritinib plus standard of care to standard of care alone in patients hospitalized with severe COVID-19, with and without cancer. The trial is sponsored by CTI BioPharma (manufacturer of pacritinib), and is taking place at 10 sites in the United States.

In a move that may raise eyebrows, PRE-VENT skipped phase 1 and 2 and went straight to phase 3. Pacritinib has yet to receive FDA approval and has mostly been studied in myelofibrosis, an intensely inflammatory disease.

The decision was based on trials of pacritinib in hematologic malignancies and also on results from a phase 2 study in China that found possible clinical benefit for the JAK 1/2 inhibitor ruxolitinib in 43 patients hospitalized with severe COVID-19, although results were not statistically significant, Dr. Mascarenhas explained.

Recent results from Lilly’s ACTT-2 study have provided further support for the role of JAK inhibitors in treating cytokine storm. ACTT-2 is a phase 3, double-blind, placebo-controlled, randomized, controlled trial sponsored by the NIH and NIAID comparing the JAK 1/2 inhibitor baricitinib plus the antiviral remdesivir with remdesivir alone in patients hospitalized with COVID-19. In September, Lilly announced that the trial met its primary endpoint of decreased time to recovery in patients who received baricitinib in combination with remdesivir.

But pacritinib’s mechanism of action may take things a step further. The drug selectively inhibits JAK2 and spares JAK1, which is important for antiviral activity in the immune system. Also, in vitro data suggests pacritinib may simultaneously reduce inflammation and fight off the virus by selectively inhibiting two additional enzymes and two other receptors.

“The rationale to me is very strong for using pacritinib,” Dr. Mascarenhas said. “I think this approach was bold but appropriate.”

The main safety concern with pacritinib could be bleeding, especially among patients on anticoagulants, Dr. Mascarenhas said. Because some patients with severe COVID-19 tend to develop blood clots, anticoagulation has become the standard of care at many institutions.

Because the trial is just beginning – only a minority of the total planned population of 358 patients has been enrolled – no interim results are available.
 

Right drug, wrong time?

IL-6 inhibition could still have a role to play in COVID-19, but the trick could be in the timing. Most of the trials so far have studied tocilizumab in patients with severe COVID-19, many of whom were already on ventilators. At that point, it may be too late to reverse the damage that has already taken place.

One of the main reasons tocilizumab works so well in CRS after CAR T therapy is that oncologists have learned how to use it early, often within 24 hours of fever onset. Oncologists use the American Society for Transplantation and Cellular Therapy consensus grading system, which helps them identify CRS when it is easier to control.

But applying the ASTCT grading system to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws off the scale,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, who has research expertise in infectious complications after CAR T therapy.

“The key is to intervene earlier to prevent damage to the lungs and other end organs. We don’t have anything magical that will reverse that damage,” Dr. Hill said.

Results from the phase 3 trial EMPACTA trial (sponsored by Genentech) seem to bear this out. EMPACTA is evaluating use of tocilizumab in hospitalized patients with less severe COVID-19 who do not yet require mechanical ventilation. The trial is notable for being the first global phase 3 trial to demonstrate efficacy for tocilizumab vs placebo in hospitalized patients with COVID-19 pneumonia, and for including a high percentage of racial/ethnic minorities (85% of 389 participants), who have been hard hit by the pandemic and have historically been underrepresented in drug trials.

Last month, Roche announced that EMPACTA met its primary endpoint. Results showed that patients hospitalized with COVID-19 pneumonia who received tocilizumab plus standard of care were 44% less likely to go on mechanical ventilation or die, compared with those who received placebo plus standard of care (P = .0348), although there were no statistically significant differences in death by day 28 between tocilizumab and placebo (10.4% vs. 8.6%, P = .5146).

However, earlier administration of tocilizumab raises another issue. IL-6 and its pathway are important for clearing viral infections. Using tocilizumab in the context of an ongoing infection could raise safety issues.

Also, tocilizumab sticks around in the body for a relatively long time. In the treatment of rheumatoid arthritis, it is dosed once a month, and it carries a black box warning for reactivation of tuberculosis.

Whereas results from EMPACTA showed similar rates of infection associated with tocilizumab and placebo (10% vs. 11%), at least one other study has found increased rates of superinfection in patients with severe COVID-19 who received tocilizumab. Overall, though, the drug was associated with decreased risk of death in the latter study.

A phase 2 trial called COVIDOSE is tackling the safety issue. COVIDOSE is evaluating whether low-dose tocilizumab is effective in noncritical COVID-19 patients, with the idea that lower doses could be safer. Early results published as a preprint before peer review indicated that low-dose tocilizumab (ranging from 40 mg to 200 mg) was associated with clinical improvement in 32 noncritical patients hospitalized with COVID-19.

Five patients (15.6%) developed bacterial superinfections, and five (15.6%) died by 28-day follow-up, although there wasn’t a perfect “overlap” between these groups of patients. Bacterial superinfection was not the cause of death in all five patients who died, and not all patients who died developed bacterial superinfections, according to senior author Pankti Reid, MD, MPH, an assistant professor of medicine at the University of Chicago.

Results from COVIDOSE also showed that treatment with tocilizumab did not seem to affect the ability of patients to develop antibodies against COVID-19. The results set the stage for a larger randomized, controlled trial (still ongoing) to determine the optimal dose of tocilizumab.

Still, Dr. Hill urges caution.

Many of these immunomodulators have been used only in the context of a clinical trial, or only for patients with terminal cancer and no other treatment options. In patients with cancer, these drugs have been studied and have shown an “acceptable safety profile,” according to Dr. Shah.

But this is a different situation, and when it comes to repurposing them to relatively healthy patients with COVID-19, Dr. Hill emphasized the need for careful research.

“We’re always very concerned about giving drugs that suppress the immune response if people have active infections,” Dr. Hill said. “Often times we think it makes things worse, and it typically does.”

Dr. Mascarenhas reported institutional research funding from CTI Biopharma. Dr. Hill, Dr. Staudt, Dr. Wilson, and Dr. Shah disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

The first study to systematically address the problem of persistent hair loss in patients who undergo radiation to the scalp for central nervous system or head and neck tumors has found that treatment with topical minoxidil leads to improvement in hair loss.

The study was published online on Aug. 5 in JAMA Dermatology.

Minoxidil has been used for many years to treat age-associated baldness in men, noted the authors. It was used off label in this study to treat radiation-associated persistent hair loss; 82% of patients showed at least some improvement.

For patients who do not improve with minoxidil, hair transplant and scalp reconstruction with plastic surgery were other options, the authors comment.

“Almost in all instances, there is something that can be done to improve persistent hair loss after radiation and give patients a sense of control,” senior author Mario E. Lacouture, MD, said in an interview. He is director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center in New York City.

About 60% of people with CNS tumors and 30% with head and neck cancer receive radiation to the head, and 75%-100% of these patients experience acute hair loss. For many, hair grows back in 2-3 months. However, for about 60%, hair loss persists for 6 or more months after completion of radiotherapy, the authors note.

In past work, Dr. Lacouture and colleagues found that persistent hair loss in cancer survivors is associated with depression, anxiety, and psychosocial distress.

“There are therapies and procedures that may mitigate persistent radiation therapy hair loss that can bring back psychosocial well-being to many of these patients,” Dr. Lacouture said. “These approaches are likely underutilized because patients are not being referred to specialists in hair or scalp reconstruction.”

Specialists can be found through the International Society for Hair Restoration Surgery and the American Academy of Dermatology, he added.

Study details

The retrospective cohort study included 71 children and adults who developed persistent hair loss after radiotherapy for primary CNS tumors (90%, n = 64) or head and neck sarcoma (10%, n = 7). The median age of the patients was 27 years (range, 4-75 years); 72% (n = 51) were female and 82% (n = 58) were White.

These patients had been treated at Memorial Sloan Kettering Cancer Center in New York City or St. Jude Children’s Hospital in Memphis from January 2011 to January 2019.

The team analyzed standardized clinical photographs of the scalp using the Common Terminology Criteria for Adverse Events version 5.0. Grade 1 alopecia was defined as hair loss of less than 50% of normal that does not require camouflage with hair pieces, scarves, or similar items. Grade 2 alopecia was defined as hair loss greater than 50% of normal that requires camouflage and is associated with negative psychosocial effects.

Over half of patients (56%, 40/70) had grade 1 hair loss. Clinical images were available for 54 patients; for most of these patients, hair loss was attributable to radiation alone (74%, n = 40). Evaluation of clinical imaging showed three variants of hair loss: localized (54%, 29/54), diffuse (24%, 13/54), and mixed pattern (22%, 12/54). Data on dermatologic imaging of the scalp (trichoscopy) were available for 28 patients; the main finding was white patches (57%, 16/28).

The median scalp radiation dose was 39.6 Gy (range, 15.1-50.0 Gy). The researchers estimate that a dose of 36.1 Gy (95% CI, 33.7-39.6 Gy) was sufficient to induce grade 2 hair loss in 50% of patients.

Severity of hair loss appeared to increase with radiation dose. For every 1-unit increase in radiation dose, the odds of grade 2 hair loss increased by 15% (odds ratio, 1.15; 95% CI, 1.04-1.28; P < .001). Proton irradiation was associated with even higher odds of severe hair loss (OR, 5.7; 95% CI, 1.05-30.8; P < .001). Results remained significant when analyses were controlled for sex, age at time of radiotherapy, and concurrent chemotherapy.

The majority of evaluable patients who were treated with topical minoxidil (5%) twice daily showed a response (82%, 28/34) during a median follow-up of 61 weeks (interquartile range, 21-105 weeks).

Among 25 of these patients for whom clinical images were available, 16% (4/25) showed complete response. Two patients improved with hair transplant, and one showed complete response with plastic surgery reconstruction of the hair.

The study had several limitations, including its retrospective design and a lack of complete data for certain variables, such as standardized clinical photographs, trichoscopy images, and radiotherapy treatment plans.

On the basis of these results, the authors are seeking funding for a prospective study of the use of minoxidil for persistent radiation-induced alopecia.

The study was funded in part by the National Institutes of Health/National Cancer Institute Cancer Center. One or more authors has relationships with pharmaceutical companies, as listed in the original article.

This article first appeared on Medscape.com.

A study has shown for the first time that knowing BRCA1/2 mutation status before a breast cancer diagnosis was associated with better survival.

The study, conducted among Ashkenazi Jewish women in Israel, showed that among women who knew their carrier status before they developed breast cancer, diagnoses were made at an earlier disease stage and 5-year survival was improved compared to women who learned their carrier status only after their disease had been diagnosed.

