Patient & Survivor Care

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.

The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers. 

Is obesity the new smoking? Not exactly.

Tracing a direct line between excess fat and cancer is much less clear-cut than it is with tobacco. While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.

Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?

There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?

When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.

A Consistent but Complicated Relationship

Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.

Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.

“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.

In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.

That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.

At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes. 

It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.

Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.

One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells. 

But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.

That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.

How Big Is the Effect?

While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably. 

Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.

With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.

A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).

Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.

Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.

CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.

Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.

When Do Extra Pounds Matter?

When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?

Some evidence suggests there’s no “safe” time for putting on excess pounds.

A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years. 

The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.

Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers. 

An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.

There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.

But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.

“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”

Does Weight Loss Help?

With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.

Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.

Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers. 

A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.

But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.

Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”

“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”

Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations. 

People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week. 

“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.

A version of this article appeared on Medscape.com.

According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.

The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers. 

Is obesity the new smoking? Not exactly.

Tracing a direct line between excess fat and cancer is much less clear-cut than it is with tobacco. While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.

Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?

There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?

When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.

A Consistent but Complicated Relationship

Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.

Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.

“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.

In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.

That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.

At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes. 

It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.

Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.

One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells. 

But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.

That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.

How Big Is the Effect?

While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably. 

Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.

With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.

A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).

Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.

Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.

CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.

Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.

When Do Extra Pounds Matter?

When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?

Some evidence suggests there’s no “safe” time for putting on excess pounds.

A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years. 

The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.

Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers. 

An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.

There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.

But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.

“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”

Does Weight Loss Help?

With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.

Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.

Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers. 

A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.

But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.

Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”

“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”

Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations. 

People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week. 

“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.

A version of this article appeared on Medscape.com.

According to the Centers for Disease Control and Prevention (CDC), over 684,000 Americans are diagnosed with an “obesity-associated” cancer each year.

The incidence of many of these cancers has been rising in recent years, particularly among younger people — a trend that sits in contrast with the overall decline in cancers with no established relationship to excess weight, such as lung and skin cancers. 

Is obesity the new smoking? Not exactly.

Tracing a direct line between excess fat and cancer is much less clear-cut than it is with tobacco. While about 42% of cancers — including common ones such as colorectal and postmenopausal breast cancers — are considered obesity-related, only about 8% of incident cancers are attributed to excess body weight. People often develop those diseases regardless of weight.

Although plenty of evidence points to excess body fat as a cancer risk factor, it’s unclear at what point excess weight has an effect. Is gaining weight later in life, for instance, better or worse for cancer risk than being overweight or obese from a young age?

There’s another glaring knowledge gap: Does losing weight at some point in adulthood change the picture? In other words, how many of those 684,000 diagnoses might have been prevented if people shed excess pounds?

When it comes to weight and cancer risk, “there’s a lot we don’t know,” said Jennifer W. Bea, PhD, associate professor, health promotion sciences, University of Arizona, Tucson.

A Consistent but Complicated Relationship

Given the growing incidence of obesity — which currently affects about 42% of US adults and 20% of children and teenagers — it’s no surprise that many studies have delved into the potential effects of excess weight on cancer rates.

Although virtually all the evidence comes from large cohort studies, leaving the cause-effect question open, certain associations keep showing up.

“What we know is that, consistently, a higher body mass index [BMI] — particularly in the obese category — leads to a higher risk of multiple cancers,” said Jeffrey A. Meyerhardt, MD, MPH, codirector, Colon and Rectal Cancer Center, Dana-Farber Cancer Institute, Boston.

In a widely cited report published in The New England Journal of Medicine in 2016, the International Agency for Research on Cancer (IARC) analyzed over 1000 epidemiologic studies on body fat and cancer. The agency pointed to over a dozen cancers, including some of the most common and deadly, linked to excess body weight.

That list includes esophageal adenocarcinoma and endometrial cancer — associated with the highest risk — along with kidney, liver, stomach (gastric cardia), pancreatic, colorectal, postmenopausal breast, gallbladder, ovarian, and thyroid cancers, plus multiple myeloma and meningioma. There’s also “limited” evidence linking excess weight to additional cancer types, including aggressive prostate cancer and certain head and neck cancers.

At the same time, Dr. Meyerhardt said, many of those same cancers are also associated with issues that lead to, or coexist with, overweight and obesity, including poor diet, lack of exercise, and metabolic conditions such as diabetes. 

It’s a complicated web, and it’s likely, Dr. Meyerhardt said, that high BMI both directly affects cancer risk and is part of a “causal pathway” of other factors that do.

Regarding direct effects, preclinical research has pointed to multiple ways in which excess body fat could contribute to cancer, said Karen M. Basen-Engquist, PhD, MPH, professor, Division of Cancer Prevention and Population Services, The University of Texas MD Anderson Cancer Center, Houston.

One broad mechanism to help explain the obesity-cancer link is chronic systemic inflammation because excess fat tissue can raise levels of substances in the body, such as tumor necrosis factor alpha and interleukin 6, which fuel inflammation. Excess fat also contributes to hyperinsulinemia — too much insulin in the blood — which can help promote the growth and spread of tumor cells. 

But the underlying reasons also appear to vary by cancer type, Dr. Basen-Engquist said. With hormonally driven cancer types, such as breast and endometrial, excess body fat may alter hormone levels in ways that spur tumor growth. Extra fat tissue may, for example, convert androgens into estrogens, which could help feed estrogen-dependent tumors.

That, Dr. Basen-Engquist noted, could be why excess weight is associated with postmenopausal, not premenopausal, breast cancer: Before menopause, body fat is a relatively minor contributor to estrogen levels but becomes more important after menopause.

How Big Is the Effect?

While more than a dozen cancers have been consistently linked to excess weight, the strength of those associations varies considerably. 

Endometrial and esophageal cancers are two that stand out. In the 2016 IARC analysis, people with severe obesity had a seven-times greater risk for endometrial cancer and 4.8-times greater risk for esophageal adenocarcinoma vs people with a normal BMI.

With other cancers, the risk increases for those with severe obesity compared with a normal BMI were far more modest: 10% for ovarian cancer, 30% for colorectal cancer, and 80% for kidney and stomach cancers, for example. For postmenopausal breast cancer, every five-unit increase in BMI was associated with a 10% relative risk increase.

A 2018 study from the American Cancer Society, which attempted to estimate the proportion of cancers in the United States attributable to modifiable risk factors — including alcohol consumption, ultraviolet rays exposure, and physical inactivity — found that smoking accounted for the highest proportion of cancer cases by a wide margin (19%), but excess weight came in second (7.8%).

Again, weight appeared to play a bigger role in certain cancers than others: An estimated 60% of endometrial cancers were linked to excess weight, as were roughly one third of esophageal, kidney, and liver cancers. At the other end of the spectrum, just over 11% of breast, 5% of colorectal, and 4% of ovarian cancers were attributable to excess weight.

Even at the lower end, those rates could make a big difference on the population level, especially for groups with higher rates of obesity.

CDC data show that obesity-related cancers are rising among women younger than 50 years, most rapidly among Hispanic women, and some less common obesity-related cancers, such as stomach, thyroid and pancreatic, are also rising among Black individuals and Hispanic Americans.

Obesity may be one reason for growing cancer disparities, said Leah Ferrucci, PhD, MPH, assistant professor, epidemiology, Yale School of Public Health, New Haven, Connecticut. But, she added, the evidence is limited because Black individuals and Hispanic Americans are understudied.

When Do Extra Pounds Matter?

When it comes to cancer risk, at what point in life does excess weight, or weight gain, matter? Is the standard weight gain in middle age, for instance, as hazardous as being overweight or obese from a young age?

Some evidence suggests there’s no “safe” time for putting on excess pounds.

A recent meta-analysis concluded that weight gain at any point after age 18 years is associated with incremental increases in the risk for postmenopausal breast cancer. A 2023 study in JAMA Network Open found a similar pattern with colorectal and other gastrointestinal cancers: People who had sustained overweight or obesity from age 20 years through middle age faced an increased risk of developing those cancers after age 55 years. 

The timing of weight gain didn’t seem to matter either. The same elevated risk held among people who were normal weight in their younger years but became overweight after age 55 years.

Those studies focused on later-onset disease. But, in recent years, experts have tracked a troubling rise in early-onset cancers — those diagnosed before age 50 years — particularly gastrointestinal cancers. 

An obvious question, Dr. Meyerhardt said, is whether the growing prevalence of obesity among young people is partly to blame.

There’s some data to support that, he said. An analysis from the Nurses’ Health Study II found that women with obesity had double the risk for early-onset colorectal cancer as those with a normal BMI. And every 5-kg increase in weight after age 18 years was associated with a 9% increase in colorectal cancer risk.

But while obesity trends probably partly explain the rise in early-onset cancers, there is likely more to the story, Dr. Meyerhardt said.

“I think all of us who see an increasing number of patients under 50 with colorectal cancer know there’s a fair number who do not fit that [high BMI] profile,” he said. “There’s a fair number over 50 who don’t either.”

Does Weight Loss Help?

