Susan London

DENVER – An increasing share of patients with lung cancer report that they have never smoked, according to a pair of retrospective cohort studies reported at a world conference on lung cancer.

At three U.S. institutions serving geographically and racially diverse populations, the proportion of never-smokers rose from 9% to 15% over a 24-year period among patients with non–small-cell lung cancer (NSCLC), but did not change among those with small-cell lung cancer (SCLC). At a U.K. tertiary care institution, the proportion of never-smokers rose from 13% to 27% over a 7-year period among patients undergoing surgery for lung cancer.

Data further suggested that these trends were due at least in part to an increase in the absolute number of never-smokers with lung cancer, and not simply to a decline in the proportion of smokers with lung cancer, or to earlier, incidental detection of tumors resulting from better imaging technology.

More research will be needed to determine the specific factors driving this increase, according to Dr. Everett E. Vokes, cochair of the conference, moderator of a related press conference, and the John E. Ultmann Professor and Chair, department of medicine, University of Chicago.

“What is causing this, for me, would be very, very speculative,” he said. “Secondhand smoke is still there, and radon is mentioned. That shouldn’t necessarily justify an increase, because those are either constant or also decreasing [like smoking]. And of course it could be pollution and factors that have to do with small particles and carcinogens in the air.”

In the first study, investigators led by Dr. Lorraine Pelosof of UT Southwestern Medical Center in Dallas used registries at three institutions – UT Southwestern Medical Center, Parkland Hospital in Dallas, and Vanderbilt University in Nashville, Tenn. – to identify patients who were diagnosed with lung cancer between 1990 and 2013.

Analyses were based on 10,593 patients with NSCLC and 1,510 patients with SCLC. The latter serve as an internal control given that cancer’s tight link with smoking, Dr. Pelosof noted.

In adjusted analyses, the proportion in the NSCLC group who reported never smoking increased from 9% to 15% during the study period (P less than .0001). In contrast, the proportion in the SCLC group held steady at roughly 2%.

Among patients with NSCLC, never-smokers were on average younger and more likely to be female compared with smokers, Dr. Pelosof reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

In teasing out the cause for the rise in never-smokers with NSCLC, analyses showed that the absolute numbers of patients with NSCLC increased during the study period.

Preliminary data suggested that earlier, incidental detection did not explain the trend, as rates of stage I, II, and III disease in never-smokers were stable or decreased, while the rate of stage IV disease increased.

In addition, the trend did not appear to be explained by an influx to the institutions of patients with mutations seeking targeted therapies on clinical trials, as the trend persisted after adjustment for race/ethnicity, which was used as a surrogate for mutational status.

The investigators plan several avenues of additional research to sort this out, Dr. Pelosof said.

“We want to look at possibly other institutions that are geographically and demographically diverse. Additional institutions would be helpful,” she said. “And then to get at some of the mechanisms, [looking at] mutational status and biology I think would be very important.”

In the second study, Dr. Eric Lim, a consultant thoracic surgeon at Royal Brompton Hospital, and a senior lecturer and reader in thoracic surgery at the National Heart and Lung Institute, Imperial College, London, and colleagues assessed smoking status among 2,170 patients who underwent surgery for lung cancer at the hospital between 2008 and 2014.

Overall, 20% of the patients in the cohort were never-smokers. Their mean age at presentation was 60 years, and two-thirds were women. The predominant tumor types were adenocarcinoma, seen in 54%, and carcinoid, seen in 27%.

The proportion who were never-smokers more than doubled during the study period, from 13% to 27%. The absolute annual number of such patients also rose, from about 60 to nearly 100.

Fully 52% of the never-smokers presented with only nonspecific symptoms of cough or chest infection, while 11% had hemoptysis. In the remaining 36%, the cancer was identified as an incidental finding on imaging done for other reasons.

“Nonsmoking lung cancer is increasing and now a significant proportion of the workload for surgeons across the United Kingdom,” concluded Dr. Lim. “Early detection in this group is challenging because they have no clear-cut symptoms, and serious symptoms were only present in a minority,” he said.

“Clearly it’s not going to be cost-effective to screen the entire population of nonsmokers for lung cancer,” he added. Since these patients “do not have established risk factors, research into early detection, ideally by noninvasive or molecular screening, is urgently required to identify early lung cancer in nonsmokers.”