The study was published online on July 9 in JAMA Oncology.

“I don’t want to belittle the complexities of knowing that you’re a carrier. But I think these results really show that knowledge is power,” first author Ephrat Levy-Lahad, MD, director of the medical genetics unit at Shaare Zedek Medical Center in Jerusalem, Israel, told Medscape Medical News.

Carrying a BRCA1/2 pathogenic mutation is associated with a 70% to 80% lifetime risk for breast cancer and about a 10% to 50% lifetime risk for ovarian cancer, depending on the specific mutation. Only about 10% of carriers will not develop either cancer during their lifetime.

The study provides support for genetic screening for pathogenic BRCA1/2 mutations, especially in high-risk populations, according to Levy-Lahad.

“For me, the results are part of a bigger picture.... I think we should be moving towards general population screening, certainly in high-risk populations like Ashkenazi Jews,” she said.

In Israel, that decision has already been made: a new policy, introduced in January 2020, offers testing for common BRCA1/2 mutations for all Ashkenazi Jewish women.

However, women in other countries may also benefit from testing, she argues. About half of BRCA1/2 carriers in a general population like that of the United States do not have a family history that would indicate a need for testing. That means many women who carry these mutations may not be taking advantage of recommended surveillance and prevention measures, she said.

But screening for BRCA1/2 mutations becomes more complicated when applied to more general populations, she acknowledged.

About 2.5% of women of Ashkenazi Jewish descent carry pathogenic mutations for BRCA1/2, compared to 0.5% in the general White population.

Also, screening in the Ashkenazi Jewish population is probably simpler than in the general population. Just three mutations are definitely known to cause disease and need to be tested for among Ashkenazi Jews. Screening in a larger population would require full sequencing of the gene. That increases the likelihood of finding variants of unknown significance (VUSs), which muddies the water. Knowledge is incomplete about whether some of these VUSs increase cancer risk, and physicians do not always know how to manage them in women who test positive.

Moreover, Israel has a national health system. Screening in a country without universal health insurance such as the United States raises questions about whether follow-up would be covered by insurance carriers for women who test positive.

Mehmet Copur, MD, an oncologist at Morrison Cancer Center in Hastings, Nebraska, questions how general population screening could be done in “real life.”

“These findings should be taken into consideration in the context of the patient population who would agree to genetic testing, who would agree to comply with the recommended guidelines for risk reduction, and who would have insurance coverage or resources to comply with the recommendations,” Copur told Medscape Medical News.

“If BRCA-positive patients did not or could not follow these recommendations, the results would different,” he added.

The most crucial component of screening for these mutations is genetic counselors, who are in short supply in the United States, according to Copur.

Another issue is that of cost. Genetic counseling is not always covered by insurance, especially for individuals who do not have a family history of BRCA-related cancers. Genetic testing is not cheap, and the costs of monitoring women who test positive could be prohibitive, especially in a healthcare system burdened by COVID-19.

“Whether our current healthcare system could bear the cost of such a change is up for debate. The screening itself may be feasible, but offering lifelong surveillance to every woman identified with mutations could present huge capacity issues,” Copur said. “Maybe in the future, the healthcare system can be ready for such an undertaking, but I don’t think we are there yet.”

Although she acknowledges the differences in risk between Ashkenazi Jews and the general population, Levy-Lahad thinks not having screening is like “throwing the baby out with the bath water.”

“Maybe we’re not ready for total general population screening, but I think we have to start thinking along those lines,” she said. “We have this incredible tool for cancer prevention, and we should really be using it, certainly in populations like Ashkenazi Jews.”

Researchers conducted a retrospective analysis that included 105 women diagnosed with breast cancer at Shaare Zedek Medical Center in Jerusalem between 2005 and 2016. Forty-two women knew they were carriers before their breast cancer diagnosis, and 63 learned of their carrier status only after diagnosis. Of the participants, 83% were Ashkenazi Jews. For both prediagnosis and postdiagnosis groups, the age at diagnosis was the same (50.4 years). For both groups, distributions of pathogenic mutations were similar. There were no significant differences in hormone receptor or ERBB2 status.

Among women who knew they were carriers before diagnosis, 80.9% (34/42) were diagnosed either with ductal carcinoma in situ or stage 1 disease. Only 9.5% (4/42) of these women were diagnosed with disease of stage 2 or higher.

In comparison, among women who learned their carrier status after diagnosis, 30% (19/63) had early-stage disease at diagnosis, and 52.4% (33/63) were diagnosed at stage 2 or higher (P < .001).

Compared to women who knew their carrier status before diagnosis, women who found out after diagnosis had 12 times higher odds of being diagnosed with disease of advanced clinical stage (P = .001) and eight times higher odds of being diagnosed with disease of advanced pathologic stage (P = .002).

A sentinel node biopsy was sufficient in 85.7% (36/42) of women who knew their carrier status before diagnosis; 7.2% (3/42) of these women needed a full lymph node dissection. In contrast, 3.2% (2/63) of women who learned their carrier status after diagnosis underwent sentinel node biopsy, and 34.9% (25/105) needed a full lymph node dissection (P < .001).

Among women who knew their carrier status before diagnosis, 54.8% (23/42) did not need chemotherapy at all, and none needed neoadjuvant chemotherapy. Only 4.8% (3/63) of women who learned their mutation status after diagnosis were able to forgo chemotherapy (P < .001); 22.2% (14/63) needed neoadjuvant therapy (P = .001).

These findings appeared to translate into better outcomes. Overall 5-year survival was significantly higher among women who knew their carrier status before diagnosis compared to women who found out afterward (94% [SE 4%] vs 78% [SE 5%]; P = .03). Only two of 42 women (4.8%) in the prediagnosis group died, compared to 16 of 63 (25.4%) in the postdiagnosis group.

Analyses that controlled for year at diagnosis showed that women who learned their carrier status before diagnosis had significantly lower risk for overall mortality compared with those who found out after diagnosis (hazard ratio [HR], 0.20; 95% CI, 0.04 – 0.93; P = .04). However, these results lost significance when controlled for age, socioeconomic index, family history, and gene variant (HR, 0.16; 95% CI, 0.02 – 1.4; P = .10).

Higher socioeconomic status (HR, 0.76; 95% CI, 0.6 – 0.97; P = .03), gene variant (BRCA2 vs BRCA1: HR, 0.15; 95% CI, 0.03 – 0.75; P = .02), and age at diagnosis (HR, 1.047; 95% CI, 1.003 – 1.093; P = .04) were all associated with overall mortality.

“I can’t infer causation, but we suspect that the reason for these results is the difference in follow-up,” Levy-Lahad said.

Most of the women (95.2%, 40/42) who knew their carrier status before diagnosis received their follow-up at the medical center’s high-risk carrier clinic. Twenty-seven of 42 (64.3%) of these women were diagnosed with breast MRI. By contrast, only 1.6% (1/63) of women who found out their carrier status after diagnosis were diagnosed with breast MRI. Breast MRI is not routinely used for breast cancer screening but can be more sensitive than mammography for detecting breast cancer.

The study was funded by the Breast Cancer Research Foundation and by a gift from Ellie and David Werber to ShaareZedek Medical Center.

Levy-Lahad received grants from the Breast Cancer Research Foundation and from the Israel Cancer Association during the conduct of the study and personal fees from AstraZeneca outside the submitted work. Copur has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A study has shown for the first time that knowing BRCA1/2 mutation status before a breast cancer diagnosis was associated with better survival.

The study, conducted among Ashkenazi Jewish women in Israel, showed that among women who knew their carrier status before they developed breast cancer, diagnoses were made at an earlier disease stage and 5-year survival was improved compared to women who learned their carrier status only after their disease had been diagnosed.

The study was published online on July 9 in JAMA Oncology.

“I don’t want to belittle the complexities of knowing that you’re a carrier. But I think these results really show that knowledge is power,” first author Ephrat Levy-Lahad, MD, director of the medical genetics unit at Shaare Zedek Medical Center in Jerusalem, Israel, told Medscape Medical News.

Carrying a BRCA1/2 pathogenic mutation is associated with a 70% to 80% lifetime risk for breast cancer and about a 10% to 50% lifetime risk for ovarian cancer, depending on the specific mutation. Only about 10% of carriers will not develop either cancer during their lifetime.

The study provides support for genetic screening for pathogenic BRCA1/2 mutations, especially in high-risk populations, according to Levy-Lahad.

“For me, the results are part of a bigger picture.... I think we should be moving towards general population screening, certainly in high-risk populations like Ashkenazi Jews,” she said.

In Israel, that decision has already been made: a new policy, introduced in January 2020, offers testing for common BRCA1/2 mutations for all Ashkenazi Jewish women.

However, women in other countries may also benefit from testing, she argues. About half of BRCA1/2 carriers in a general population like that of the United States do not have a family history that would indicate a need for testing. That means many women who carry these mutations may not be taking advantage of recommended surveillance and prevention measures, she said.

But screening for BRCA1/2 mutations becomes more complicated when applied to more general populations, she acknowledged.

About 2.5% of women of Ashkenazi Jewish descent carry pathogenic mutations for BRCA1/2, compared to 0.5% in the general White population.

Also, screening in the Ashkenazi Jewish population is probably simpler than in the general population. Just three mutations are definitely known to cause disease and need to be tested for among Ashkenazi Jews. Screening in a larger population would require full sequencing of the gene. That increases the likelihood of finding variants of unknown significance (VUSs), which muddies the water. Knowledge is incomplete about whether some of these VUSs increase cancer risk, and physicians do not always know how to manage them in women who test positive.

Moreover, Israel has a national health system. Screening in a country without universal health insurance such as the United States raises questions about whether follow-up would be covered by insurance carriers for women who test positive.

Mehmet Copur, MD, an oncologist at Morrison Cancer Center in Hastings, Nebraska, questions how general population screening could be done in “real life.”

“These findings should be taken into consideration in the context of the patient population who would agree to genetic testing, who would agree to comply with the recommended guidelines for risk reduction, and who would have insurance coverage or resources to comply with the recommendations,” Copur told Medscape Medical News.

“If BRCA-positive patients did not or could not follow these recommendations, the results would different,” he added.

The most crucial component of screening for these mutations is genetic counselors, who are in short supply in the United States, according to Copur.