With all the evidence pointing to high BMI as a cancer risk factor, a logical conclusion is that weight loss should reduce that excess risk. However, Dr. Bea said, there’s actually little data to support that, and what exists comes from observational studies.

Some research has focused on people who had substantial weight loss after bariatric surgery, with encouraging results. A study published in JAMA found that among 5053 people who underwent bariatric surgery, 2.9% developed an obesity-related cancer over 10 years compared with 4.9% in the nonsurgery group.

Most people, however, aim for less dramatic weight loss, with the help of diet and exercise or sometimes medication. Some evidence shows that a modest degree of weight loss may lower the risks for postmenopausal breast and endometrial cancers. 

A 2020 pooled analysis found, for instance, that among women aged ≥ 50 years, those who lost as little as 2.0-4.5 kg, or 4.4-10.0 pounds, and kept it off for 10 years had a lower risk for breast cancer than women whose weight remained stable. And losing more weight — 9 kg, or about 20 pounds, or more — was even better for lowering cancer risk.

But other research suggests the opposite. A recent analysis found that people who lost weight within the past 2 years through diet and exercise had a higher risk for a range of cancers compared with those who did not lose weight. Overall, though, the increased risk was quite low.

Whatever the research does, or doesn’t, show about weight and cancer risk, Dr. Basen-Engquist said, it’s important that risk factors, obesity and otherwise, aren’t “used as blame tools.”

“With obesity, behavior certainly plays into it,” she said. “But there are so many influences on our behavior that are socially determined.”

Both Dr. Basen-Engquist and Dr. Meyerhardt said it’s important for clinicians to consider the individual in front of them and for everyone to set realistic expectations. 

People with obesity should not feel they have to become thin to be healthier, and no one has to leap from being sedentary to exercising several hours a week. 

“We don’t want patients to feel that if they don’t get to a stated goal in a guideline, it’s all for naught,” Dr. Meyerhardt said.

A version of this article appeared on Medscape.com.

To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer. While guided biopsies with multiparametric MRI can improve the diagnosis of grade 2 prostate cancers, widespread implementation remains challenging. The use of noninvasive biomarkers to stratify the risk for prostate cancer may be a more practical option.

The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
 

Development Cohort

In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).

Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
 

Validation and Analyses

The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.

The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).

Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
 

MPS2 and Competitors

Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.

Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.

This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.

In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer. While guided biopsies with multiparametric MRI can improve the diagnosis of grade 2 prostate cancers, widespread implementation remains challenging. The use of noninvasive biomarkers to stratify the risk for prostate cancer may be a more practical option.

The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
 

Development Cohort

In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).

Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
 

Validation and Analyses

The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.

The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).

Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
 

MPS2 and Competitors

Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.

Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.

This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.

In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

To date, men undergoing screening through the measurement of prostate-specific antigen (PSA) levels have had a significant reduction in neoplastic mortality. Because of its low specificity, however, this practice often leads to frequent, unnecessary, invasive biopsies and the diagnosis of low-grade, indolent cancer. While guided biopsies with multiparametric MRI can improve the diagnosis of grade 2 prostate cancers, widespread implementation remains challenging. The use of noninvasive biomarkers to stratify the risk for prostate cancer may be a more practical option.

The National Comprehensive Cancer Network proposes a test consisting of six blood and urine biomarkers for all grades of prostate cancer, and it outperforms PSA testing. However, current practice focuses on detecting high-grade cancers. It has been hypothesized that increasing the number of biomarkers by including molecules specifically expressed in aggressive high-grade prostate cancers could improve test accuracy. Based on the identification of new genes that are overexpressed in high-grade cancers, a polymerase chain reaction (PCR) technique targeting 54 candidate markers was used to develop an optimal 18-gene test that could be used before imaging (with MRI) and biopsy and to assess whether the latter procedures are warranted.
 

Development Cohort

In the development cohort (n = 815; median age, 63 years), quantitative PCR (qPCR) analysis of the 54 candidate genes was performed on urine samples that had been prospectively collected before biopsy following a digital rectal examination. Patients with previously diagnosed prostate cancer, abnormal MRI results, and those who had already undergone a prostate biopsy were excluded. Participants’ PSA levels ranged from 3 to 10 ng/mL (median interquartile range [IQR], 5.6 [4.6-7.2] ng/mL). Valid qPCR results were obtained from 761 participants (93.4%). Subsequently, prostate biopsy revealed grade 2 or higher cancer in 293 participants (38.5%).

Thus, a urine test called MyProstateScore 2.0 (MPSA) was developed, with two formulations: MPSA2 and MPSA2+, depending on whether a prostate volume was considered. The final MPSA2 development model included clinical data and 17 of the most informative markers, including nine specific to cancer, which were associated with the KLK3 reference gene.
 

Validation and Analyses

The external validation cohort (n = 813) consisted of participants in the NCI EDRN PCA3 Evaluation trial. Valid qPCR results were obtained from 743 participants, of whom 151 (20.3%) were found to have high-grade prostate cancer.

The median MPS2 score was higher in patients with grade 2 or higher prostate cancer (0.44; IQR, 0.23-0.69) than in those with noncontributory biopsies (0.08; IQR, 0.03-0.19; P < .001) or grade 1 cancer (0.25; IQR, 0.09-0.48; P < .01).

Comparative analyses included PSA, the Prostate Cancer Prevention Trial risk calculator, the Prostate Health Index (PHI), and various previous genetic models. Decision curve analyses quantified the benefit of each biomarker studied. The 151 participants with high-grade prostate cancer had operating curve values ranging from 0.60 for PSA alone to 0.77 for PHI and 0.76 for a two-gene multiplex model. The MPSA model had values of 0.81 and 0.82 for MPSA2+. For a required sensitivity of 95%, the MPS2 model could reduce the rate of unnecessary initial biopsies in the population by 35%-42%, with an impact of 15%-30% for other tests. Among the subgroups analyzed, MPS2 models showed negative predictive values of 95%-99% for grade 2 or higher prostate cancers and 99% for grade 3 or higher tumors.
 

MPS2 and Competitors

Existing biomarkers have reduced selectivity in detecting high-grade prostate tumors. This lower performance has led to the development of a new urine test including, for the first time, markers specifically overexpressed in high-grade prostate cancer. This new MPS2 test has a sensitivity of 95% for high-grade prostate cancer and a specificity ranging from 35% to 51%, depending on the subgroups. For clinicians, widespread use of MPS2 could greatly reduce the number of unnecessary biopsies while maintaining a high detection rate of grade 2 or higher prostate cancer.

Among patients who have had a negative first biopsy, MPS2 would have a sensitivity of 94.4% and a specificity of 51%, which is much higher than other tests like prostate cancer antigen 3 gene, three-gene model, and MPS. In addition, in patients with grade 1 prostate cancer, urinary markers for high-grade cancer could indicate the existence of a more aggressive tumor requiring increased monitoring.

This study has limitations, however. The ethnic diversity of its population was limited. A few Black men were included, for example. Second, a systematic biopsy was used as the reference, which can increase negative predictive value and decrease positive predictive value. Classification errors may have occurred. Therefore, further studies are needed to confirm these initial results and the long-term positive impact of using MPS2.

In conclusion, an 18-gene urine test seems to be more relevant for diagnosing high-grade prostate cancer than existing tests. It could prevent additional imaging or biopsy examinations in 35%-41% of patients. Therefore, the use of such tests in patients with high PSA levels could reduce the potential risks associated with prostate cancer screening while preserving its long-term benefits.

This story was translated from JIM, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Most younger women diagnosed with nonmetastatic breast cancer will succeed if they attempt to become pregnant after treatment, according to new research.

The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).

Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.

During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.

Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.

“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”

The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”

Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”

She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.

Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”

Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.

The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”

Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.

Most younger women diagnosed with nonmetastatic breast cancer will succeed if they attempt to become pregnant after treatment, according to new research.

The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).

Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.

During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.

Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.

“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”

The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”

Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”

She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.

Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”

Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.

The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”

Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.

Most younger women diagnosed with nonmetastatic breast cancer will succeed if they attempt to become pregnant after treatment, according to new research.

The findings, presented May 23 in advance of the annual meeting of the American Society of Clinical Oncology (ASCO) represent the most comprehensive look to date at fertility outcomes following treatment for women diagnosed with breast cancer before age 40 (Abstract 1518).

Kimia Sorouri, MD, a research fellow at the Dana-Farber Cancer Center in Boston, Massachusetts, and her colleagues, looked at data from the Young Women’s Breast Cancer study, a multicenter longitudinal cohort study, for 1213 U.S. and Canadian women (74% non-Hispanic white) who were diagnosed with stages 0-III breast cancer between 2006 and 2016. None of the included patients had metastatic disease, prior hysterectomy, or prior oophorectomy at diagnosis.

During a median 11 years of follow up, 197 of the women reported attempting pregnancy. Of these, 73% reported becoming pregnant, and 65% delivered a live infant a median 4 years after cancer diagnosis. The median age at diagnosis was 32 years, and 28% opted for egg or embryo freezing to preserve fertility. Importantly, 68% received chemotherapy, which can impair fertility, with only a small percentage undergoing ovarian suppression during chemotherapy treatment.