Dr. Pelosof and Dr. Lim reported having no conflicts of interest.

DENVER – An increasing share of patients with lung cancer report that they have never smoked, according to a pair of retrospective cohort studies reported at a world conference on lung cancer.

At three U.S. institutions serving geographically and racially diverse populations, the proportion of never-smokers rose from 9% to 15% over a 24-year period among patients with non–small-cell lung cancer (NSCLC), but did not change among those with small-cell lung cancer (SCLC). At a U.K. tertiary care institution, the proportion of never-smokers rose from 13% to 27% over a 7-year period among patients undergoing surgery for lung cancer.

Data further suggested that these trends were due at least in part to an increase in the absolute number of never-smokers with lung cancer, and not simply to a decline in the proportion of smokers with lung cancer, or to earlier, incidental detection of tumors resulting from better imaging technology.

More research will be needed to determine the specific factors driving this increase, according to Dr. Everett E. Vokes, cochair of the conference, moderator of a related press conference, and the John E. Ultmann Professor and Chair, department of medicine, University of Chicago.

“What is causing this, for me, would be very, very speculative,” he said. “Secondhand smoke is still there, and radon is mentioned. That shouldn’t necessarily justify an increase, because those are either constant or also decreasing [like smoking]. And of course it could be pollution and factors that have to do with small particles and carcinogens in the air.”

In the first study, investigators led by Dr. Lorraine Pelosof of UT Southwestern Medical Center in Dallas used registries at three institutions – UT Southwestern Medical Center, Parkland Hospital in Dallas, and Vanderbilt University in Nashville, Tenn. – to identify patients who were diagnosed with lung cancer between 1990 and 2013.

Analyses were based on 10,593 patients with NSCLC and 1,510 patients with SCLC. The latter serve as an internal control given that cancer’s tight link with smoking, Dr. Pelosof noted.

In adjusted analyses, the proportion in the NSCLC group who reported never smoking increased from 9% to 15% during the study period (P less than .0001). In contrast, the proportion in the SCLC group held steady at roughly 2%.

Among patients with NSCLC, never-smokers were on average younger and more likely to be female compared with smokers, Dr. Pelosof reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

In teasing out the cause for the rise in never-smokers with NSCLC, analyses showed that the absolute numbers of patients with NSCLC increased during the study period.

Preliminary data suggested that earlier, incidental detection did not explain the trend, as rates of stage I, II, and III disease in never-smokers were stable or decreased, while the rate of stage IV disease increased.

In addition, the trend did not appear to be explained by an influx to the institutions of patients with mutations seeking targeted therapies on clinical trials, as the trend persisted after adjustment for race/ethnicity, which was used as a surrogate for mutational status.

The investigators plan several avenues of additional research to sort this out, Dr. Pelosof said.

“We want to look at possibly other institutions that are geographically and demographically diverse. Additional institutions would be helpful,” she said. “And then to get at some of the mechanisms, [looking at] mutational status and biology I think would be very important.”

In the second study, Dr. Eric Lim, a consultant thoracic surgeon at Royal Brompton Hospital, and a senior lecturer and reader in thoracic surgery at the National Heart and Lung Institute, Imperial College, London, and colleagues assessed smoking status among 2,170 patients who underwent surgery for lung cancer at the hospital between 2008 and 2014.

Overall, 20% of the patients in the cohort were never-smokers. Their mean age at presentation was 60 years, and two-thirds were women. The predominant tumor types were adenocarcinoma, seen in 54%, and carcinoid, seen in 27%.

The proportion who were never-smokers more than doubled during the study period, from 13% to 27%. The absolute annual number of such patients also rose, from about 60 to nearly 100.

Fully 52% of the never-smokers presented with only nonspecific symptoms of cough or chest infection, while 11% had hemoptysis. In the remaining 36%, the cancer was identified as an incidental finding on imaging done for other reasons.

“Nonsmoking lung cancer is increasing and now a significant proportion of the workload for surgeons across the United Kingdom,” concluded Dr. Lim. “Early detection in this group is challenging because they have no clear-cut symptoms, and serious symptoms were only present in a minority,” he said.

“Clearly it’s not going to be cost-effective to screen the entire population of nonsmokers for lung cancer,” he added. Since these patients “do not have established risk factors, research into early detection, ideally by noninvasive or molecular screening, is urgently required to identify early lung cancer in nonsmokers.”