Another issue is that of cost. Genetic counseling is not always covered by insurance, especially for individuals who do not have a family history of BRCA-related cancers. Genetic testing is not cheap, and the costs of monitoring women who test positive could be prohibitive, especially in a healthcare system burdened by COVID-19.

“Whether our current healthcare system could bear the cost of such a change is up for debate. The screening itself may be feasible, but offering lifelong surveillance to every woman identified with mutations could present huge capacity issues,” Copur said. “Maybe in the future, the healthcare system can be ready for such an undertaking, but I don’t think we are there yet.”

Although she acknowledges the differences in risk between Ashkenazi Jews and the general population, Levy-Lahad thinks not having screening is like “throwing the baby out with the bath water.”

“Maybe we’re not ready for total general population screening, but I think we have to start thinking along those lines,” she said. “We have this incredible tool for cancer prevention, and we should really be using it, certainly in populations like Ashkenazi Jews.”

Researchers conducted a retrospective analysis that included 105 women diagnosed with breast cancer at Shaare Zedek Medical Center in Jerusalem between 2005 and 2016. Forty-two women knew they were carriers before their breast cancer diagnosis, and 63 learned of their carrier status only after diagnosis. Of the participants, 83% were Ashkenazi Jews. For both prediagnosis and postdiagnosis groups, the age at diagnosis was the same (50.4 years). For both groups, distributions of pathogenic mutations were similar. There were no significant differences in hormone receptor or ERBB2 status.

Among women who knew they were carriers before diagnosis, 80.9% (34/42) were diagnosed either with ductal carcinoma in situ or stage 1 disease. Only 9.5% (4/42) of these women were diagnosed with disease of stage 2 or higher.

In comparison, among women who learned their carrier status after diagnosis, 30% (19/63) had early-stage disease at diagnosis, and 52.4% (33/63) were diagnosed at stage 2 or higher (P < .001).

Compared to women who knew their carrier status before diagnosis, women who found out after diagnosis had 12 times higher odds of being diagnosed with disease of advanced clinical stage (P = .001) and eight times higher odds of being diagnosed with disease of advanced pathologic stage (P = .002).

A sentinel node biopsy was sufficient in 85.7% (36/42) of women who knew their carrier status before diagnosis; 7.2% (3/42) of these women needed a full lymph node dissection. In contrast, 3.2% (2/63) of women who learned their carrier status after diagnosis underwent sentinel node biopsy, and 34.9% (25/105) needed a full lymph node dissection (P < .001).

Among women who knew their carrier status before diagnosis, 54.8% (23/42) did not need chemotherapy at all, and none needed neoadjuvant chemotherapy. Only 4.8% (3/63) of women who learned their mutation status after diagnosis were able to forgo chemotherapy (P < .001); 22.2% (14/63) needed neoadjuvant therapy (P = .001).

These findings appeared to translate into better outcomes. Overall 5-year survival was significantly higher among women who knew their carrier status before diagnosis compared to women who found out afterward (94% [SE 4%] vs 78% [SE 5%]; P = .03). Only two of 42 women (4.8%) in the prediagnosis group died, compared to 16 of 63 (25.4%) in the postdiagnosis group.

Analyses that controlled for year at diagnosis showed that women who learned their carrier status before diagnosis had significantly lower risk for overall mortality compared with those who found out after diagnosis (hazard ratio [HR], 0.20; 95% CI, 0.04 – 0.93; P = .04). However, these results lost significance when controlled for age, socioeconomic index, family history, and gene variant (HR, 0.16; 95% CI, 0.02 – 1.4; P = .10).

Higher socioeconomic status (HR, 0.76; 95% CI, 0.6 – 0.97; P = .03), gene variant (BRCA2 vs BRCA1: HR, 0.15; 95% CI, 0.03 – 0.75; P = .02), and age at diagnosis (HR, 1.047; 95% CI, 1.003 – 1.093; P = .04) were all associated with overall mortality.

“I can’t infer causation, but we suspect that the reason for these results is the difference in follow-up,” Levy-Lahad said.

Most of the women (95.2%, 40/42) who knew their carrier status before diagnosis received their follow-up at the medical center’s high-risk carrier clinic. Twenty-seven of 42 (64.3%) of these women were diagnosed with breast MRI. By contrast, only 1.6% (1/63) of women who found out their carrier status after diagnosis were diagnosed with breast MRI. Breast MRI is not routinely used for breast cancer screening but can be more sensitive than mammography for detecting breast cancer.

The study was funded by the Breast Cancer Research Foundation and by a gift from Ellie and David Werber to ShaareZedek Medical Center.

Levy-Lahad received grants from the Breast Cancer Research Foundation and from the Israel Cancer Association during the conduct of the study and personal fees from AstraZeneca outside the submitted work. Copur has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A study has shown for the first time that knowing BRCA1/2 mutation status before a breast cancer diagnosis was associated with better survival.

The study, conducted among Ashkenazi Jewish women in Israel, showed that among women who knew their carrier status before they developed breast cancer, diagnoses were made at an earlier disease stage and 5-year survival was improved compared to women who learned their carrier status only after their disease had been diagnosed.

The study was published online on July 9 in JAMA Oncology.

“I don’t want to belittle the complexities of knowing that you’re a carrier. But I think these results really show that knowledge is power,” first author Ephrat Levy-Lahad, MD, director of the medical genetics unit at Shaare Zedek Medical Center in Jerusalem, Israel, told Medscape Medical News.

Carrying a BRCA1/2 pathogenic mutation is associated with a 70% to 80% lifetime risk for breast cancer and about a 10% to 50% lifetime risk for ovarian cancer, depending on the specific mutation. Only about 10% of carriers will not develop either cancer during their lifetime.

The study provides support for genetic screening for pathogenic BRCA1/2 mutations, especially in high-risk populations, according to Levy-Lahad.

“For me, the results are part of a bigger picture.... I think we should be moving towards general population screening, certainly in high-risk populations like Ashkenazi Jews,” she said.

In Israel, that decision has already been made: a new policy, introduced in January 2020, offers testing for common BRCA1/2 mutations for all Ashkenazi Jewish women.

However, women in other countries may also benefit from testing, she argues. About half of BRCA1/2 carriers in a general population like that of the United States do not have a family history that would indicate a need for testing. That means many women who carry these mutations may not be taking advantage of recommended surveillance and prevention measures, she said.

But screening for BRCA1/2 mutations becomes more complicated when applied to more general populations, she acknowledged.

About 2.5% of women of Ashkenazi Jewish descent carry pathogenic mutations for BRCA1/2, compared to 0.5% in the general White population.

Also, screening in the Ashkenazi Jewish population is probably simpler than in the general population. Just three mutations are definitely known to cause disease and need to be tested for among Ashkenazi Jews. Screening in a larger population would require full sequencing of the gene. That increases the likelihood of finding variants of unknown significance (VUSs), which muddies the water. Knowledge is incomplete about whether some of these VUSs increase cancer risk, and physicians do not always know how to manage them in women who test positive.

Moreover, Israel has a national health system. Screening in a country without universal health insurance such as the United States raises questions about whether follow-up would be covered by insurance carriers for women who test positive.

Mehmet Copur, MD, an oncologist at Morrison Cancer Center in Hastings, Nebraska, questions how general population screening could be done in “real life.”

“These findings should be taken into consideration in the context of the patient population who would agree to genetic testing, who would agree to comply with the recommended guidelines for risk reduction, and who would have insurance coverage or resources to comply with the recommendations,” Copur told Medscape Medical News.

“If BRCA-positive patients did not or could not follow these recommendations, the results would different,” he added.

The most crucial component of screening for these mutations is genetic counselors, who are in short supply in the United States, according to Copur.

Another issue is that of cost. Genetic counseling is not always covered by insurance, especially for individuals who do not have a family history of BRCA-related cancers. Genetic testing is not cheap, and the costs of monitoring women who test positive could be prohibitive, especially in a healthcare system burdened by COVID-19.

“Whether our current healthcare system could bear the cost of such a change is up for debate. The screening itself may be feasible, but offering lifelong surveillance to every woman identified with mutations could present huge capacity issues,” Copur said. “Maybe in the future, the healthcare system can be ready for such an undertaking, but I don’t think we are there yet.”

Although she acknowledges the differences in risk between Ashkenazi Jews and the general population, Levy-Lahad thinks not having screening is like “throwing the baby out with the bath water.”

“Maybe we’re not ready for total general population screening, but I think we have to start thinking along those lines,” she said. “We have this incredible tool for cancer prevention, and we should really be using it, certainly in populations like Ashkenazi Jews.”

Researchers conducted a retrospective analysis that included 105 women diagnosed with breast cancer at Shaare Zedek Medical Center in Jerusalem between 2005 and 2016. Forty-two women knew they were carriers before their breast cancer diagnosis, and 63 learned of their carrier status only after diagnosis. Of the participants, 83% were Ashkenazi Jews. For both prediagnosis and postdiagnosis groups, the age at diagnosis was the same (50.4 years). For both groups, distributions of pathogenic mutations were similar. There were no significant differences in hormone receptor or ERBB2 status.

Among women who knew they were carriers before diagnosis, 80.9% (34/42) were diagnosed either with ductal carcinoma in situ or stage 1 disease. Only 9.5% (4/42) of these women were diagnosed with disease of stage 2 or higher.

In comparison, among women who learned their carrier status after diagnosis, 30% (19/63) had early-stage disease at diagnosis, and 52.4% (33/63) were diagnosed at stage 2 or higher (P < .001).

Compared to women who knew their carrier status before diagnosis, women who found out after diagnosis had 12 times higher odds of being diagnosed with disease of advanced clinical stage (P = .001) and eight times higher odds of being diagnosed with disease of advanced pathologic stage (P = .002).

A sentinel node biopsy was sufficient in 85.7% (36/42) of women who knew their carrier status before diagnosis; 7.2% (3/42) of these women needed a full lymph node dissection. In contrast, 3.2% (2/63) of women who learned their carrier status after diagnosis underwent sentinel node biopsy, and 34.9% (25/105) needed a full lymph node dissection (P < .001).

Among women who knew their carrier status before diagnosis, 54.8% (23/42) did not need chemotherapy at all, and none needed neoadjuvant chemotherapy. Only 4.8% (3/63) of women who learned their mutation status after diagnosis were able to forgo chemotherapy (P < .001); 22.2% (14/63) needed neoadjuvant therapy (P = .001).

These findings appeared to translate into better outcomes. Overall 5-year survival was significantly higher among women who knew their carrier status before diagnosis compared to women who found out afterward (94% [SE 4%] vs 78% [SE 5%]; P = .03). Only two of 42 women (4.8%) in the prediagnosis group died, compared to 16 of 63 (25.4%) in the postdiagnosis group.