Key predictors of pregnancy or live birth in this study were “financial comfort,” a self-reported measure defined as having money left over to spend after bills are paid (odds ratio [OR], 2.04; 95% CI 1.01-4.12; P = .047); younger age at the time of diagnosis; and undergoing fertility preservation interventions at diagnosis (OR, 2.78; 95% CI 1.29-6.00; P = .009). Chemotherapy and other treatment factors were not seen to be associated with pregnancy or birth outcomes.

“Current research that informs our understanding of the impact of breast cancer treatment on pregnancy and live birth rates is fairly limited,” Dr. Sorouri said during an online press conference announcing the findings. Quality data on fertility outcomes has been limited to studies in certain subgroups, such as women with estrogen receptor–positive breast cancers, she noted, while other studies “have short-term follow-up and critically lack prospective assessment of attempt at conception.”

The new findings show, Dr. Sorouri said, “that in this modern cohort with a heightened awareness of fertility, access to fertility preservation can help to mitigate a portion of the damage from chemotherapy and other agents. Importantly, this highlights the need for increased accessibility of fertility preservation services for women newly diagnosed with breast cancer who are interested in a future pregnancy.”

Commenting on Dr. Sorouri and colleagues’ findings, Julie Gralow, MD, a breast cancer researcher and ASCO’s chief medical officer, stressed that, while younger age at diagnosis and financial comfort were two factors outside the scope of clinical oncology practice, “we can impact fertility preservation prior to treatment.”

She called it “critical” that every patient be informed of the impact of a breast cancer diagnosis and treatment on future fertility, and that all young patients interested in future fertility be offered fertility preservation prior to beginning treatment.

Ann Partridge, MD, of Dana-Farber, said in an interview that the findings reflected a decades’ long change in approach. “Twenty years ago when we first started this cohort, people would tell women ‘you can’t get pregnant. It’s too dangerous. You won’t be able to.’ And some indeed aren’t able to, but the majority who are attempting are succeeding, especially if they preserve their eggs or embryos. So even if chemo puts you into menopause or made you subfertile, if you’ve preserved eggs or embryos, we now can mitigate that distressing effect that many cancer patients have suffered from historically. That’s the good news here.”

Nonetheless, Dr. Partridge, an oncologist and the last author of the study, noted, the results reflected success only for women actively attempting pregnancy. “Remember, we’re not including the people who didn’t attempt. There may be some who went into menopause who never banked eggs or embryos, and may never have tried because they went to a doctor who told them they’re not fertile.” Further, she said, not all insurances cover in vitro fertilization for women who have had breast cancer.

The fact that financial comfort was correlated with reproductive success, Dr. Partridge said, speaks to broader issues about access. “It may not be all about insurers. It may be to have the ability, to have the time, the education and the wherewithal to do this right — and about being with doctors who talk about it.”

Dr. Sorouri and colleagues’ study was sponsored by the Breast Cancer Research Foundation and Susan G. Komen. Several co-authors disclosed receiving speaking and/or consulting fees from pharmaceutical companies, and one reported being an employee of GlaxoSmithKline. Dr. Sorouri reported no industry funding, while Dr. Partridge reported research funding from Novartis.

TOPLINE:

Vaginal estrogen therapy does not increase the risk for recurrence in women with hormone receptor (HR)–negative breast cancer or in those with HR–positive tumors concurrently treated with tamoxifen but should be avoided in aromatase inhibitor users, a French study suggested.

METHODOLOGY:

• Survivors of breast cancer often experience genitourinary symptoms due to declining estrogen levels. Vaginal estrogen therapies, including estriol and promestriene (3-propyl ethyl, 17B-methyl estradiol), can prevent these symptoms, but the effect on breast cancer outcomes remains uncertain.
• Researchers used French insurance claims data to emulate a target trial assessing the effect of initiating vaginal estrogen therapy — any molecule, promestriene, or estriol — on disease-free survival in survivors of breast cancer.
• Patients included in the study had a median age of 54 years; 85% were HR-positive, and 15% were HR–negative. The researchers conducted subgroup analyses based on HR status and endocrine therapy regimen.

TAKEAWAY:

• Among 134,942 unique patients, 1739 started vaginal estrogen therapy — 56%, promestriene; 34%, estriol; and 10%, both. 
• Initiation of vaginal estrogen therapy led to a modest decrease in disease-free survival in patients with HR–positive tumors (−2.1 percentage point at 5 years), particularly in those concurrently treated with an aromatase inhibitor (−3.0 percentage points).
• No decrease in disease-free survival was observed in patients with HR–negative tumors or in those treated with tamoxifen.
• In aromatase inhibitor users, starting estriol led to a “more severe and premature” decrease in disease-free survival (−4.2 percentage point after 3 years) compared with initiating promestriene (1.0 percentage point difference at 3 years).

IN PRACTICE:

“This study addresses a very important survivorship issue — sexual dysfunction in cancer patients — which is associated with anxiety and depression and should be considered a crucial component of survivorship care,” said study discussant Matteo Lambertini, MD, PhD, with University of Genova, Genova, Italy.

Our results suggest that using vaginal estrogen therapy “is safe in individuals with HR-negative tumors and in those concurrently treated with tamoxifen,” said study presenter Elise Dumas, PhD, with Institut Curie, Paris, France. For breast cancer survivors treated with aromatase inhibitors, vaginal estrogen therapy should be avoided as much as possible, but promestriene is preferred over estriol in this subgroup of patients.

SOURCE:

The research (Abstract 268MO) was presented at the European Society for Medical Oncology Breast Cancer 2024 Annual Congress on May 17, 2024.

LIMITATIONS:

No limitations were discussed in the presentation.

DISCLOSURES:

Funding was provided by Monoprix and the French National Cancer Institute. Dumas declared no conflicts of interest. Lambertini has financial relationships with various pharmaceutical companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, and others.

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

TOPLINE:

Vaginal estrogen therapy does not increase the risk for recurrence in women with hormone receptor (HR)–negative breast cancer or in those with HR–positive tumors concurrently treated with tamoxifen but should be avoided in aromatase inhibitor users, a French study suggested.

METHODOLOGY:

• Survivors of breast cancer often experience genitourinary symptoms due to declining estrogen levels. Vaginal estrogen therapies, including estriol and promestriene (3-propyl ethyl, 17B-methyl estradiol), can prevent these symptoms, but the effect on breast cancer outcomes remains uncertain.
• Researchers used French insurance claims data to emulate a target trial assessing the effect of initiating vaginal estrogen therapy — any molecule, promestriene, or estriol — on disease-free survival in survivors of breast cancer.
• Patients included in the study had a median age of 54 years; 85% were HR-positive, and 15% were HR–negative. The researchers conducted subgroup analyses based on HR status and endocrine therapy regimen.

TAKEAWAY:

• Among 134,942 unique patients, 1739 started vaginal estrogen therapy — 56%, promestriene; 34%, estriol; and 10%, both. 
• Initiation of vaginal estrogen therapy led to a modest decrease in disease-free survival in patients with HR–positive tumors (−2.1 percentage point at 5 years), particularly in those concurrently treated with an aromatase inhibitor (−3.0 percentage points).
• No decrease in disease-free survival was observed in patients with HR–negative tumors or in those treated with tamoxifen.
• In aromatase inhibitor users, starting estriol led to a “more severe and premature” decrease in disease-free survival (−4.2 percentage point after 3 years) compared with initiating promestriene (1.0 percentage point difference at 3 years).

IN PRACTICE:

“This study addresses a very important survivorship issue — sexual dysfunction in cancer patients — which is associated with anxiety and depression and should be considered a crucial component of survivorship care,” said study discussant Matteo Lambertini, MD, PhD, with University of Genova, Genova, Italy.

Our results suggest that using vaginal estrogen therapy “is safe in individuals with HR-negative tumors and in those concurrently treated with tamoxifen,” said study presenter Elise Dumas, PhD, with Institut Curie, Paris, France. For breast cancer survivors treated with aromatase inhibitors, vaginal estrogen therapy should be avoided as much as possible, but promestriene is preferred over estriol in this subgroup of patients.

SOURCE:

The research (Abstract 268MO) was presented at the European Society for Medical Oncology Breast Cancer 2024 Annual Congress on May 17, 2024.

LIMITATIONS:

No limitations were discussed in the presentation.

DISCLOSURES:

Funding was provided by Monoprix and the French National Cancer Institute. Dumas declared no conflicts of interest. Lambertini has financial relationships with various pharmaceutical companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, and others.

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

TOPLINE:

Vaginal estrogen therapy does not increase the risk for recurrence in women with hormone receptor (HR)–negative breast cancer or in those with HR–positive tumors concurrently treated with tamoxifen but should be avoided in aromatase inhibitor users, a French study suggested.

METHODOLOGY:

• Survivors of breast cancer often experience genitourinary symptoms due to declining estrogen levels. Vaginal estrogen therapies, including estriol and promestriene (3-propyl ethyl, 17B-methyl estradiol), can prevent these symptoms, but the effect on breast cancer outcomes remains uncertain.
• Researchers used French insurance claims data to emulate a target trial assessing the effect of initiating vaginal estrogen therapy — any molecule, promestriene, or estriol — on disease-free survival in survivors of breast cancer.
• Patients included in the study had a median age of 54 years; 85% were HR-positive, and 15% were HR–negative. The researchers conducted subgroup analyses based on HR status and endocrine therapy regimen.