Dr. Pelosof and Dr. Lim reported having no conflicts of interest.

DENVER – An increasing share of patients with lung cancer report that they have never smoked, according to a pair of retrospective cohort studies reported at a world conference on lung cancer.

At three U.S. institutions serving geographically and racially diverse populations, the proportion of never-smokers rose from 9% to 15% over a 24-year period among patients with non–small-cell lung cancer (NSCLC), but did not change among those with small-cell lung cancer (SCLC). At a U.K. tertiary care institution, the proportion of never-smokers rose from 13% to 27% over a 7-year period among patients undergoing surgery for lung cancer.

Data further suggested that these trends were due at least in part to an increase in the absolute number of never-smokers with lung cancer, and not simply to a decline in the proportion of smokers with lung cancer, or to earlier, incidental detection of tumors resulting from better imaging technology.

More research will be needed to determine the specific factors driving this increase, according to Dr. Everett E. Vokes, cochair of the conference, moderator of a related press conference, and the John E. Ultmann Professor and Chair, department of medicine, University of Chicago.

“What is causing this, for me, would be very, very speculative,” he said. “Secondhand smoke is still there, and radon is mentioned. That shouldn’t necessarily justify an increase, because those are either constant or also decreasing [like smoking]. And of course it could be pollution and factors that have to do with small particles and carcinogens in the air.”

In the first study, investigators led by Dr. Lorraine Pelosof of UT Southwestern Medical Center in Dallas used registries at three institutions – UT Southwestern Medical Center, Parkland Hospital in Dallas, and Vanderbilt University in Nashville, Tenn. – to identify patients who were diagnosed with lung cancer between 1990 and 2013.

Analyses were based on 10,593 patients with NSCLC and 1,510 patients with SCLC. The latter serve as an internal control given that cancer’s tight link with smoking, Dr. Pelosof noted.

In adjusted analyses, the proportion in the NSCLC group who reported never smoking increased from 9% to 15% during the study period (P less than .0001). In contrast, the proportion in the SCLC group held steady at roughly 2%.

Among patients with NSCLC, never-smokers were on average younger and more likely to be female compared with smokers, Dr. Pelosof reported at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

In teasing out the cause for the rise in never-smokers with NSCLC, analyses showed that the absolute numbers of patients with NSCLC increased during the study period.

Preliminary data suggested that earlier, incidental detection did not explain the trend, as rates of stage I, II, and III disease in never-smokers were stable or decreased, while the rate of stage IV disease increased.

In addition, the trend did not appear to be explained by an influx to the institutions of patients with mutations seeking targeted therapies on clinical trials, as the trend persisted after adjustment for race/ethnicity, which was used as a surrogate for mutational status.

The investigators plan several avenues of additional research to sort this out, Dr. Pelosof said.

“We want to look at possibly other institutions that are geographically and demographically diverse. Additional institutions would be helpful,” she said. “And then to get at some of the mechanisms, [looking at] mutational status and biology I think would be very important.”

In the second study, Dr. Eric Lim, a consultant thoracic surgeon at Royal Brompton Hospital, and a senior lecturer and reader in thoracic surgery at the National Heart and Lung Institute, Imperial College, London, and colleagues assessed smoking status among 2,170 patients who underwent surgery for lung cancer at the hospital between 2008 and 2014.

Overall, 20% of the patients in the cohort were never-smokers. Their mean age at presentation was 60 years, and two-thirds were women. The predominant tumor types were adenocarcinoma, seen in 54%, and carcinoid, seen in 27%.

The proportion who were never-smokers more than doubled during the study period, from 13% to 27%. The absolute annual number of such patients also rose, from about 60 to nearly 100.

Fully 52% of the never-smokers presented with only nonspecific symptoms of cough or chest infection, while 11% had hemoptysis. In the remaining 36%, the cancer was identified as an incidental finding on imaging done for other reasons.

“Nonsmoking lung cancer is increasing and now a significant proportion of the workload for surgeons across the United Kingdom,” concluded Dr. Lim. “Early detection in this group is challenging because they have no clear-cut symptoms, and serious symptoms were only present in a minority,” he said.