Analyses that controlled for year at diagnosis showed that women who learned their carrier status before diagnosis had significantly lower risk for overall mortality compared with those who found out after diagnosis (hazard ratio [HR], 0.20; 95% CI, 0.04 – 0.93; P = .04). However, these results lost significance when controlled for age, socioeconomic index, family history, and gene variant (HR, 0.16; 95% CI, 0.02 – 1.4; P = .10).

Higher socioeconomic status (HR, 0.76; 95% CI, 0.6 – 0.97; P = .03), gene variant (BRCA2 vs BRCA1: HR, 0.15; 95% CI, 0.03 – 0.75; P = .02), and age at diagnosis (HR, 1.047; 95% CI, 1.003 – 1.093; P = .04) were all associated with overall mortality.

“I can’t infer causation, but we suspect that the reason for these results is the difference in follow-up,” Levy-Lahad said.

Most of the women (95.2%, 40/42) who knew their carrier status before diagnosis received their follow-up at the medical center’s high-risk carrier clinic. Twenty-seven of 42 (64.3%) of these women were diagnosed with breast MRI. By contrast, only 1.6% (1/63) of women who found out their carrier status after diagnosis were diagnosed with breast MRI. Breast MRI is not routinely used for breast cancer screening but can be more sensitive than mammography for detecting breast cancer.

The study was funded by the Breast Cancer Research Foundation and by a gift from Ellie and David Werber to ShaareZedek Medical Center.

Levy-Lahad received grants from the Breast Cancer Research Foundation and from the Israel Cancer Association during the conduct of the study and personal fees from AstraZeneca outside the submitted work. Copur has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

When a patient with cancer hears there isn’t much left that doctors can do, it always stays fresh in the mind.

Doug Olson was first diagnosed with chronic lymphocytic leukemia (CLL) over 20 years ago, in 1996. For several years, his doctors used the watch-and-wait approach. But then his cancer progressed and needed treatment. By 2010, it had mutated so much that it no longer responded to standard therapy.

He was rapidly running out of options. Back then, the only treatment left was a bone marrow transplant. Without one, his doctors said, he would have 1 or 2 years left to live.

“I was really trying to avoid a bone marrow transplant. You’re playing your last card if that doesn’t work. It’s a pretty rough procedure,” Olson told Medscape Medical News.

Looking back, Olson counts himself as lucky – for being in the right place, at the right time, with the right doctor. His oncologist was David Porter, MD, the principal investigator on a trial at the University of Pennsylvania that was investigating a brand new approach to treating cancer: chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell therapy uses a patient’s own T cells engineered to express a receptor that targets proteins on cancer cells. CAR T cells are considered “living drugs” because they expand inside the body and stick around for years – maybe for a lifetime – to fight the cancer if it tries to come back.

“I was certainly intrigued by the approach. It had worked in mice, and it was the sort of thing that looked like it would work,” Olson recalled.

Science is not a foreign language to Olson. He holds a PhD in medicinal chemistry, spent most of his career in the in vitro diagnostics industry, and currently acts as chief executive officer of Buhlmann Diagnostics Corp.

So he read the clinical protocol for the first in-human trial of CAR T cells and agreed to become patient number two.

Olson’s T cells were harvested, engineered to attack the CD19 antigen found on malignant and normal B lymphocytes, and then were expanded into millions in the lab. After undergoing preconditioning with chemotherapy to minimize rejection and boost the CAR T cells’ expansion inside the body, he received several infusions of the new therapy over the course of 3 days.

Nothing really happened for 2 weeks. Then he developed severe flu-like symptoms – so bad that he was hospitalized.

Ironically, getting sick was a sign that the CAR T cells were working. Olson was experiencing one of the main short-term effects of CAR T-cell therapy: cytokine release syndrome. Symptoms include extremely high fevers and dangerous drops in blood pressure that can potentially cause end-organ damage.

In the early trials of these products, some patients experienced such a severe reaction that they needed intensive care, and some died. With increasing clinical experience, doctors have learned to control the reaction with the use of steroids and interleukein-6 inhibitors such as tocilizumab (Actemra).

Fortunately for Olson, the reaction passed, and he was eventually discharged.

Then the “aha moment” happened. Four weeks after receiving the CAR T cells, Olson found out that he was cancer free.

“It still gives me shivers,” he said. “Dr Porter said, ‘Your bone marrow’s completely free. We just can’t find a cancer cell anywhere.’ “

The remission has lasted, and it is now 10 years later.
 

Balancing long-term risks vs benefits

Long-term data have been accumulating for these novel therapies since Olson’s treatment in 2010. This is particularly important for CAR T-cell therapy, because of its longevity. Because these are living cells and are expected to persist in the body for years, there is great interest in longer-term data, especially the risks for toxicity.

The FDA requires clinical follow-up for at least 15 years for patients treated with CAR T-cell therapy or any other genetically modified cells.

So far, most of the experience with CAR T cells comes from anti-CD19-directed therapy, which has shown “remarkable” remission rates in the 50% to 85% range, said Nirali Shah, MD, head of the hematologic malignancies section of the Pediatric Oncology Branch at the National Cancer Institute (NCI).

The most recent results presented at this year’s annual meeting of the American Society of Clinical Oncology support earlier efficacy data, she noted. In the longest follow-up to date, researchers reported remissions lasting over 9 years in patients with relapsed/refractory B-cell lymphoma or CLL treated with Kite›s axicaptagene cilleucel (Yescarta), one of two anti-CD19-directed CAR T-cell therapies approved by the FDA in 2017 (the other is Novartis’ tisagenlecleucel [Kymriah]).

This study included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved in 54% of patients, and 22% had partial remission.

The other focus is long-term safety. Although some of the long-term adverse effects are known and are manageable, others fall into the theoretical realm. In early May 2020, the NCI held a multidisciplinary virtual conference on CAR T-cell therapy «to encourage collaborative research about the subacute and potentially long-term toxicity profile of these treatments.»

“We know just a little at this point about late- and long-term effects of CAR-T therapy, because we are relatively early in the era of CAR T cells,” said Merav Bar, MD, from the Fred Hutchinson Cancer Research Center in Seattle, Washington.
 

B-cell aplasia and risk for new infections

What is known is that B-cell aplasia represents the most common long-term adverse effect of CAR T-cell therapy. B-cell aplasia results when anti-CD19 CAR-T therapy wipes out healthy B cells as well as the malignant ones responsible for leukemia/lymphoma.

As major players in the immune system, B cells are a key defense against viruses. So B-cell aplasia represents a very specific type of immunosuppression. It is generally less severe than immunosuppression that occurs after organ transplant, which hits the immune system pretty much across the board and carries a much higher risk for infection.

The main concern is what happens when someone with B-cell aplasia encounters a new pathogen, such as SARS-CoV-2.

After infection, B cells generate memory cells, which are not killed off by anti-CD19 therapy and that stick around for life. So a patient such as Olson would still make antibodies that fight infections they experienced before receiving CAR-T therapy, such as childhood chickenpox. But now they are unable to make new memory cells, so these patients receive monthly immunoglobulin infusions to protect against pathogens they have not previously encountered.

Olson takes this in stride and says he isn’t overly worried about COVID-19. He follows the recommended precautions for a man his age. He wears a mask, washes his hands frequently, and tries to maintain social distancing. But he doesn’t stay locked up in his New Hampshire home.

“I took the attitude when I was diagnosed with cancer that I’m going to live my life,” he said. “Quality of life to me is more important than quantity.”
 

Neuropsychiatric toxicity

Another problem is the possibility of neuropsychiatric toxicity. Past studies have reported a wide range of such toxicities associated with CAR T-cell therapy, including seizures and hallucinations. Most have occurred early in the course of treatment and appear to be short-lived and reversible. However, there remain questions about long-term neuropsychiatric problems.

In a long-term study of 40 patients with relapsed/refractory CLL, non-Hodgkin lymphoma, and ALL, nearly half of patients (47.5%, 19/40) self-reported at least one clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty) 1 to 5 years after anti-CD19 CAR T-cell therapy. In addition, 37.5% (15/40) self-reported cognitive difficulties.

“Patients with more severe neurotoxicity showed a trend for more cognitive difficulties afterwards,» said Bar, senior author of the study.

However, teasing out the role that CAR T-cell therapy plays in these problems poses a challenge. All of these patients had been heavily pretreated with previous cancer therapy, which has also been associated with neuropsychiatric problems.

“So far, we don’t know what caused it,” Bar said. “Nevertheless, people need to pay attention to neuropsychiatric symptoms in CAR T-cell therapy. It is important to continue to monitor these patients for these issues.”
 

Graft-vs-host disease

Another potential problem is graft-vs-host disease (GVHD). This is not uncommon after hematopoietic stem cell transplants. It develops when the donor T cells view antigens on healthy recipient cells as foreign and attack them.

For patients who are treated with CAR T cells, GVHD is mostly a concern among individuals who have previously had a transplant and who are already at increased risk for it.

In a study of late effects among 86 adults treated with anti-CD19 CAR T cells for relapsed/refractory non-Hodgkin lymphoma, Bar and colleagues found that GVHD occurred only among patients who had received a previous donor stem cell transplant. Of these, 20% (3/15) developed GVHD about 28 months after CAR-T therapy.

“The data for CAR T cells causing GVHD really hasn’t shown that it’s a huge problem, although we have seen it and are continuing to monitor for it,” the NCI’s Shah commented to Medscape Medical News.

Other Long-term Adverse Effects

A range of other long-term adverse effects have been reported with CAR-T therapy, including prolonged cytopenias (reduced mature blood cells), myelodysplasia (bone marrow failure), and second malignancies.

In the study with the longest follow-up to date, 16% (7/43) of patients developed second malignancies, which is comparable to data from Bar’s study in Seattle (15%, 13/86). The researchers in this study consider this rate to be no higher than expected: these patients had already received extensive chemotherapy, which increases the risk for other cancers, they point out.

However, this brings up theoretical concerns about the long-term effects of gene modification. CAR T cells are engineered using retroviruses (mainly lentiviruses), which randomly insert the CAR genes into the host genome. Doing so may cause mutations that could promote cancer. These lentiviruses also carry the theoretical risk of becoming capable of viral replication once inside the body.

To address these concerns, viruses used to engineer CAR T cells go through comprehensive safety testing. After therapy, patients are checked every few months during the first year and annually after that.