TAKEAWAY:

• Among 134,942 unique patients, 1739 started vaginal estrogen therapy — 56%, promestriene; 34%, estriol; and 10%, both. 
• Initiation of vaginal estrogen therapy led to a modest decrease in disease-free survival in patients with HR–positive tumors (−2.1 percentage point at 5 years), particularly in those concurrently treated with an aromatase inhibitor (−3.0 percentage points).
• No decrease in disease-free survival was observed in patients with HR–negative tumors or in those treated with tamoxifen.
• In aromatase inhibitor users, starting estriol led to a “more severe and premature” decrease in disease-free survival (−4.2 percentage point after 3 years) compared with initiating promestriene (1.0 percentage point difference at 3 years).

IN PRACTICE:

“This study addresses a very important survivorship issue — sexual dysfunction in cancer patients — which is associated with anxiety and depression and should be considered a crucial component of survivorship care,” said study discussant Matteo Lambertini, MD, PhD, with University of Genova, Genova, Italy.

Our results suggest that using vaginal estrogen therapy “is safe in individuals with HR-negative tumors and in those concurrently treated with tamoxifen,” said study presenter Elise Dumas, PhD, with Institut Curie, Paris, France. For breast cancer survivors treated with aromatase inhibitors, vaginal estrogen therapy should be avoided as much as possible, but promestriene is preferred over estriol in this subgroup of patients.

SOURCE:

The research (Abstract 268MO) was presented at the European Society for Medical Oncology Breast Cancer 2024 Annual Congress on May 17, 2024.

LIMITATIONS:

No limitations were discussed in the presentation.

DISCLOSURES:

Funding was provided by Monoprix and the French National Cancer Institute. Dumas declared no conflicts of interest. Lambertini has financial relationships with various pharmaceutical companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, and others.

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

Five experts discussed research that they considered to be highlights of the European Society of Medical Oncology (ESMO) Breast Cancer annual congress during a “Key Takeaways” session at the meeting.

Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.

In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.

Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.

A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.

She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
 

Translational Research

“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.

In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.

The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.

A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.

Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.

Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
 

Early Breast Cancer

Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.

She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.

The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.

The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
 

Advanced Breast Cancer

Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.

Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.

Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.

New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.

The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).

The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.

Supportive Care

Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.

A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.

Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.

Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.

Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.

Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.

Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.

Dr. May had no financial conflicts to disclose.

Five experts discussed research that they considered to be highlights of the European Society of Medical Oncology (ESMO) Breast Cancer annual congress during a “Key Takeaways” session at the meeting.

Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.

In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.

Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.

A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.

She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
 

Translational Research

“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.

In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.

The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.

A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.

Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.

Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
 

Early Breast Cancer

Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.

She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.

The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.

The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
 

Advanced Breast Cancer

Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.

Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.

Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.

New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.

The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).

The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.

Supportive Care

Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.

A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.

Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.

Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.

Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.

Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.

Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.

Dr. May had no financial conflicts to disclose.

Five experts discussed research that they considered to be highlights of the European Society of Medical Oncology (ESMO) Breast Cancer annual congress during a “Key Takeaways” session at the meeting.

Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.

In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.

Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.

A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.

She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
 

Translational Research

“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.

In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.

The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.

A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.

Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.

Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
 

Early Breast Cancer

Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.

She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.

The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.

The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
 

Advanced Breast Cancer

Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.

Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.

Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.

New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.

The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).

The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.

Supportive Care

Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.

A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.

Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.

Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.

Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.

Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.

Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.

Dr. May had no financial conflicts to disclose.

Patients with metastatic or advanced cancer treated in practices that have high rates of giving systemic care in the last two weeks of life do not have longer survival rates than patients in practices that have low rates of such care.

This conclusion of a new study published online May 16 in JAMA Oncology may help reassure oncologists that giving systemic anticancer therapy (SACT) at the most advanced stages of cancer will not improve the patient’s life, the authors wrote. It also may encourage them to instead focus more on honest communication with patients about their choices, Maureen E. Canavan, PhD, at the Cancer and Outcomes, Public Policy and Effectiveness Research (COPPER) Center at the Yale School of Medicine in New Haven, Connecticut, and colleagues, wrote in their paper.
 

How Was the Study Conducted?

Researchers used Flatiron Health, a nationwide electronic health records database of academic and community practices throughout the United State. They identified 78,446 adults with advanced or metastatic stages of one of six common cancers (breast, colorectal, urothelial, non–small cell lung cancer [NSCLC], pancreatic and renal cell carcinoma) who were treated at healthcare practices from 2015 to 2019. They then stratified practices into quintiles based on how often the practices treated patients with any systemic therapy, including chemotherapy and immunotherapy, in their last 14 days of life. They compared whether patients in practices with greater use of systemic treatment at very advanced stages had longer overall survival.

What Were the Main Findings?

“We saw that there were absolutely no survival differences between the practices that used more systemic therapy for very advanced cancer than the practices that use less,” said senior author Kerin Adelson, MD, chief quality and value officer at MD Anderson Cancer Center in Houston, Texas. In some cancers, those in the lowest quintile (those with the lowest rates of systemic end-of-life care) lived fewer years compared with those in the highest quintiles. In other cancers, those in the lowest quintiles lived more years than those in the highest quintiles.

“What’s important is that none of those differences, after you control for other factors, was statistically significant,” Dr. Adelson said. “That was the same in every cancer type we looked at.”

An example is seen in advanced urothelial cancer. Those in the first quintile (lowest rates of systemic care at end of life) had an SACT rate range of 4.0-9.1. The SACT rate range in the highest quintile was 19.8-42.6. But the median overall survival (OS) rate for those in the lowest quintile was 12.7 months, not statistically different from the median OS in the highest quintile (11 months.)
 

How Does This Study Add to the Literature?

The American Society of Clinical Oncology (ASCO) and the National Quality Forum (NQF) developed a cancer quality metric to reduce SACT at the end of life. The NQF 0210 is a ratio of patients who get systemic treatment within 14 days of death over all patients who die of cancer. The quality metric has been widely adopted and used in value-based care reporting.

But the metric has been criticized because it focuses only on people who died and not people who lived longer because they benefited from the systemic therapy, the authors wrote.

Dr. Canavan’s team focused on all patients treated in the practice, not just those who died, Dr. Adelson said. This may put that criticism to rest, Dr. Adelson said.

“I personally believed the ASCO and NQF metric was appropriate and the criticisms were off base,” said Otis Brawley, MD, associate director of community outreach and engagement at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine in Baltimore. “Canavan’s study is evidence suggesting the metrics were appropriate.”

This study included not just chemotherapy, as some other studies have, but targeted therapies and immunotherapies as well. Dr. Adelson said some think that the newer drugs might change the prognosis at end of life. But this study shows “even those drugs are not helping patients to survive with very advanced cancer,” she said.

 

Could This Change Practice?

The authors noted that end-of life SACT has been linked with more acute care use, delays in conversations about care goals, late enrollment in hospice, higher costs, and potentially shorter and poorer quality life.

Dr. Adelson said she’s hoping that the knowledge that there’s no survival benefit for use of SACT for patients with advanced solid tumors who are nearing the end of life will lead instead to more conversations about prognosis with patients and transitions to palliative care.

“Palliative care has actually been shown to improve quality of life and, in some studies, even survival,” she said.

“I doubt it will change practice, but it should,” Dr. Brawley said. “The study suggests that doctors and patients have too much hope for chemotherapy as patients’ disease progresses. In the US especially, there is a tendency to believe we have better therapies than we truly do and we have difficulty accepting that the patient is dying. Many patients get third- and fourth-line chemotherapy that is highly likely to increase suffering without realistic hope of prolonging life and especially no hope of prolonging life with good quality.”

Dr. Adelson disclosed ties with AbbVie, Quantum Health, Gilead, ParetoHealth, and Carrum Health. Various coauthors disclosed ties with Roche, AbbVie, Johnson & Johnson, Genentech, the National Comprehensive Cancer Network, and AstraZeneca. The study was funded by Flatiron Health, an independent member of the Roche group. Dr. Brawley reports no relevant financial disclosures.

Patients with metastatic or advanced cancer treated in practices that have high rates of giving systemic care in the last two weeks of life do not have longer survival rates than patients in practices that have low rates of such care.

This conclusion of a new study published online May 16 in JAMA Oncology may help reassure oncologists that giving systemic anticancer therapy (SACT) at the most advanced stages of cancer will not improve the patient’s life, the authors wrote. It also may encourage them to instead focus more on honest communication with patients about their choices, Maureen E. Canavan, PhD, at the Cancer and Outcomes, Public Policy and Effectiveness Research (COPPER) Center at the Yale School of Medicine in New Haven, Connecticut, and colleagues, wrote in their paper.
 

How Was the Study Conducted?