“Clearly it’s not going to be cost-effective to screen the entire population of nonsmokers for lung cancer,” he added. Since these patients “do not have established risk factors, research into early detection, ideally by noninvasive or molecular screening, is urgently required to identify early lung cancer in nonsmokers.”

Dr. Pelosof and Dr. Lim reported having no conflicts of interest.

DENVER – The International Association for the Study of Lung Cancer (IASLC) this week released an updated Tobacco Control and Smoking Cessation declaration that outlines a set of measures aimed at reducing smoking and lung cancer.

The declaration could be viewed as a vaccine of sorts, according to Kenneth Michael Cummings, PhD, a professor at the Hollings Cancer Center, Medical University of South Carolina, and Co-Chair of IASLC’s Tobacco Control and Smoking Cessation Committee.

©bilderbox/fotolia.com

“How about a vaccine to prevent 80% of lung cancer deaths worldwide? We have it: get rid of cigarettes,” he said in a press conference at the World Congress on Lung Cancer, where the declaration was released.

The previous declaration, released in 2008, focused heavily on giving the Food and Drug Administration (FDA) the authority to regulate tobacco in the United States, which it now has. Since then, the economics of tobacco have evolved rapidly, and new products such as e-cigarettes have become available.

Also, 180 countries have ratified the World Health Organization’s Framework Convention on Tobacco Control (FCTC) treaty, allowing them to implement evidence-based policies such as smoke-free environments, warning labels, advertising bans, and taxation.

Nevertheless, lung cancer still accounts for nearly 2 million cases and 1.6 million lives lost each year. And at least 80% of those deaths are directly attributable to smoking, Dr. Cummings said.

In some parts of the world, cigarette consumption has declined, but “that’s not happening everywhere,” he said. “In parts of Asia, such as China, Japan, and Southeast Asia, and in Latin America, we are still seeing a rapid increase in lung cancer deaths. And in parts of the world which have not taken up smoking but are the targets of the industry, such as Africa and Indonesia, we are likely going to see an epidemic there, which can be prevented, which is really the point of our new statement.”

The 2015 declaration has five components that address tobacco control and smoking cessation.

The first component calls for forceful implementation of the FCTC treaty, especially through higher cigarette prices via taxation. “This is…the most important component of our ‘vaccine,’ for every member of this organization to really advocate for raising the cigarette prices to a level where it makes it unaffordable for young people to take up the behavior,” Dr. Cummings said. In low- and middle-income countries, where cigarettes remain relatively inexpensive, imposing a tax of at least 70% of the retail price would immediately cut consumption by about a third (N Engl J Med. 2014;370:60-8).

Trade policies and tobacco interference are related issues, he noted. “Our organization has been strong in trying to keep tobacco out of trade agreements.” Some countries, such as Malaysia, have refused to allow tobacco to be part of the Trans-Pacific Partnership agreement now under negotiation. “We need to support that (stance) because if tobacco is in there, we have countries being sued under trade agreements for doing the right things in terms of implementing policies.”

The declaration’s second component calls for holding cigarette companies civilly and criminally accountable for their actions. While Philip Morris International has stated that they support evidence-based regulation of tobacco, “I think our organization can help (by taking) cigarettes off the shelf today,” Dr. Cummings said. Holding manufacturers accountable in courts is another way to raise the price of cigarettes and thereby reduce consumption, he added.

The third component of the declaration is to support policies that keep young people from starting to smoke, such as raising the legal age of use to 21. “The neurobiology is very clear: the younger you are when you get exposed to an addictive substance, the more likely it is you are going to find it hard to quit at the end. So raising the legal age is certainly something we ought to do,” Dr. Cummings asserted, adding that 21 “is sort of a compromise” as the brain continues to develop until the age of 25.

Ensuring provision of tobacco-cessation services to all smokers, the declaration’s fourth component, is important no matter what a patient’s status. “Even in our cancer patients, it’s not too late. It has a big effect on their outcomes,” he said.

The fifth component is support for policies that address alternatives for nicotine delivery that are likely safer than cigarettes. “I don’t really care if companies make money selling something, but they don’t have to kill one out of two of their consumers to do it,” Dr. Cummings commented.

These alternatives might include e-cigarettes, provided evidence supports their inclusion. “I think that’s the problem we have with e-cigarettes today,” he said, noting that much less is known about them as compared with standard cigarettes, and that the products and manufacturers change monthly.