So far, there have been no reports of cancers associated with CAR T-cell therapy.

“Any type of cancer is a very theoretical risk,” Bar told Medscape Medical News. «Most likely the malignancies in our study were related to prior treatment that the patients received. None of them had any evidence of replication-competent lentivirus, or any other evidence that the malignancies were related to the CAR T cells.»

Another theoretical concern is the possibility of new-onset autoimmune disease, although, once again, no cases have been reported so far.

“We think of it as a theoretic possibility. Whenever you jack up the immune system, autoimmune disease is a potential risk,” said Carl June, MD, director of the Center for Cellular Immunotherapies at the University of Pennsylvania.

June was the co–principal investigator of the trial in which Olson participated. He is also the inventor on patents for CAR T cells licensed by the University of Pennsylvania to Novartis and Tmunity and is a scientific founder with equity in Tmunity.

Still, autoimmunity could occur, and scientists are looking out for it.

“We are continuing to be vigilant in our monitoring for autoimmune disease,” Shah added. “We’ve been doing CAR T-cell therapy since 2012, and I think we have yet to see true autoimmunity beyond GVHD.”
 

Future directions

In the 10 years since Olson received CAR T-cell therapy, an entire industry has sprung up. Over 100 companies worldwide are now developing CAR T-cell therapies targeting various antigens. These therapies are directed at about 60 different tumor types, including solid tumors. Nearly 200 clinical trials are underway, though most are still in early stages: as of September 2019, only 5% had reached phase 3.

Clinical data show promising results for CAR T-cell therapy directed against CD22 (overexpressed on ALL cells), and BCMA (found on almost all multiple myeloma cells). Yet questions remain as to whether CAR T cells will be as effective if they target antigens other than CD19 or cells other than B lymphocytes. One of the biggest research questions is whether they will be effective against solid tumors.

One research avenue being watched with great interest is the development of universal CAR T cells. So far, such products are at very early stages of development (phase 1 trials), but they are attractive because of the potential advantages they offer over bespoke CAR T cells. Automating the process holds the promise of immediate availability, standardizing production, expanding access, and lowering costs. And because the T cells for this universal product come from healthy donors, they may function better than T cells that have been battered and bruised by past cancer treatments, or even the cancer itself.

However, precisely because they are developed from healthy donor T cells, universal CAR T cells may pose increased risk for GVHD. Scientists are trying to get around this problem by engineering universal CAR T cells that lack the T-cell receptor involved in GVHD.

There are also other concerns. Nature has a penchant for mutation. Engineering CAR T cells without T-cell receptors means the body may no longer detect or reject a universal CAR T cell if it goes rogue. Also, gene insertion in universal CAR-T therapy is targeted rather than random (as in bespoke CAR T cells), which could create off-target effects. Both issues create a theoretical risk of such products inducing an untreatable CAR T-cell therapy–associated cancer.

“The theoretic risk with universal cells is that their safety profile may not be as good for long term,” June commented.
 

Hope for the future

From that first trial in which June and Porter used CAR T cells, two of three patients they treated are still alive 10 years later.

Olson is one of these two, and he still undergoes monitoring every 3 months to check for relapse. So far, none of his tests have shown signs of his cancer returning.

After going into remission, Doug spent the next 6 to 9 months regaining his health and strength.

“I figured if I had this amazing treatment that saved my life, I had an obligation to stay alive,” he said. “I’d better not die of something like a heart attack!”

He took up long distance running and has completed six half marathons. He became involved in the Leukemia and Lymphoma Society, participating in fund-raising and helping newly diagnosed patients. Over the years, he has also given talks for researchers, people with cancer, and healthcare providers.

Doug is now 73. Today, he marvels at how rapidly the CAR-T field has progressed.

“Twenty years ago, if you had cancer, your prospects weren’t nearly as good as these days. In 2010, people still didn’t believe in CAR T-cell therapy,” he said. “My goal always in telling my story is a message of hope.”

This article first appeared on Medscape.com.

Although priority number one lies in controlling the spread of COVID-19, public health researchers are calling attention to the long-term repercussions of the pandemic on children’s health.

School closures could noticeably worsen the epidemic of childhood obesity that already threatens many children in the United States, say Paul Rundle, DrPH, and colleagues from Columbia University Mailman School of Public Health, New York City, in a perspective published online March 30 in Obesity.

“In part, we wrote the perspective to remind people that summer unhealthy weight gain seems to accumulate year to year,” he told Medscape Medical News in an email.

Rundle and colleagues estimate that time spent out of school will double this year because of school closures due to COVID-19. That, along with shelter-in-place orders, will pose challenges both for physical activity and healthy eating among children.

In addition, playgrounds have closed in many areas, and even where parks remain open, social distancing decreases opportunities for exercise. Team sports are on hold, and without physical education taught in schools, many children will not be getting as much active outdoor play as needed.

That’s especially true for children in urban areas, who may find it even more difficult to exercise inside cramped apartments, they add.

As a result, more and more children may turn to sedentary activities, and increased screen time goes hand in hand with childhood overweight and obesity, not just because of the lack of exercise but also because of snacking on unhealthy, empty-calorie foods while glued to the screen.

“We were hoping to get the word out on this issue, do some education or reminding, and at least let people know that this should be something to keep an eye on, among so many other things,” Rundle added.

Excess Eating Because of Stress and Boredom

Jessica Sparks Lilley, MD, director of the Pediatric Diabetes and Lipid Program at the Mississippi Center for Advanced Medicine in Madison, agrees that it is crucial to address these issues.

“Just like adults, children eat in response to emotions, including stress and boredom, and stress levels are high during these uncertain times,” she told Medscape Medical News.

Although both Rundle and Sparks Lilley acknowledged the challenges of finding good solutions at this time, they do offer some tips.

Schools should make physical education and at-home exercise a priority alongside other remote teaching. Physical education teachers could even stream exercise classes to children at home.

Even just walking in the park while maintaining social distancing could be better than nothing, and a brisk walk is probably even better.

Depending on the age of the child, online yoga may also be useful. Even though yoga burns relatively few calories, it incorporates mindfulness training that may be helpful.

“I think focusing on promoting mindful eating as compared to mindless or distracted eating is important. Even in the best of circumstances, it is hard to exercise enough to burn off high energy snacks,” Rundle said.

Additional Stressors From Poverty: Schools Can Help With Meals

Children living in poverty, already the most vulnerable to obesity and related health problems, have additional stressors, add the two experts.

“As more Americans are losing jobs, poverty is a real threat to many of the children I care for. Families living in poverty often rely on processed, high-calorie, low-nutrient foods for survival, because they are inexpensive and shelf-stable,” Sparks Lilley said.

Rundle and colleagues agree: “Our own experiences in supermarkets show...shelves that held...crackers, chips, ramen noodles, soda, sugary cereals, and processed ready-to-eat meals are quite empty. We anticipate that many children will experience higher calorie diets during the pandemic response.”

Similar to how they address food insecurity during summer holidays, school districts have responded by offering grab-and-go meals, Rundle and colleagues note.

To maintain social distancing for people with vulnerable family members, some school districts have also started delivering food using school buses that run along regularly scheduled routes.

Rundle also stresses that farmers’ markets, which often provide foods that appeal to immigrant and ethnic communities, should be considered part of essential food services.

As such, social distancing protocols should be established for them and they should be allowed to stay open, he argues.

“The safety of American children is at stake in many ways. The threat to themselves or their caregivers being infected with COVID-19 is rightly foremost in our concerns,” Sparks Lilley stressed.

“However, there is other fallout to consider. We’ve seen very clearly the need for public health and preventive medicine and can’t let vulnerable children fall through the cracks.”

Rundle agrees. Although it is a “priority” to mitigate the immediate impact of COVID-19, “it is important to consider ways to prevent its long-term effects, including new risks for childhood obesity.”

Rundle and coauthors, as well as Sparks Lilley, have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Although priority number one lies in controlling the spread of COVID-19, public health researchers are calling attention to the long-term repercussions of the pandemic on children’s health.

School closures could noticeably worsen the epidemic of childhood obesity that already threatens many children in the United States, say Paul Rundle, DrPH, and colleagues from Columbia University Mailman School of Public Health, New York City, in a perspective published online March 30 in Obesity.

“In part, we wrote the perspective to remind people that summer unhealthy weight gain seems to accumulate year to year,” he told Medscape Medical News in an email.

Rundle and colleagues estimate that time spent out of school will double this year because of school closures due to COVID-19. That, along with shelter-in-place orders, will pose challenges both for physical activity and healthy eating among children.

In addition, playgrounds have closed in many areas, and even where parks remain open, social distancing decreases opportunities for exercise. Team sports are on hold, and without physical education taught in schools, many children will not be getting as much active outdoor play as needed.

That’s especially true for children in urban areas, who may find it even more difficult to exercise inside cramped apartments, they add.

As a result, more and more children may turn to sedentary activities, and increased screen time goes hand in hand with childhood overweight and obesity, not just because of the lack of exercise but also because of snacking on unhealthy, empty-calorie foods while glued to the screen.

“We were hoping to get the word out on this issue, do some education or reminding, and at least let people know that this should be something to keep an eye on, among so many other things,” Rundle added.

Excess Eating Because of Stress and Boredom

Jessica Sparks Lilley, MD, director of the Pediatric Diabetes and Lipid Program at the Mississippi Center for Advanced Medicine in Madison, agrees that it is crucial to address these issues.

“Just like adults, children eat in response to emotions, including stress and boredom, and stress levels are high during these uncertain times,” she told Medscape Medical News.

Although both Rundle and Sparks Lilley acknowledged the challenges of finding good solutions at this time, they do offer some tips.

Schools should make physical education and at-home exercise a priority alongside other remote teaching. Physical education teachers could even stream exercise classes to children at home.

Even just walking in the park while maintaining social distancing could be better than nothing, and a brisk walk is probably even better.

Depending on the age of the child, online yoga may also be useful. Even though yoga burns relatively few calories, it incorporates mindfulness training that may be helpful.

“I think focusing on promoting mindful eating as compared to mindless or distracted eating is important. Even in the best of circumstances, it is hard to exercise enough to burn off high energy snacks,” Rundle said.

Additional Stressors From Poverty: Schools Can Help With Meals

Children living in poverty, already the most vulnerable to obesity and related health problems, have additional stressors, add the two experts.

“As more Americans are losing jobs, poverty is a real threat to many of the children I care for. Families living in poverty often rely on processed, high-calorie, low-nutrient foods for survival, because they are inexpensive and shelf-stable,” Sparks Lilley said.