Researchers used Flatiron Health, a nationwide electronic health records database of academic and community practices throughout the United State. They identified 78,446 adults with advanced or metastatic stages of one of six common cancers (breast, colorectal, urothelial, non–small cell lung cancer [NSCLC], pancreatic and renal cell carcinoma) who were treated at healthcare practices from 2015 to 2019. They then stratified practices into quintiles based on how often the practices treated patients with any systemic therapy, including chemotherapy and immunotherapy, in their last 14 days of life. They compared whether patients in practices with greater use of systemic treatment at very advanced stages had longer overall survival.

What Were the Main Findings?

“We saw that there were absolutely no survival differences between the practices that used more systemic therapy for very advanced cancer than the practices that use less,” said senior author Kerin Adelson, MD, chief quality and value officer at MD Anderson Cancer Center in Houston, Texas. In some cancers, those in the lowest quintile (those with the lowest rates of systemic end-of-life care) lived fewer years compared with those in the highest quintiles. In other cancers, those in the lowest quintiles lived more years than those in the highest quintiles.

“What’s important is that none of those differences, after you control for other factors, was statistically significant,” Dr. Adelson said. “That was the same in every cancer type we looked at.”

An example is seen in advanced urothelial cancer. Those in the first quintile (lowest rates of systemic care at end of life) had an SACT rate range of 4.0-9.1. The SACT rate range in the highest quintile was 19.8-42.6. But the median overall survival (OS) rate for those in the lowest quintile was 12.7 months, not statistically different from the median OS in the highest quintile (11 months.)
 

How Does This Study Add to the Literature?

The American Society of Clinical Oncology (ASCO) and the National Quality Forum (NQF) developed a cancer quality metric to reduce SACT at the end of life. The NQF 0210 is a ratio of patients who get systemic treatment within 14 days of death over all patients who die of cancer. The quality metric has been widely adopted and used in value-based care reporting.

But the metric has been criticized because it focuses only on people who died and not people who lived longer because they benefited from the systemic therapy, the authors wrote.

Dr. Canavan’s team focused on all patients treated in the practice, not just those who died, Dr. Adelson said. This may put that criticism to rest, Dr. Adelson said.

“I personally believed the ASCO and NQF metric was appropriate and the criticisms were off base,” said Otis Brawley, MD, associate director of community outreach and engagement at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine in Baltimore. “Canavan’s study is evidence suggesting the metrics were appropriate.”

This study included not just chemotherapy, as some other studies have, but targeted therapies and immunotherapies as well. Dr. Adelson said some think that the newer drugs might change the prognosis at end of life. But this study shows “even those drugs are not helping patients to survive with very advanced cancer,” she said.

 

Could This Change Practice?

The authors noted that end-of life SACT has been linked with more acute care use, delays in conversations about care goals, late enrollment in hospice, higher costs, and potentially shorter and poorer quality life.

Dr. Adelson said she’s hoping that the knowledge that there’s no survival benefit for use of SACT for patients with advanced solid tumors who are nearing the end of life will lead instead to more conversations about prognosis with patients and transitions to palliative care.

“Palliative care has actually been shown to improve quality of life and, in some studies, even survival,” she said.

“I doubt it will change practice, but it should,” Dr. Brawley said. “The study suggests that doctors and patients have too much hope for chemotherapy as patients’ disease progresses. In the US especially, there is a tendency to believe we have better therapies than we truly do and we have difficulty accepting that the patient is dying. Many patients get third- and fourth-line chemotherapy that is highly likely to increase suffering without realistic hope of prolonging life and especially no hope of prolonging life with good quality.”

Dr. Adelson disclosed ties with AbbVie, Quantum Health, Gilead, ParetoHealth, and Carrum Health. Various coauthors disclosed ties with Roche, AbbVie, Johnson & Johnson, Genentech, the National Comprehensive Cancer Network, and AstraZeneca. The study was funded by Flatiron Health, an independent member of the Roche group. Dr. Brawley reports no relevant financial disclosures.

Patients with metastatic or advanced cancer treated in practices that have high rates of giving systemic care in the last two weeks of life do not have longer survival rates than patients in practices that have low rates of such care.

This conclusion of a new study published online May 16 in JAMA Oncology may help reassure oncologists that giving systemic anticancer therapy (SACT) at the most advanced stages of cancer will not improve the patient’s life, the authors wrote. It also may encourage them to instead focus more on honest communication with patients about their choices, Maureen E. Canavan, PhD, at the Cancer and Outcomes, Public Policy and Effectiveness Research (COPPER) Center at the Yale School of Medicine in New Haven, Connecticut, and colleagues, wrote in their paper.
 

How Was the Study Conducted?

Researchers used Flatiron Health, a nationwide electronic health records database of academic and community practices throughout the United State. They identified 78,446 adults with advanced or metastatic stages of one of six common cancers (breast, colorectal, urothelial, non–small cell lung cancer [NSCLC], pancreatic and renal cell carcinoma) who were treated at healthcare practices from 2015 to 2019. They then stratified practices into quintiles based on how often the practices treated patients with any systemic therapy, including chemotherapy and immunotherapy, in their last 14 days of life. They compared whether patients in practices with greater use of systemic treatment at very advanced stages had longer overall survival.

What Were the Main Findings?

“We saw that there were absolutely no survival differences between the practices that used more systemic therapy for very advanced cancer than the practices that use less,” said senior author Kerin Adelson, MD, chief quality and value officer at MD Anderson Cancer Center in Houston, Texas. In some cancers, those in the lowest quintile (those with the lowest rates of systemic end-of-life care) lived fewer years compared with those in the highest quintiles. In other cancers, those in the lowest quintiles lived more years than those in the highest quintiles.

“What’s important is that none of those differences, after you control for other factors, was statistically significant,” Dr. Adelson said. “That was the same in every cancer type we looked at.”

An example is seen in advanced urothelial cancer. Those in the first quintile (lowest rates of systemic care at end of life) had an SACT rate range of 4.0-9.1. The SACT rate range in the highest quintile was 19.8-42.6. But the median overall survival (OS) rate for those in the lowest quintile was 12.7 months, not statistically different from the median OS in the highest quintile (11 months.)
 

How Does This Study Add to the Literature?

The American Society of Clinical Oncology (ASCO) and the National Quality Forum (NQF) developed a cancer quality metric to reduce SACT at the end of life. The NQF 0210 is a ratio of patients who get systemic treatment within 14 days of death over all patients who die of cancer. The quality metric has been widely adopted and used in value-based care reporting.

But the metric has been criticized because it focuses only on people who died and not people who lived longer because they benefited from the systemic therapy, the authors wrote.

Dr. Canavan’s team focused on all patients treated in the practice, not just those who died, Dr. Adelson said. This may put that criticism to rest, Dr. Adelson said.

“I personally believed the ASCO and NQF metric was appropriate and the criticisms were off base,” said Otis Brawley, MD, associate director of community outreach and engagement at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine in Baltimore. “Canavan’s study is evidence suggesting the metrics were appropriate.”

This study included not just chemotherapy, as some other studies have, but targeted therapies and immunotherapies as well. Dr. Adelson said some think that the newer drugs might change the prognosis at end of life. But this study shows “even those drugs are not helping patients to survive with very advanced cancer,” she said.

 

Could This Change Practice?

The authors noted that end-of life SACT has been linked with more acute care use, delays in conversations about care goals, late enrollment in hospice, higher costs, and potentially shorter and poorer quality life.

Dr. Adelson said she’s hoping that the knowledge that there’s no survival benefit for use of SACT for patients with advanced solid tumors who are nearing the end of life will lead instead to more conversations about prognosis with patients and transitions to palliative care.

“Palliative care has actually been shown to improve quality of life and, in some studies, even survival,” she said.

“I doubt it will change practice, but it should,” Dr. Brawley said. “The study suggests that doctors and patients have too much hope for chemotherapy as patients’ disease progresses. In the US especially, there is a tendency to believe we have better therapies than we truly do and we have difficulty accepting that the patient is dying. Many patients get third- and fourth-line chemotherapy that is highly likely to increase suffering without realistic hope of prolonging life and especially no hope of prolonging life with good quality.”

Dr. Adelson disclosed ties with AbbVie, Quantum Health, Gilead, ParetoHealth, and Carrum Health. Various coauthors disclosed ties with Roche, AbbVie, Johnson & Johnson, Genentech, the National Comprehensive Cancer Network, and AstraZeneca. The study was funded by Flatiron Health, an independent member of the Roche group. Dr. Brawley reports no relevant financial disclosures.

In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.

The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.

Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.

The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m², while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.

While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.

“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
 

No Head-to-Head Comparison

Uncertainty surrounding the benefits of NALIRIFOX is largely driven by the fact that NALIRIFOX wasn’t compared with FOLFIRINOX in the phase 3 trial that won liposomal irinotecan approval.

Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.

Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.

Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.

The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.

Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.

With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.

When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.

However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.

NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).

The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m² instead of 85 mg/m².
 

Is It Worth It?

During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.

The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”

However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.

In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.

The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.

Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.

On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.

Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.

In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.

The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.

Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”

The higher cost of NALIRIFOX, in particular, remains a major drawback.

“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.

Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.

Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.

NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.

A version of this article appeared on Medscape.com.

In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.

The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.

Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.

The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m², while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.

While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.

“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
 

No Head-to-Head Comparison

Uncertainty surrounding the benefits of NALIRIFOX is largely driven by the fact that NALIRIFOX wasn’t compared with FOLFIRINOX in the phase 3 trial that won liposomal irinotecan approval.

Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.

Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.

Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.

The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.

Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.

With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.

When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.

However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.

NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).

The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m² instead of 85 mg/m².
 

Is It Worth It?

During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.

The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”

However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.

In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.

The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.

Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.

On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.

Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.

In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.

The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.

Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”

The higher cost of NALIRIFOX, in particular, remains a major drawback.

“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.

Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.

Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.

NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.

A version of this article appeared on Medscape.com.

In February, the US Food and Drug Administration (FDA) approved irinotecan liposome (Onivyde) as part of a new regimen for first-line metastatic pancreatic adenocarcinoma called NALIRIFOX.

The main difference between NALIRIFOX and a standard go-to regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan — irinotecan encased in a lipid nanoparticle — is used instead of free irinotecan.

Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.

The substitution, however, raises the cost of treatment substantially. According to one estimate, a single cycle of FOLFIRINOX costs about $500 at a body surface area of 2 m², while the equivalent single cycle of NALIRIFOX costs $7800 — over 15-fold more expensive.

While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the extra cost.

“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX” Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, told this news organization. “Most of us in the academic setting have the same take on this.”
 

No Head-to-Head Comparison

Uncertainty surrounding the benefits of NALIRIFOX is largely driven by the fact that NALIRIFOX wasn’t compared with FOLFIRINOX in the phase 3 trial that won liposomal irinotecan approval.

Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX — which also includes oxaliplatin, fluorouracil, and leucovorin — with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were moderately better with NALIRIFOX.

Oncologists have said that the true value of the trial is that it conclusively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate the more intensive therapy.

Eileen M. O’Reilly, MD, the senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the 2023 ASCO annual meeting.

The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer but “does not address the question of NALIRIFOX versus FOLFIRINOX,” said Dr. O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at Memorial Sloan Kettering Cancer Center in New York City.

Comparing them directly in the study “probably wouldn’t have been in the interest of the sponsor,” said Dr. O’Reilly.

With no head-to-head comparison, oncologists have been comparing NAPOLI 3 results with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX its place as a first-line regimen.

When comparing the trials, median overall survival was exactly the same for the two regimens — 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate — 48.4% with FOLFIRINOX vs 45.6% with NALIRIFOX.

However, Dr. O’Reilly and her colleagues also highlighted comparisons between the two trials that favored NAPOLI 3.

NAPOLI 3 had no age limit, while PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX — 7.4 months vs 6.4 months in PRODIGE — and overall response rates were higher as well — 41.8% in NAPOLI 3 vs 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs 9.0%, respectively).

The authors explained that the lower rate of neuropathy could be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m² instead of 85 mg/m².
 

Is It Worth It?

During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen can be considered the new reference regimen for first-line treatment of metastatic pancreatic adenocarcinoma.

The study discussant, Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”

However, other oncologists remain skeptical about the benefits of the new regimen over FOLFIRINOX for patients with metastatic pancreatic adenocarcinoma.

In a recent editorial, Dr. Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for both regimens.

The experts pointed out that overall response rates were assessed by investigators in NAPOLI 3 and not by an independent review committee, as in PRODIGE 4, and might have been overestimated.

Although the lack of an age limit was touted as a benefit of NAPOLI 3, Dr. Garrido-Laguna and Dr. Nevala-Plagemann doubt whether enough patients over 75 years old participated to draw any meaningful conclusions about using NALIRIFOX in older, frailer patients. If anything, patients in PRODIGE 4 might have been less fit because, among other things, the trial allowed patients with serum albumins < 3 g/dL.

On the adverse event front, the authors highlighted the higher incidences of grade 3 or worse diarrhea with NALIRIFOX (20% vs 12.7%) and questioned if there truly is less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also questioned whether the differences in neuropathy rates between the two trials were big enough to be clinically meaningful.

Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX vs FOLFIRINOX.

In the analysis, the team found no meaningful difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX did carry a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.

The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer, but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens as well as consideration of financial toxicity.

Dr. Garrido-Laguna had a different take. With the current data, NALIRIFOX does not seem to “add anything substantially different to what we already” have with FOLFIRINOX, he told this news organization. Given that, “we can’t really justify NALIRIFOX over FOLFIRINOX without more of a head-to-head comparison.”

The higher cost of NALIRIFOX, in particular, remains a major drawback.

“We think it would be an economic disservice to our healthcare systems if we used NALIRIFOX instead of FOLFIRINOX for these patients on the basis of [NAPOLI 3] data,” Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, said in a recent essay.

Dr. Garrido-Laguna and Dr. Nevala-Plagemann reiterated this concern.

Overall, “NALIRIFOX does not seem to raise the bar but rather exposes patients and healthcare systems to financial toxicities,” Dr. Garrido-Laguna and Dr. Nevala-Plagemann wrote in their review.

NAPOLI 3 was funded by Ipsen and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. Dr. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Dr. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not Ipsen. Dr. Nevala-Plagemann is an advisor for Seagen and reported institutional research funding from Theriva. Dr. Gyawali is a consultant for Vivio Health; Dr. Booth had no disclosures. Two meta-analysis authors reported grants or personal fees from Ipsen as well as ties to other companies.

A version of this article appeared on Medscape.com.

The next frontier in cancer detection could be the humble urine test.

Emerging science suggests that the body’s “liquid gold” could be particularly useful for liquid biopsies, offering a convenient, pain-free, and cost-effective way to spot otherwise hard-to-detect cancers.

“The search for cancer biomarkers that can be detected in urine could provide an enormous step forward to decrease cancer patient mortality,” said Kenneth R. Shroyer, MD, PhD, a pathologist at Stony Brook University, Stony Brook, New York, who studies cancer biomarkers.

Physicians have long known that urine can reveal a lot about our health — that’s why urinalysis has been part of medicine for 6000 years. Urine tests can detect diabetes, pregnancy, drug use, and urinary or kidney conditions.

But other conditions leave clues in urine, too, and cancer may be one of the most promising. “Urine testing could detect biomarkers of early-stage cancers, not only from local but also distant sites,” Dr. Shroyer said. It could also help flag recurrence in cancer survivors who have undergone treatment.

Granted, cancer biomarkers in urine are not nearly as widely studied as those in the blood, Dr. Shroyer noted. But a new wave of urine tests suggests research is gaining pace.

“The recent availability of high-throughput screening technologies has enabled researchers to investigate cancer from a top-down, comprehensive approach,” said Pak Kin Wong, PhD, professor of mechanical engineering, biomedical engineering, and surgery at The Pennsylvania State University. “We are starting to understand the rich information that can be obtained from urine.”

Urine is mostly water (about 95%) and urea, a metabolic byproduct that imparts that signature yellow color (about 2%). The other 3% is a mix of waste products, minerals, and other compounds the kidneys removed from the blood. Even in trace amounts, these substances say a lot.

Among them are “exfoliated cancer cells, cell-free DNA, hormones, and the urine microbiota — the collection of microbes in our urinary tract system,” Dr. Wong said.

“It is highly promising to be one of the major biological fluids used for screening, diagnosis, prognosis, and monitoring treatment efficiency in the era of precision medicine,” Dr. Wong said.

How Urine Testing Could Reveal Cancer

Still, as exciting as the prospect is, there’s a lot to consider in the hunt for cancer biomarkers in urine. These biomarkers must be able to pass through the renal nephrons (filtering units), remain stable in urine, and have high-level sensitivity, Dr. Shroyer said. They should also have high specificity for cancer vs benign conditions and be expressed at early stages, before the primary tumor has spread.

“At this stage, few circulating biomarkers have been found that are both sensitive and specific for early-stage disease,” said Dr. Shroyer.

But there are a few promising examples under investigation in humans:

Prostate cancer. Researchers at the University of Michigan have developed a urine test that detects high-grade prostate cancer more accurately than existing tests, including PHI, SelectMDx, 4Kscore, EPI, MPS, and IsoPSA.

The MyProstateScore 2.0 (MPS2) test, which looks for 18 genes associated with high-grade tumors, could reduce unnecessary biopsies in men with elevated prostate-specific antigen levels, according to a paper published in JAMA Oncology.

It makes sense. The prostate gland secretes fluid that becomes part of the semen, traces of which enter urine. After a digital rectal exam, even more prostate fluid enters the urine. If a patient has prostate cancer, genetic material from the cancer cells will infiltrate the urine.

In the MPS2 test, researchers used polymerase chain reaction (PCR) testing in urine. “The technology used for COVID PCR is essentially the same as the PCR used to detect transcripts associated with high-grade prostate cancer in urine,” said study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan, Ann Arbor. “In the case of the MPS2 test, we are doing PCR on 18 genes simultaneously on urine samples.”

A statistical model uses levels of that genetic material to predict the risk for high-grade disease, helping doctors decide what to do next. At 95% sensitivity, the MPS2 model could eliminate 35%-45% of unnecessary biopsies, compared with 15%-30% for the other tests, and reduce repeat biopsies by 46%-51%, compared with 9%-21% for the other tests.