These factors have made it difficult for the FDA to address e-cigarettes. “They have done one thing I would have recommended they do: they have proposed deeming authority to take into account a whole variety of [tobacco] products,” he said. Although e-cigarettes contain a nicotine nebulizer with an electronic device, and as such could potentially have been regulated as medical devices just like nicotine patches and gum, courts have instead ruled that they are tobacco products.

“It’s a complex issue, but I’m all for getting people off of cigarettes, and there are alternative nicotine delivery devices,” Dr. Cummings concluded. “I think they need to be shown to be safe and effective.”

DENVER – The International Association for the Study of Lung Cancer (IASLC) this week released an updated Tobacco Control and Smoking Cessation declaration that outlines a set of measures aimed at reducing smoking and lung cancer.

The declaration could be viewed as a vaccine of sorts, according to Kenneth Michael Cummings, PhD, a professor at the Hollings Cancer Center, Medical University of South Carolina, and Co-Chair of IASLC’s Tobacco Control and Smoking Cessation Committee.

©bilderbox/fotolia.com

“How about a vaccine to prevent 80% of lung cancer deaths worldwide? We have it: get rid of cigarettes,” he said in a press conference at the World Congress on Lung Cancer, where the declaration was released.

The previous declaration, released in 2008, focused heavily on giving the Food and Drug Administration (FDA) the authority to regulate tobacco in the United States, which it now has. Since then, the economics of tobacco have evolved rapidly, and new products such as e-cigarettes have become available.

Also, 180 countries have ratified the World Health Organization’s Framework Convention on Tobacco Control (FCTC) treaty, allowing them to implement evidence-based policies such as smoke-free environments, warning labels, advertising bans, and taxation.

Nevertheless, lung cancer still accounts for nearly 2 million cases and 1.6 million lives lost each year. And at least 80% of those deaths are directly attributable to smoking, Dr. Cummings said.

In some parts of the world, cigarette consumption has declined, but “that’s not happening everywhere,” he said. “In parts of Asia, such as China, Japan, and Southeast Asia, and in Latin America, we are still seeing a rapid increase in lung cancer deaths. And in parts of the world which have not taken up smoking but are the targets of the industry, such as Africa and Indonesia, we are likely going to see an epidemic there, which can be prevented, which is really the point of our new statement.”

The 2015 declaration has five components that address tobacco control and smoking cessation.

The first component calls for forceful implementation of the FCTC treaty, especially through higher cigarette prices via taxation. “This is…the most important component of our ‘vaccine,’ for every member of this organization to really advocate for raising the cigarette prices to a level where it makes it unaffordable for young people to take up the behavior,” Dr. Cummings said. In low- and middle-income countries, where cigarettes remain relatively inexpensive, imposing a tax of at least 70% of the retail price would immediately cut consumption by about a third (N Engl J Med. 2014;370:60-8).

Trade policies and tobacco interference are related issues, he noted. “Our organization has been strong in trying to keep tobacco out of trade agreements.” Some countries, such as Malaysia, have refused to allow tobacco to be part of the Trans-Pacific Partnership agreement now under negotiation. “We need to support that (stance) because if tobacco is in there, we have countries being sued under trade agreements for doing the right things in terms of implementing policies.”

The declaration’s second component calls for holding cigarette companies civilly and criminally accountable for their actions. While Philip Morris International has stated that they support evidence-based regulation of tobacco, “I think our organization can help (by taking) cigarettes off the shelf today,” Dr. Cummings said. Holding manufacturers accountable in courts is another way to raise the price of cigarettes and thereby reduce consumption, he added.

The third component of the declaration is to support policies that keep young people from starting to smoke, such as raising the legal age of use to 21. “The neurobiology is very clear: the younger you are when you get exposed to an addictive substance, the more likely it is you are going to find it hard to quit at the end. So raising the legal age is certainly something we ought to do,” Dr. Cummings asserted, adding that 21 “is sort of a compromise” as the brain continues to develop until the age of 25.

Ensuring provision of tobacco-cessation services to all smokers, the declaration’s fourth component, is important no matter what a patient’s status. “Even in our cancer patients, it’s not too late. It has a big effect on their outcomes,” he said.

The fifth component is support for policies that address alternatives for nicotine delivery that are likely safer than cigarettes. “I don’t really care if companies make money selling something, but they don’t have to kill one out of two of their consumers to do it,” Dr. Cummings commented.