Rundle and colleagues agree: “Our own experiences in supermarkets show...shelves that held...crackers, chips, ramen noodles, soda, sugary cereals, and processed ready-to-eat meals are quite empty. We anticipate that many children will experience higher calorie diets during the pandemic response.”

Similar to how they address food insecurity during summer holidays, school districts have responded by offering grab-and-go meals, Rundle and colleagues note.

To maintain social distancing for people with vulnerable family members, some school districts have also started delivering food using school buses that run along regularly scheduled routes.

Rundle also stresses that farmers’ markets, which often provide foods that appeal to immigrant and ethnic communities, should be considered part of essential food services.

As such, social distancing protocols should be established for them and they should be allowed to stay open, he argues.

“The safety of American children is at stake in many ways. The threat to themselves or their caregivers being infected with COVID-19 is rightly foremost in our concerns,” Sparks Lilley stressed.

“However, there is other fallout to consider. We’ve seen very clearly the need for public health and preventive medicine and can’t let vulnerable children fall through the cracks.”

Rundle agrees. Although it is a “priority” to mitigate the immediate impact of COVID-19, “it is important to consider ways to prevent its long-term effects, including new risks for childhood obesity.”

Rundle and coauthors, as well as Sparks Lilley, have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Although priority number one lies in controlling the spread of COVID-19, public health researchers are calling attention to the long-term repercussions of the pandemic on children’s health.

School closures could noticeably worsen the epidemic of childhood obesity that already threatens many children in the United States, say Paul Rundle, DrPH, and colleagues from Columbia University Mailman School of Public Health, New York City, in a perspective published online March 30 in Obesity.

“In part, we wrote the perspective to remind people that summer unhealthy weight gain seems to accumulate year to year,” he told Medscape Medical News in an email.

Rundle and colleagues estimate that time spent out of school will double this year because of school closures due to COVID-19. That, along with shelter-in-place orders, will pose challenges both for physical activity and healthy eating among children.

In addition, playgrounds have closed in many areas, and even where parks remain open, social distancing decreases opportunities for exercise. Team sports are on hold, and without physical education taught in schools, many children will not be getting as much active outdoor play as needed.

That’s especially true for children in urban areas, who may find it even more difficult to exercise inside cramped apartments, they add.

As a result, more and more children may turn to sedentary activities, and increased screen time goes hand in hand with childhood overweight and obesity, not just because of the lack of exercise but also because of snacking on unhealthy, empty-calorie foods while glued to the screen.

“We were hoping to get the word out on this issue, do some education or reminding, and at least let people know that this should be something to keep an eye on, among so many other things,” Rundle added.

Excess Eating Because of Stress and Boredom

Jessica Sparks Lilley, MD, director of the Pediatric Diabetes and Lipid Program at the Mississippi Center for Advanced Medicine in Madison, agrees that it is crucial to address these issues.

“Just like adults, children eat in response to emotions, including stress and boredom, and stress levels are high during these uncertain times,” she told Medscape Medical News.

Although both Rundle and Sparks Lilley acknowledged the challenges of finding good solutions at this time, they do offer some tips.

Schools should make physical education and at-home exercise a priority alongside other remote teaching. Physical education teachers could even stream exercise classes to children at home.

Even just walking in the park while maintaining social distancing could be better than nothing, and a brisk walk is probably even better.

Depending on the age of the child, online yoga may also be useful. Even though yoga burns relatively few calories, it incorporates mindfulness training that may be helpful.

“I think focusing on promoting mindful eating as compared to mindless or distracted eating is important. Even in the best of circumstances, it is hard to exercise enough to burn off high energy snacks,” Rundle said.

Additional Stressors From Poverty: Schools Can Help With Meals

Children living in poverty, already the most vulnerable to obesity and related health problems, have additional stressors, add the two experts.

“As more Americans are losing jobs, poverty is a real threat to many of the children I care for. Families living in poverty often rely on processed, high-calorie, low-nutrient foods for survival, because they are inexpensive and shelf-stable,” Sparks Lilley said.

Rundle and colleagues agree: “Our own experiences in supermarkets show...shelves that held...crackers, chips, ramen noodles, soda, sugary cereals, and processed ready-to-eat meals are quite empty. We anticipate that many children will experience higher calorie diets during the pandemic response.”

Similar to how they address food insecurity during summer holidays, school districts have responded by offering grab-and-go meals, Rundle and colleagues note.

To maintain social distancing for people with vulnerable family members, some school districts have also started delivering food using school buses that run along regularly scheduled routes.

Rundle also stresses that farmers’ markets, which often provide foods that appeal to immigrant and ethnic communities, should be considered part of essential food services.

As such, social distancing protocols should be established for them and they should be allowed to stay open, he argues.

“The safety of American children is at stake in many ways. The threat to themselves or their caregivers being infected with COVID-19 is rightly foremost in our concerns,” Sparks Lilley stressed.

“However, there is other fallout to consider. We’ve seen very clearly the need for public health and preventive medicine and can’t let vulnerable children fall through the cracks.”

Rundle agrees. Although it is a “priority” to mitigate the immediate impact of COVID-19, “it is important to consider ways to prevent its long-term effects, including new risks for childhood obesity.”

Rundle and coauthors, as well as Sparks Lilley, have reported no relevant financial relationships.

This article first appeared on Medscape.com.

Hot on the heels of a review from top nutrition scientists that cautioned against drinking cow’s milk comes another study with another caution: Drinking milk increases the risk of developing breast cancer, say the researchers. But this finding comes from an observational study, and there may be confounders that are not accounted for, says an expert not involved with the study.  

The latest research was based on data from the long-running larger study called Adventist Health Study-2 (AHS-2), which is looking at diet and health among Seventh Day Adventists in North America. Past results from this study have suggested that Seventh Day Adventists have longer life spans and lower rates of some cancers, perhaps because of healthier lifestyles.

The latest analysis suggests that milk raises breast cancer risk, and the more you drink the higher your risk may be.

“Consuming as little as 1/4 to 1/3 cup of dairy milk per day was associated with an increased risk of breast cancer of 30%,” first author Gary E. Fraser, MBChB, PhD, said in a press statement. Fraser is affiliated with the School of Public Health at Loma Linda University, California.

“By drinking up to 1 cup per day, the associated risk went up to 50%, and for those drinking 2 to 3 cups per day, the risk increased further to 70% to 80%,” he added.

The findings were published February 25 in the International Journal of Epidemiology.

“The AHS study is provocative, but it’s not enough to warrant a change in guidelines. The caution being espoused by the authors is not warranted given the observational nature of this study,” commented Don Dizon, MD, director of Women’s Cancers, Lifespan Cancer Institute at Brown University in Providence, Rhode Island. He was not involved with the study and was approached by Medscape Medical News for comment.

Because of its observational design, the study cannot prove that cow’s milk causes breast cancer, Dizon emphasized.

“I’d want to see if the findings are replicated [by others]. Outside of a randomized trial of [cow’s] milk vs no milk or even soy, and incident breast cancers, there will never be undisputable data,” he said.

“Probably the biggest point [about this study] is not to overinflate the data,” Dizon added.

He noted that the results were significant only for postmenopausal women, and not for premenopausal women. Moreover, analyses showed significant associations only for hormone receptor–positive cancers.

“We know that breast cancer increases in incidence with age, so this tracks with that particular trend. It suggests there may be confounders not accounted for in this study,” he said.

Research so far has been inconclusive on a possible link between dairy and increased risk for breast cancer. Dairy has even been tied to decreased risk for breast cancer, according to the World Cancer Research Fund.
 

Study Details

The current study included 52,795 Seventh Day Adventist women from North America who did not have cancer at the start of the study. Women had a mean age of 57.1 years, and 29.7% were black. At baseline, women reported their dietary patterns for the past year using food frequency questionnaires. For 1011 women, researchers double-checked food intake with 24-hour diet questionnaires, and verified soy intake by analyzing urine levels of soy isoflavones.

Data on invasive breast cancer diagnoses came from national registries in the US and Canada. Over the course of 7.9 years, 1057 women developed invasive breast cancer. Results were adjusted for a range of factors related to breast cancer risk, including diet, lifestyle, and family history of breast cancer.

Overall, women who consumed the most calories from dairy per day had 22% increased risk for breast cancer, compared with women with the fewest calories from dairy (hazard ratio, 1.22; 95% confidence interval, 1.05-1.40; P = .008). Women who drank the most cow›s milk per day had 50% increased risk for breast cancer compared with women who drank the least (HR, 1.50; 95% CI, 1.22 - 1.84; P less than .001). 

Drinking full or reduced fat cow’s milk did not change the findings (P for trend = .002 and P for trend less than .0001, respectively).

No significant association was found between breast cancer risk and cheese or yogurt consumption (P = .35 and P = .80, respectively).

Need for Change?

US dietary guidelines are under review. A new version, which will cover pregnant women and children under age 2 for the first time, is expected later this year.

Current guidelines recommend that adults and children aged 9 and over drink three 8 oz glasses of milk per day, or equivalent portions of yogurt, cheese, and other dairy products.

“Evidence from this study suggests that people should view that recommendation with caution,” Fraser said.
 

Milk Is Complex Topic

A top nutrition scientist agrees. Walter Willett, MD, DrPH, professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health in Boston, Massachusetts, told Medscape Medical News: “There is little scientific justification for the recommendation of 3 cups of milk per day. This new study adds a further reason for caution.” 

“This was a high-quality study conducted by experienced investigators,” Willett said. Strengths of the study include the high soy intake and low consumption of foods from animal sources, factors that are hard to study in other populations.

Willett was a coauthor, along with David Ludwig, MD, PhD, also from Harvard, of the recent review published in the New England Journal of Medicine that questioned the science behind milk-drinking recommendations. An article about this review on Medscape Medical News has attracted a huge number of comments from our readers.  

Milk is a complex topic, Willett explained. As a good source of essential nutrients, especially calcium and vitamin D, cow’s milk has been touted to have several health benefits, especially decreased fracture risk. But Willett said calcium recommendations have probably been overstated, and current evidence does not support high milk intake for fracture prevention.

Other benefits include improved nutrition in low-income settings, taller stature, and decreased colorectal cancer risk. But cow’s milk has also been linked to increased risk for some cancers, including prostate and endometrial cancer. Many of the benefits derived from nutrients found in milk may be obtained from other sources without these risks, according to Willett.