Head and neck cancer. In a paper published in JCI Insight, researchers described a test that finds ultra-short fragments of DNA in urine to enable early detection of head and neck cancers caused by human papillomavirus.

“Our data show that a relatively small volume of urine (30-60 mL) gives overall detection results comparable to a tube of blood,” said study author Muneesh Tewari, MD, PhD, professor of hematology and oncology at the University of Michigan .

A larger volume of urine could potentially “make cancer detection even more sensitive than blood,” Dr. Tewari said, “allowing cancers to be detected at the earliest stages when they are more curable.”

The team used a technique called droplet digital PCR to detect DNA fragments that are “ultra-short” (less than 50 base pairs long) and usually missed by conventional PCR testing. This transrenal cell-free tumor DNA, which travels from the tumor into the bloodstream, is broken down small enough to pass through the kidneys and into the urine. But the fragments are still long enough to carry information about the tumor’s genetic signature.

This test could spot cancer before a tumor grows big enough — about a centimeter wide and carrying a billion cells — to spot on a CT scan or other imaging test. “When we are instead detecting fragments of DNA released from a tumor,” said Dr. Tewari, “our testing methods are very sensitive and can detect DNA in urine that came from just 5-10 cells in a tumor that died and released their DNA into the blood, which then made its way into the urine.”

Pancreatic cancer. Pancreatic ductal adenocarcinoma is one of the deadliest cancers, largely because it is diagnosed so late. A urine panel now in clinical trials could help doctors diagnose the cancer before it has spread so more people can have the tumor surgically removed, improving prognosis.

Using enzyme-linked immunosorbent assay test, a common lab method that detects antibodies and other proteins, the team measured expression levels for three genes (LYVE1, REG1B, and TFF1) in urine samples collected from people up to 5 years before they were diagnosed with pancreatic cancer. The researchers combined this result with patients’ urinary creatinine levels, a common component of existing urinalysis, and their age to develop a risk score.

This score performed similarly to an existing blood test, CA19-9, in predicting patients’ risk for pancreatic cancer up to 1 year before diagnosis. When combined with CA19-9, the urinary panel helped spot cancer up to 2 years before diagnosis.

According to a paper in the International Journal of Cancer, “the urine panel and affiliated PancRISK are currently being validated in a prospective clinical study (UroPanc).” If all goes well, they could be implemented in clinical practice in a few years as a “noninvasive stratification tool” to identify patients for further testing, speeding up diagnosis, and saving lives.

Limitations and Promises

Each cancer type is different, and more research is needed to map out which substances in urine predict which cancers and to develop tests for mass adoption. “There are medical and technological hurdles to the large-scale implementation of urine analysis for complex diseases such as cancer,” said Dr. Wong.

One possibility: Scientists and clinicians could collaborate and use artificial intelligence techniques to combine urine test results with other data.

“It is likely that future diagnostics may combine urine with other biological samples such as feces and saliva, among others,” said Dr. Wong. “This is especially true when novel data science and machine learning techniques can integrate comprehensive data from patients that span genetic, proteomic, metabolic, microbiomic, and even behavioral data to evaluate a patient’s condition.”

One thing that excites Dr. Tewari about urine-based cancer testing: “We think it could be especially impactful for patients living in rural areas or other areas with less access to healthcare services,” he said.
 

A version of this article appeared on Medscape.com.

The next frontier in cancer detection could be the humble urine test.

Emerging science suggests that the body’s “liquid gold” could be particularly useful for liquid biopsies, offering a convenient, pain-free, and cost-effective way to spot otherwise hard-to-detect cancers.

“The search for cancer biomarkers that can be detected in urine could provide an enormous step forward to decrease cancer patient mortality,” said Kenneth R. Shroyer, MD, PhD, a pathologist at Stony Brook University, Stony Brook, New York, who studies cancer biomarkers.

Physicians have long known that urine can reveal a lot about our health — that’s why urinalysis has been part of medicine for 6000 years. Urine tests can detect diabetes, pregnancy, drug use, and urinary or kidney conditions.

But other conditions leave clues in urine, too, and cancer may be one of the most promising. “Urine testing could detect biomarkers of early-stage cancers, not only from local but also distant sites,” Dr. Shroyer said. It could also help flag recurrence in cancer survivors who have undergone treatment.

Granted, cancer biomarkers in urine are not nearly as widely studied as those in the blood, Dr. Shroyer noted. But a new wave of urine tests suggests research is gaining pace.

“The recent availability of high-throughput screening technologies has enabled researchers to investigate cancer from a top-down, comprehensive approach,” said Pak Kin Wong, PhD, professor of mechanical engineering, biomedical engineering, and surgery at The Pennsylvania State University. “We are starting to understand the rich information that can be obtained from urine.”

Urine is mostly water (about 95%) and urea, a metabolic byproduct that imparts that signature yellow color (about 2%). The other 3% is a mix of waste products, minerals, and other compounds the kidneys removed from the blood. Even in trace amounts, these substances say a lot.

Among them are “exfoliated cancer cells, cell-free DNA, hormones, and the urine microbiota — the collection of microbes in our urinary tract system,” Dr. Wong said.

“It is highly promising to be one of the major biological fluids used for screening, diagnosis, prognosis, and monitoring treatment efficiency in the era of precision medicine,” Dr. Wong said.

How Urine Testing Could Reveal Cancer

Still, as exciting as the prospect is, there’s a lot to consider in the hunt for cancer biomarkers in urine. These biomarkers must be able to pass through the renal nephrons (filtering units), remain stable in urine, and have high-level sensitivity, Dr. Shroyer said. They should also have high specificity for cancer vs benign conditions and be expressed at early stages, before the primary tumor has spread.

“At this stage, few circulating biomarkers have been found that are both sensitive and specific for early-stage disease,” said Dr. Shroyer.

But there are a few promising examples under investigation in humans:

Prostate cancer. Researchers at the University of Michigan have developed a urine test that detects high-grade prostate cancer more accurately than existing tests, including PHI, SelectMDx, 4Kscore, EPI, MPS, and IsoPSA.

The MyProstateScore 2.0 (MPS2) test, which looks for 18 genes associated with high-grade tumors, could reduce unnecessary biopsies in men with elevated prostate-specific antigen levels, according to a paper published in JAMA Oncology.

It makes sense. The prostate gland secretes fluid that becomes part of the semen, traces of which enter urine. After a digital rectal exam, even more prostate fluid enters the urine. If a patient has prostate cancer, genetic material from the cancer cells will infiltrate the urine.

In the MPS2 test, researchers used polymerase chain reaction (PCR) testing in urine. “The technology used for COVID PCR is essentially the same as the PCR used to detect transcripts associated with high-grade prostate cancer in urine,” said study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan, Ann Arbor. “In the case of the MPS2 test, we are doing PCR on 18 genes simultaneously on urine samples.”

A statistical model uses levels of that genetic material to predict the risk for high-grade disease, helping doctors decide what to do next. At 95% sensitivity, the MPS2 model could eliminate 35%-45% of unnecessary biopsies, compared with 15%-30% for the other tests, and reduce repeat biopsies by 46%-51%, compared with 9%-21% for the other tests.

Head and neck cancer. In a paper published in JCI Insight, researchers described a test that finds ultra-short fragments of DNA in urine to enable early detection of head and neck cancers caused by human papillomavirus.

“Our data show that a relatively small volume of urine (30-60 mL) gives overall detection results comparable to a tube of blood,” said study author Muneesh Tewari, MD, PhD, professor of hematology and oncology at the University of Michigan .

A larger volume of urine could potentially “make cancer detection even more sensitive than blood,” Dr. Tewari said, “allowing cancers to be detected at the earliest stages when they are more curable.”

The team used a technique called droplet digital PCR to detect DNA fragments that are “ultra-short” (less than 50 base pairs long) and usually missed by conventional PCR testing. This transrenal cell-free tumor DNA, which travels from the tumor into the bloodstream, is broken down small enough to pass through the kidneys and into the urine. But the fragments are still long enough to carry information about the tumor’s genetic signature.

This test could spot cancer before a tumor grows big enough — about a centimeter wide and carrying a billion cells — to spot on a CT scan or other imaging test. “When we are instead detecting fragments of DNA released from a tumor,” said Dr. Tewari, “our testing methods are very sensitive and can detect DNA in urine that came from just 5-10 cells in a tumor that died and released their DNA into the blood, which then made its way into the urine.”

Pancreatic cancer. Pancreatic ductal adenocarcinoma is one of the deadliest cancers, largely because it is diagnosed so late. A urine panel now in clinical trials could help doctors diagnose the cancer before it has spread so more people can have the tumor surgically removed, improving prognosis.

Using enzyme-linked immunosorbent assay test, a common lab method that detects antibodies and other proteins, the team measured expression levels for three genes (LYVE1, REG1B, and TFF1) in urine samples collected from people up to 5 years before they were diagnosed with pancreatic cancer. The researchers combined this result with patients’ urinary creatinine levels, a common component of existing urinalysis, and their age to develop a risk score.