These alternatives might include e-cigarettes, provided evidence supports their inclusion. “I think that’s the problem we have with e-cigarettes today,” he said, noting that much less is known about them as compared with standard cigarettes, and that the products and manufacturers change monthly.

These factors have made it difficult for the FDA to address e-cigarettes. “They have done one thing I would have recommended they do: they have proposed deeming authority to take into account a whole variety of [tobacco] products,” he said. Although e-cigarettes contain a nicotine nebulizer with an electronic device, and as such could potentially have been regulated as medical devices just like nicotine patches and gum, courts have instead ruled that they are tobacco products.

“It’s a complex issue, but I’m all for getting people off of cigarettes, and there are alternative nicotine delivery devices,” Dr. Cummings concluded. “I think they need to be shown to be safe and effective.”

DENVER – The International Association for the Study of Lung Cancer (IASLC) this week released an updated Tobacco Control and Smoking Cessation declaration that outlines a set of measures aimed at reducing smoking and lung cancer.

The declaration could be viewed as a vaccine of sorts, according to Kenneth Michael Cummings, PhD, a professor at the Hollings Cancer Center, Medical University of South Carolina, and Co-Chair of IASLC’s Tobacco Control and Smoking Cessation Committee.

©bilderbox/fotolia.com

“How about a vaccine to prevent 80% of lung cancer deaths worldwide? We have it: get rid of cigarettes,” he said in a press conference at the World Congress on Lung Cancer, where the declaration was released.

The previous declaration, released in 2008, focused heavily on giving the Food and Drug Administration (FDA) the authority to regulate tobacco in the United States, which it now has. Since then, the economics of tobacco have evolved rapidly, and new products such as e-cigarettes have become available.

Also, 180 countries have ratified the World Health Organization’s Framework Convention on Tobacco Control (FCTC) treaty, allowing them to implement evidence-based policies such as smoke-free environments, warning labels, advertising bans, and taxation.

Nevertheless, lung cancer still accounts for nearly 2 million cases and 1.6 million lives lost each year. And at least 80% of those deaths are directly attributable to smoking, Dr. Cummings said.

In some parts of the world, cigarette consumption has declined, but “that’s not happening everywhere,” he said. “In parts of Asia, such as China, Japan, and Southeast Asia, and in Latin America, we are still seeing a rapid increase in lung cancer deaths. And in parts of the world which have not taken up smoking but are the targets of the industry, such as Africa and Indonesia, we are likely going to see an epidemic there, which can be prevented, which is really the point of our new statement.”

The 2015 declaration has five components that address tobacco control and smoking cessation.

The first component calls for forceful implementation of the FCTC treaty, especially through higher cigarette prices via taxation. “This is…the most important component of our ‘vaccine,’ for every member of this organization to really advocate for raising the cigarette prices to a level where it makes it unaffordable for young people to take up the behavior,” Dr. Cummings said. In low- and middle-income countries, where cigarettes remain relatively inexpensive, imposing a tax of at least 70% of the retail price would immediately cut consumption by about a third (N Engl J Med. 2014;370:60-8).

Trade policies and tobacco interference are related issues, he noted. “Our organization has been strong in trying to keep tobacco out of trade agreements.” Some countries, such as Malaysia, have refused to allow tobacco to be part of the Trans-Pacific Partnership agreement now under negotiation. “We need to support that (stance) because if tobacco is in there, we have countries being sued under trade agreements for doing the right things in terms of implementing policies.”

The declaration’s second component calls for holding cigarette companies civilly and criminally accountable for their actions. While Philip Morris International has stated that they support evidence-based regulation of tobacco, “I think our organization can help (by taking) cigarettes off the shelf today,” Dr. Cummings said. Holding manufacturers accountable in courts is another way to raise the price of cigarettes and thereby reduce consumption, he added.

The third component of the declaration is to support policies that keep young people from starting to smoke, such as raising the legal age of use to 21. “The neurobiology is very clear: the younger you are when you get exposed to an addictive substance, the more likely it is you are going to find it hard to quit at the end. So raising the legal age is certainly something we ought to do,” Dr. Cummings asserted, adding that 21 “is sort of a compromise” as the brain continues to develop until the age of 25.