“Given the risks and benefits, we suggest a possible range from zero to two servings per day of dairy foods, including milk, cheese, and yogurt. If intake is zero or one serving, taking a calcium/vitamin D supplement would be good to consider,” he said.

However, Fraser and Willett also suggested another option: replacing cow’s milk with soy milk. Analyses from the current study showed no significant association between consumption of soy and breast cancer, independent of dairy (P for trend = .22).

In addition, substituting average amounts of soy milk for cow’s milk was linked to a 32% drop in risk for breast cancer among postmenopausal women (HR, 0.68; 95% CI, 0.55-0.85, P = .002). However, these results were not significant among premenopausal women (HR, 0.70; 95% CI, 0.36-1.38; P = .31).

“The suggestion that replacing some or all of [cow’s] milk with soy milk may reduce risk of breast cancer is consistent with other studies supporting a benefit of soy milk for risk of breast cancer,” Willett said.

“If someone does choose soy milk, picking one with minimal amounts of added sugar is desirable,” he added.

Drinking Milk, or Some Related Factor?

Fraser, the lead author of the current study, said in a statement that the results provide “fairly strong evidence that either dairy milk or some other factor closely related to drinking dairy milk is a cause of breast cancer in women.”

That ‘other’ factor is probably complicated, but may be related to what humans have done to cows. To increase milk production, humans have bred cows to have higher levels of insulin-like growth factor, which in turn has been linked to some cancers, including breast cancer.

Sex hormones in cow’s milk may also be involved. About 75% of a dairy herd is pregnant and the cows are by definition lactating. So the milk they produce may have higher levels of progestins and estrogens, which may play a role in hormone-responsive breast cancer. 

Other factors that researchers did not measure in this study, such as poverty and the income of participants, may be at play.

But to know what’s really going on, all agree that more research is needed.

“The overall evidence so far has not shown a clear increase or decrease in risk of breast cancer with higher [cow’s] milk intake. Thus, this topic needs further examination,” Willett said.

The study was funded by the National Cancer Institute at the National Institutes of Health, and the World Cancer Research Fund in the UK. Three of the authors report following largely vegetarian diets. All authors report regular and free use of dairy products without religious or other restrictions. No authors report associations with the soy product or dairy industries. Willett reports being a consultant during the design and early years of the Adventist study, but has not been involved with it for at least 8 years. Dizon has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Hot on the heels of a review from top nutrition scientists that cautioned against drinking cow’s milk comes another study with another caution: Drinking milk increases the risk of developing breast cancer, say the researchers. But this finding comes from an observational study, and there may be confounders that are not accounted for, says an expert not involved with the study.  

The latest research was based on data from the long-running larger study called Adventist Health Study-2 (AHS-2), which is looking at diet and health among Seventh Day Adventists in North America. Past results from this study have suggested that Seventh Day Adventists have longer life spans and lower rates of some cancers, perhaps because of healthier lifestyles.

The latest analysis suggests that milk raises breast cancer risk, and the more you drink the higher your risk may be.

“Consuming as little as 1/4 to 1/3 cup of dairy milk per day was associated with an increased risk of breast cancer of 30%,” first author Gary E. Fraser, MBChB, PhD, said in a press statement. Fraser is affiliated with the School of Public Health at Loma Linda University, California.

“By drinking up to 1 cup per day, the associated risk went up to 50%, and for those drinking 2 to 3 cups per day, the risk increased further to 70% to 80%,” he added.

The findings were published February 25 in the International Journal of Epidemiology.

“The AHS study is provocative, but it’s not enough to warrant a change in guidelines. The caution being espoused by the authors is not warranted given the observational nature of this study,” commented Don Dizon, MD, director of Women’s Cancers, Lifespan Cancer Institute at Brown University in Providence, Rhode Island. He was not involved with the study and was approached by Medscape Medical News for comment.

Because of its observational design, the study cannot prove that cow’s milk causes breast cancer, Dizon emphasized.

“I’d want to see if the findings are replicated [by others]. Outside of a randomized trial of [cow’s] milk vs no milk or even soy, and incident breast cancers, there will never be undisputable data,” he said.

“Probably the biggest point [about this study] is not to overinflate the data,” Dizon added.

He noted that the results were significant only for postmenopausal women, and not for premenopausal women. Moreover, analyses showed significant associations only for hormone receptor–positive cancers.

“We know that breast cancer increases in incidence with age, so this tracks with that particular trend. It suggests there may be confounders not accounted for in this study,” he said.

Research so far has been inconclusive on a possible link between dairy and increased risk for breast cancer. Dairy has even been tied to decreased risk for breast cancer, according to the World Cancer Research Fund.
 

Study Details

The current study included 52,795 Seventh Day Adventist women from North America who did not have cancer at the start of the study. Women had a mean age of 57.1 years, and 29.7% were black. At baseline, women reported their dietary patterns for the past year using food frequency questionnaires. For 1011 women, researchers double-checked food intake with 24-hour diet questionnaires, and verified soy intake by analyzing urine levels of soy isoflavones.

Data on invasive breast cancer diagnoses came from national registries in the US and Canada. Over the course of 7.9 years, 1057 women developed invasive breast cancer. Results were adjusted for a range of factors related to breast cancer risk, including diet, lifestyle, and family history of breast cancer.

Overall, women who consumed the most calories from dairy per day had 22% increased risk for breast cancer, compared with women with the fewest calories from dairy (hazard ratio, 1.22; 95% confidence interval, 1.05-1.40; P = .008). Women who drank the most cow›s milk per day had 50% increased risk for breast cancer compared with women who drank the least (HR, 1.50; 95% CI, 1.22 - 1.84; P less than .001). 

Drinking full or reduced fat cow’s milk did not change the findings (P for trend = .002 and P for trend less than .0001, respectively).

No significant association was found between breast cancer risk and cheese or yogurt consumption (P = .35 and P = .80, respectively).

Need for Change?

US dietary guidelines are under review. A new version, which will cover pregnant women and children under age 2 for the first time, is expected later this year.

Current guidelines recommend that adults and children aged 9 and over drink three 8 oz glasses of milk per day, or equivalent portions of yogurt, cheese, and other dairy products.

“Evidence from this study suggests that people should view that recommendation with caution,” Fraser said.
 

Milk Is Complex Topic

A top nutrition scientist agrees. Walter Willett, MD, DrPH, professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health in Boston, Massachusetts, told Medscape Medical News: “There is little scientific justification for the recommendation of 3 cups of milk per day. This new study adds a further reason for caution.” 

“This was a high-quality study conducted by experienced investigators,” Willett said. Strengths of the study include the high soy intake and low consumption of foods from animal sources, factors that are hard to study in other populations.

Willett was a coauthor, along with David Ludwig, MD, PhD, also from Harvard, of the recent review published in the New England Journal of Medicine that questioned the science behind milk-drinking recommendations. An article about this review on Medscape Medical News has attracted a huge number of comments from our readers.  

Milk is a complex topic, Willett explained. As a good source of essential nutrients, especially calcium and vitamin D, cow’s milk has been touted to have several health benefits, especially decreased fracture risk. But Willett said calcium recommendations have probably been overstated, and current evidence does not support high milk intake for fracture prevention.

Other benefits include improved nutrition in low-income settings, taller stature, and decreased colorectal cancer risk. But cow’s milk has also been linked to increased risk for some cancers, including prostate and endometrial cancer. Many of the benefits derived from nutrients found in milk may be obtained from other sources without these risks, according to Willett.

“Given the risks and benefits, we suggest a possible range from zero to two servings per day of dairy foods, including milk, cheese, and yogurt. If intake is zero or one serving, taking a calcium/vitamin D supplement would be good to consider,” he said.

However, Fraser and Willett also suggested another option: replacing cow’s milk with soy milk. Analyses from the current study showed no significant association between consumption of soy and breast cancer, independent of dairy (P for trend = .22).

In addition, substituting average amounts of soy milk for cow’s milk was linked to a 32% drop in risk for breast cancer among postmenopausal women (HR, 0.68; 95% CI, 0.55-0.85, P = .002). However, these results were not significant among premenopausal women (HR, 0.70; 95% CI, 0.36-1.38; P = .31).

“The suggestion that replacing some or all of [cow’s] milk with soy milk may reduce risk of breast cancer is consistent with other studies supporting a benefit of soy milk for risk of breast cancer,” Willett said.

“If someone does choose soy milk, picking one with minimal amounts of added sugar is desirable,” he added.

Drinking Milk, or Some Related Factor?

Fraser, the lead author of the current study, said in a statement that the results provide “fairly strong evidence that either dairy milk or some other factor closely related to drinking dairy milk is a cause of breast cancer in women.”

That ‘other’ factor is probably complicated, but may be related to what humans have done to cows. To increase milk production, humans have bred cows to have higher levels of insulin-like growth factor, which in turn has been linked to some cancers, including breast cancer.

Sex hormones in cow’s milk may also be involved. About 75% of a dairy herd is pregnant and the cows are by definition lactating. So the milk they produce may have higher levels of progestins and estrogens, which may play a role in hormone-responsive breast cancer. 

Other factors that researchers did not measure in this study, such as poverty and the income of participants, may be at play.

But to know what’s really going on, all agree that more research is needed.

“The overall evidence so far has not shown a clear increase or decrease in risk of breast cancer with higher [cow’s] milk intake. Thus, this topic needs further examination,” Willett said.

The study was funded by the National Cancer Institute at the National Institutes of Health, and the World Cancer Research Fund in the UK. Three of the authors report following largely vegetarian diets. All authors report regular and free use of dairy products without religious or other restrictions. No authors report associations with the soy product or dairy industries. Willett reports being a consultant during the design and early years of the Adventist study, but has not been involved with it for at least 8 years. Dizon has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Hot on the heels of a review from top nutrition scientists that cautioned against drinking cow’s milk comes another study with another caution: Drinking milk increases the risk of developing breast cancer, say the researchers. But this finding comes from an observational study, and there may be confounders that are not accounted for, says an expert not involved with the study.  

The latest research was based on data from the long-running larger study called Adventist Health Study-2 (AHS-2), which is looking at diet and health among Seventh Day Adventists in North America. Past results from this study have suggested that Seventh Day Adventists have longer life spans and lower rates of some cancers, perhaps because of healthier lifestyles.

The latest analysis suggests that milk raises breast cancer risk, and the more you drink the higher your risk may be.