This score performed similarly to an existing blood test, CA19-9, in predicting patients’ risk for pancreatic cancer up to 1 year before diagnosis. When combined with CA19-9, the urinary panel helped spot cancer up to 2 years before diagnosis.

According to a paper in the International Journal of Cancer, “the urine panel and affiliated PancRISK are currently being validated in a prospective clinical study (UroPanc).” If all goes well, they could be implemented in clinical practice in a few years as a “noninvasive stratification tool” to identify patients for further testing, speeding up diagnosis, and saving lives.

Limitations and Promises

Each cancer type is different, and more research is needed to map out which substances in urine predict which cancers and to develop tests for mass adoption. “There are medical and technological hurdles to the large-scale implementation of urine analysis for complex diseases such as cancer,” said Dr. Wong.

One possibility: Scientists and clinicians could collaborate and use artificial intelligence techniques to combine urine test results with other data.

“It is likely that future diagnostics may combine urine with other biological samples such as feces and saliva, among others,” said Dr. Wong. “This is especially true when novel data science and machine learning techniques can integrate comprehensive data from patients that span genetic, proteomic, metabolic, microbiomic, and even behavioral data to evaluate a patient’s condition.”

One thing that excites Dr. Tewari about urine-based cancer testing: “We think it could be especially impactful for patients living in rural areas or other areas with less access to healthcare services,” he said.
 

A version of this article appeared on Medscape.com.

The next frontier in cancer detection could be the humble urine test.

Emerging science suggests that the body’s “liquid gold” could be particularly useful for liquid biopsies, offering a convenient, pain-free, and cost-effective way to spot otherwise hard-to-detect cancers.

“The search for cancer biomarkers that can be detected in urine could provide an enormous step forward to decrease cancer patient mortality,” said Kenneth R. Shroyer, MD, PhD, a pathologist at Stony Brook University, Stony Brook, New York, who studies cancer biomarkers.

Physicians have long known that urine can reveal a lot about our health — that’s why urinalysis has been part of medicine for 6000 years. Urine tests can detect diabetes, pregnancy, drug use, and urinary or kidney conditions.

But other conditions leave clues in urine, too, and cancer may be one of the most promising. “Urine testing could detect biomarkers of early-stage cancers, not only from local but also distant sites,” Dr. Shroyer said. It could also help flag recurrence in cancer survivors who have undergone treatment.

Granted, cancer biomarkers in urine are not nearly as widely studied as those in the blood, Dr. Shroyer noted. But a new wave of urine tests suggests research is gaining pace.

“The recent availability of high-throughput screening technologies has enabled researchers to investigate cancer from a top-down, comprehensive approach,” said Pak Kin Wong, PhD, professor of mechanical engineering, biomedical engineering, and surgery at The Pennsylvania State University. “We are starting to understand the rich information that can be obtained from urine.”

Urine is mostly water (about 95%) and urea, a metabolic byproduct that imparts that signature yellow color (about 2%). The other 3% is a mix of waste products, minerals, and other compounds the kidneys removed from the blood. Even in trace amounts, these substances say a lot.

Among them are “exfoliated cancer cells, cell-free DNA, hormones, and the urine microbiota — the collection of microbes in our urinary tract system,” Dr. Wong said.

“It is highly promising to be one of the major biological fluids used for screening, diagnosis, prognosis, and monitoring treatment efficiency in the era of precision medicine,” Dr. Wong said.

How Urine Testing Could Reveal Cancer

Still, as exciting as the prospect is, there’s a lot to consider in the hunt for cancer biomarkers in urine. These biomarkers must be able to pass through the renal nephrons (filtering units), remain stable in urine, and have high-level sensitivity, Dr. Shroyer said. They should also have high specificity for cancer vs benign conditions and be expressed at early stages, before the primary tumor has spread.

“At this stage, few circulating biomarkers have been found that are both sensitive and specific for early-stage disease,” said Dr. Shroyer.

But there are a few promising examples under investigation in humans:

Prostate cancer. Researchers at the University of Michigan have developed a urine test that detects high-grade prostate cancer more accurately than existing tests, including PHI, SelectMDx, 4Kscore, EPI, MPS, and IsoPSA.

The MyProstateScore 2.0 (MPS2) test, which looks for 18 genes associated with high-grade tumors, could reduce unnecessary biopsies in men with elevated prostate-specific antigen levels, according to a paper published in JAMA Oncology.

It makes sense. The prostate gland secretes fluid that becomes part of the semen, traces of which enter urine. After a digital rectal exam, even more prostate fluid enters the urine. If a patient has prostate cancer, genetic material from the cancer cells will infiltrate the urine.

In the MPS2 test, researchers used polymerase chain reaction (PCR) testing in urine. “The technology used for COVID PCR is essentially the same as the PCR used to detect transcripts associated with high-grade prostate cancer in urine,” said study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan, Ann Arbor. “In the case of the MPS2 test, we are doing PCR on 18 genes simultaneously on urine samples.”

A statistical model uses levels of that genetic material to predict the risk for high-grade disease, helping doctors decide what to do next. At 95% sensitivity, the MPS2 model could eliminate 35%-45% of unnecessary biopsies, compared with 15%-30% for the other tests, and reduce repeat biopsies by 46%-51%, compared with 9%-21% for the other tests.

Head and neck cancer. In a paper published in JCI Insight, researchers described a test that finds ultra-short fragments of DNA in urine to enable early detection of head and neck cancers caused by human papillomavirus.

“Our data show that a relatively small volume of urine (30-60 mL) gives overall detection results comparable to a tube of blood,” said study author Muneesh Tewari, MD, PhD, professor of hematology and oncology at the University of Michigan .

A larger volume of urine could potentially “make cancer detection even more sensitive than blood,” Dr. Tewari said, “allowing cancers to be detected at the earliest stages when they are more curable.”

The team used a technique called droplet digital PCR to detect DNA fragments that are “ultra-short” (less than 50 base pairs long) and usually missed by conventional PCR testing. This transrenal cell-free tumor DNA, which travels from the tumor into the bloodstream, is broken down small enough to pass through the kidneys and into the urine. But the fragments are still long enough to carry information about the tumor’s genetic signature.

This test could spot cancer before a tumor grows big enough — about a centimeter wide and carrying a billion cells — to spot on a CT scan or other imaging test. “When we are instead detecting fragments of DNA released from a tumor,” said Dr. Tewari, “our testing methods are very sensitive and can detect DNA in urine that came from just 5-10 cells in a tumor that died and released their DNA into the blood, which then made its way into the urine.”

Pancreatic cancer. Pancreatic ductal adenocarcinoma is one of the deadliest cancers, largely because it is diagnosed so late. A urine panel now in clinical trials could help doctors diagnose the cancer before it has spread so more people can have the tumor surgically removed, improving prognosis.

Using enzyme-linked immunosorbent assay test, a common lab method that detects antibodies and other proteins, the team measured expression levels for three genes (LYVE1, REG1B, and TFF1) in urine samples collected from people up to 5 years before they were diagnosed with pancreatic cancer. The researchers combined this result with patients’ urinary creatinine levels, a common component of existing urinalysis, and their age to develop a risk score.

This score performed similarly to an existing blood test, CA19-9, in predicting patients’ risk for pancreatic cancer up to 1 year before diagnosis. When combined with CA19-9, the urinary panel helped spot cancer up to 2 years before diagnosis.

According to a paper in the International Journal of Cancer, “the urine panel and affiliated PancRISK are currently being validated in a prospective clinical study (UroPanc).” If all goes well, they could be implemented in clinical practice in a few years as a “noninvasive stratification tool” to identify patients for further testing, speeding up diagnosis, and saving lives.

Limitations and Promises

Each cancer type is different, and more research is needed to map out which substances in urine predict which cancers and to develop tests for mass adoption. “There are medical and technological hurdles to the large-scale implementation of urine analysis for complex diseases such as cancer,” said Dr. Wong.

One possibility: Scientists and clinicians could collaborate and use artificial intelligence techniques to combine urine test results with other data.

“It is likely that future diagnostics may combine urine with other biological samples such as feces and saliva, among others,” said Dr. Wong. “This is especially true when novel data science and machine learning techniques can integrate comprehensive data from patients that span genetic, proteomic, metabolic, microbiomic, and even behavioral data to evaluate a patient’s condition.”

One thing that excites Dr. Tewari about urine-based cancer testing: “We think it could be especially impactful for patients living in rural areas or other areas with less access to healthcare services,” he said.
 

A version of this article appeared on Medscape.com.

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.

Breast cancer mortality was significantly lower among patients who used statins than in those who did not use these cholesterol-lowering drugs, a new study finds.

Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
 

What Is Known About Statins and Breast Cancer?

Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.

Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.

The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
 

How Was the Current Study Designed?

To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.

As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.

The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.

The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
 

What Did the Results Show?

The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).

The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).

The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.

“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.

The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
 

What Is the Takeaway Message for Clinical Practice?

“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.

What Are the Next Steps for Research?

The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.

However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.

Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
 

What Do Clinicians Think of the Study?

The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.

Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.

“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.

Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.

“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.

The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.

The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.

The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.