“Consuming as little as 1/4 to 1/3 cup of dairy milk per day was associated with an increased risk of breast cancer of 30%,” first author Gary E. Fraser, MBChB, PhD, said in a press statement. Fraser is affiliated with the School of Public Health at Loma Linda University, California.

“By drinking up to 1 cup per day, the associated risk went up to 50%, and for those drinking 2 to 3 cups per day, the risk increased further to 70% to 80%,” he added.

The findings were published February 25 in the International Journal of Epidemiology.

“The AHS study is provocative, but it’s not enough to warrant a change in guidelines. The caution being espoused by the authors is not warranted given the observational nature of this study,” commented Don Dizon, MD, director of Women’s Cancers, Lifespan Cancer Institute at Brown University in Providence, Rhode Island. He was not involved with the study and was approached by Medscape Medical News for comment.

Because of its observational design, the study cannot prove that cow’s milk causes breast cancer, Dizon emphasized.

“I’d want to see if the findings are replicated [by others]. Outside of a randomized trial of [cow’s] milk vs no milk or even soy, and incident breast cancers, there will never be undisputable data,” he said.

“Probably the biggest point [about this study] is not to overinflate the data,” Dizon added.

He noted that the results were significant only for postmenopausal women, and not for premenopausal women. Moreover, analyses showed significant associations only for hormone receptor–positive cancers.

“We know that breast cancer increases in incidence with age, so this tracks with that particular trend. It suggests there may be confounders not accounted for in this study,” he said.

Research so far has been inconclusive on a possible link between dairy and increased risk for breast cancer. Dairy has even been tied to decreased risk for breast cancer, according to the World Cancer Research Fund.
 

Study Details

The current study included 52,795 Seventh Day Adventist women from North America who did not have cancer at the start of the study. Women had a mean age of 57.1 years, and 29.7% were black. At baseline, women reported their dietary patterns for the past year using food frequency questionnaires. For 1011 women, researchers double-checked food intake with 24-hour diet questionnaires, and verified soy intake by analyzing urine levels of soy isoflavones.

Data on invasive breast cancer diagnoses came from national registries in the US and Canada. Over the course of 7.9 years, 1057 women developed invasive breast cancer. Results were adjusted for a range of factors related to breast cancer risk, including diet, lifestyle, and family history of breast cancer.

Overall, women who consumed the most calories from dairy per day had 22% increased risk for breast cancer, compared with women with the fewest calories from dairy (hazard ratio, 1.22; 95% confidence interval, 1.05-1.40; P = .008). Women who drank the most cow›s milk per day had 50% increased risk for breast cancer compared with women who drank the least (HR, 1.50; 95% CI, 1.22 - 1.84; P less than .001). 

Drinking full or reduced fat cow’s milk did not change the findings (P for trend = .002 and P for trend less than .0001, respectively).

No significant association was found between breast cancer risk and cheese or yogurt consumption (P = .35 and P = .80, respectively).

Need for Change?

US dietary guidelines are under review. A new version, which will cover pregnant women and children under age 2 for the first time, is expected later this year.

Current guidelines recommend that adults and children aged 9 and over drink three 8 oz glasses of milk per day, or equivalent portions of yogurt, cheese, and other dairy products.

“Evidence from this study suggests that people should view that recommendation with caution,” Fraser said.
 

Milk Is Complex Topic

A top nutrition scientist agrees. Walter Willett, MD, DrPH, professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health in Boston, Massachusetts, told Medscape Medical News: “There is little scientific justification for the recommendation of 3 cups of milk per day. This new study adds a further reason for caution.” 

“This was a high-quality study conducted by experienced investigators,” Willett said. Strengths of the study include the high soy intake and low consumption of foods from animal sources, factors that are hard to study in other populations.

Willett was a coauthor, along with David Ludwig, MD, PhD, also from Harvard, of the recent review published in the New England Journal of Medicine that questioned the science behind milk-drinking recommendations. An article about this review on Medscape Medical News has attracted a huge number of comments from our readers.  

Milk is a complex topic, Willett explained. As a good source of essential nutrients, especially calcium and vitamin D, cow’s milk has been touted to have several health benefits, especially decreased fracture risk. But Willett said calcium recommendations have probably been overstated, and current evidence does not support high milk intake for fracture prevention.

Other benefits include improved nutrition in low-income settings, taller stature, and decreased colorectal cancer risk. But cow’s milk has also been linked to increased risk for some cancers, including prostate and endometrial cancer. Many of the benefits derived from nutrients found in milk may be obtained from other sources without these risks, according to Willett.

“Given the risks and benefits, we suggest a possible range from zero to two servings per day of dairy foods, including milk, cheese, and yogurt. If intake is zero or one serving, taking a calcium/vitamin D supplement would be good to consider,” he said.

However, Fraser and Willett also suggested another option: replacing cow’s milk with soy milk. Analyses from the current study showed no significant association between consumption of soy and breast cancer, independent of dairy (P for trend = .22).

In addition, substituting average amounts of soy milk for cow’s milk was linked to a 32% drop in risk for breast cancer among postmenopausal women (HR, 0.68; 95% CI, 0.55-0.85, P = .002). However, these results were not significant among premenopausal women (HR, 0.70; 95% CI, 0.36-1.38; P = .31).

“The suggestion that replacing some or all of [cow’s] milk with soy milk may reduce risk of breast cancer is consistent with other studies supporting a benefit of soy milk for risk of breast cancer,” Willett said.

“If someone does choose soy milk, picking one with minimal amounts of added sugar is desirable,” he added.

Drinking Milk, or Some Related Factor?

Fraser, the lead author of the current study, said in a statement that the results provide “fairly strong evidence that either dairy milk or some other factor closely related to drinking dairy milk is a cause of breast cancer in women.”

That ‘other’ factor is probably complicated, but may be related to what humans have done to cows. To increase milk production, humans have bred cows to have higher levels of insulin-like growth factor, which in turn has been linked to some cancers, including breast cancer.

Sex hormones in cow’s milk may also be involved. About 75% of a dairy herd is pregnant and the cows are by definition lactating. So the milk they produce may have higher levels of progestins and estrogens, which may play a role in hormone-responsive breast cancer. 

Other factors that researchers did not measure in this study, such as poverty and the income of participants, may be at play.

But to know what’s really going on, all agree that more research is needed.

“The overall evidence so far has not shown a clear increase or decrease in risk of breast cancer with higher [cow’s] milk intake. Thus, this topic needs further examination,” Willett said.

The study was funded by the National Cancer Institute at the National Institutes of Health, and the World Cancer Research Fund in the UK. Three of the authors report following largely vegetarian diets. All authors report regular and free use of dairy products without religious or other restrictions. No authors report associations with the soy product or dairy industries. Willett reports being a consultant during the design and early years of the Adventist study, but has not been involved with it for at least 8 years. Dizon has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.

The first trial of robot-assisted, high-precision supermicrosurgery in humans has shown that the technique was safe for treating breast cancer–related lymphedema.

Although results were preliminary – only 20 patients participated, and a single highly skilled surgeon performed the supermicrosurgery – additional trials are underway to test the new robotic technique at other centers.

The pilot study was published online Feb. 11 in Nature Communications.

The new device, known as MUSA, was supplied by MicroSure.

MUSA allowed surgeons to connect tiny vessels, as small as 0.3-0.8 mm across, a technique referred to as supermicrosurgery. This technique can be used to connect blocked lymph vessels to veins, which can reestablish flow of lymphatic fluid and decrease arm swelling in women with breast cancer–related lymphedema, the researchers explain.

Only a few highly skilled surgeons worldwide can conduct supermicrosurgery using current surgical techniques, the authors comment.

“The success of supermicrosurgery is limited by the precision and stability of the surgeon’s hands. Robot-assisted supermicrosurgery has the potential to overcome this obstacle because more refined and subtle movements can be performed. Before now, no robots were able to perform this type of surgery,” coauthor Rutger M. Schols, MD, PhD, of Maastricht (the Netherlands) University Medical Center, said in an interview.

Robot-assisted surgery is not new – the Da Vinci system was the first robotic surgery device to be approved by the Food and Drug Administration. It was approved in 2000. However, Da Vinci was developed for minimally invasive surgery and is not precise enough for supermicrosurgery. And despite its $2 million price tag, Da Vinci has yet to show that it performs better than traditional surgery.

Designed specifically for supermicrosurgery

The MUSA robot was designed by surgeons at the Maastricht University Medical Center, engineers at the Eindhoven University of Technology, and the medical technology company Microsure specifically for reconstructive supermicrosurgery; all are located in the Netherlands. Two of the authors of the article hold positions and are shareholders in the company.

Surgeons activate MUSA using foot pedals and operate forceps-like joysticks to control high-precision surgical instruments that filter out hand tremors and scale down motions. For example, moving the joystick 1 cm causes the robot to move 0.10 mm. MUSA also works with standard microscopes found in most operating rooms.

To test MUSA, Dr. Schols and colleagues conducted a prospective, randomized trial that included 20 women with breast cancer–related lymphedema. The team randomly assigned eight women to undergo supermicrosurgery with MUSA and 12 women to undergo manual supermicrosurgery performed by a single surgeon. Two microsurgeons who were blinded to treatment groups evaluated the quality of the surgery using standardized scoring methods.

The results, which were adjusted for baseline factors, showed no significant differences in upper-limb lymphedema between the two groups 1 and 3 months after surgery, nor were there significant differences between the two groups in quality of life.

A slightly higher percentage of women in the MUSA group were able to discontinue daily use of a compressive garment to treat arm swelling at 3 months, compared with the group that underwent manual supermicrosurgery (87.5% vs. 83.3%). Participants reported no serious adverse events.

For the group that underwent manual surgery, the quality of anastomosis was significantly better, compared with the MUSA group. Surgical competency also was significantly higher in the group that underwent manual surgery.

The MUSA group experienced a longer total surgery time (mean, 115 min), compared with the group that underwent manual surgery (mean, 81 min). But the authors note that duration of surgery declined steeply over time for the MUSA group, suggesting a learning curve in using the robot.

The researchers caution that the study may have been too small to detect significant differences between groups. Larger studies are needed to test MUSA with other surgeons operating in other centers, the authors note.

“With respect to treatment of breast cancer–related lymphedema, we are continuing trials with more patients, more surgeons, and more centers,” Dr. Schols said in an interview.

“We expect that other centers – both national and international – are willing to test the MUSA,” he added.

Dr. Schols and several coauthors have disclosed no relevant financial relationships. Two coauthors are shareholders and hold positions at MicroSure.
 

This article first appeared on Medscape.com.