Ensuring provision of tobacco-cessation services to all smokers, the declaration’s fourth component, is important no matter what a patient’s status. “Even in our cancer patients, it’s not too late. It has a big effect on their outcomes,” he said.

The fifth component is support for policies that address alternatives for nicotine delivery that are likely safer than cigarettes. “I don’t really care if companies make money selling something, but they don’t have to kill one out of two of their consumers to do it,” Dr. Cummings commented.

These alternatives might include e-cigarettes, provided evidence supports their inclusion. “I think that’s the problem we have with e-cigarettes today,” he said, noting that much less is known about them as compared with standard cigarettes, and that the products and manufacturers change monthly.

These factors have made it difficult for the FDA to address e-cigarettes. “They have done one thing I would have recommended they do: they have proposed deeming authority to take into account a whole variety of [tobacco] products,” he said. Although e-cigarettes contain a nicotine nebulizer with an electronic device, and as such could potentially have been regulated as medical devices just like nicotine patches and gum, courts have instead ruled that they are tobacco products.

“It’s a complex issue, but I’m all for getting people off of cigarettes, and there are alternative nicotine delivery devices,” Dr. Cummings concluded. “I think they need to be shown to be safe and effective.”

DENVER – In its third CT Screening Workshop, the Strategic Screening Advisory Committee of the International Association for the Study of Lung Cancer discussed the finer points of using this technology to screen for lung cancer, including issues such as metrics, quality control, and cost-effectiveness.

“Lung cancer is the major problem of all cancers,” committee chair Dr. John K. Field maintained in press conference at the annual World Conference on Lung Cancer, which was held in conjunction with the workshop. This cancer still causes more deaths than all of those from breast, colon, and prostate cancer combined.

“However, the good news is that the future does lie in early detection,” he said. The National Lung Screening Trial established that low-dose CT screening reduces the risk of lung cancer death by 20% compared with plain chest radiographic screening (N Engl J Med. 2011;365:395-409).

“That was the first time anybody had actually demonstrated such a mortality advantage with anything in lung cancer, so it led to an enormous stage shift in our thinking,” noted Dr. Field, who is also Personal Clinical Chair in Molecular Oncology at the University of Liverpool, England.

In the workshop, committee members reviewed new guidelines on managing screen-detected nodules from the ongoing NELSON (Dutch Belgian Randomised Lung Cancer Screening Trial) (Lancet Oncol. 2014;15:1332-41) and from the British Thoracic Society (Thorax. 2015;70:794-8). Main results from NELSON, as well as from the similar U.K. Lung Cancer Screening Trial, are expected shortly.

“We also looked at quality control for future screening programs. It’s extremely important that if we do have screening in place, that we have the necessary quality control behind it,” Dr. Field asserted.

Another topic discussed was whether CT screening is cost-effective. “Cost-effectiveness is going to be a major issue, especially in Europe,” where policy makers are awaiting results from the two trials before implementing screening, he said. “At this moment in time, it looks as though we will be cost-effective.”

The committee also assessed the potential of lung cancer biomarkers. “If we can actually improve the CT screening by using a particular biomarker, that would help us identify individuals easier. But also, once we undertake the CT, we are sometimes left with a gray situation of nodules that may become malignant but are not large enough to actually undertake any surgical intervention. And if we had a biomarker that would tell us if it was an aggressive tumor, that would be an enormous advantage,” Dr. Field elaborated.

Finally, the committee reviewed the status of national plans for implementing lung cancer CT screening around the world. Implementation is a multistep process requiring clinical experts and policy makers to hammer out a variety of issues, he noted (Lancet. 2013;382:732-41).

These issues include how best to identify individuals at high risk, typically accomplished with the LLP (Liverpool Lung Project) risk model in the United Kingdom and the PLCO (Prostate, Lung, Colorectal, and Ovarian) risk model in the United States. Screening age must also be considered. “In the U.K., our recommendation would probably be 60-75, but in the U.S. it would be 55-80, which came from the U.S. Preventive Services Task Force,” Dr. Field noted.

Another issue is whether nodules identified on CT are better measured by their maximal diameter (used in the National Lung Screening Trial) or their volume (used in the ongoing NELSON and U.K. trials). “There are advantages and disadvantages of both. We feel that volume is the way forward,” he said.

The nature of any subsequent work-up, including whether a biopsy is performed and additional tests, is also a consideration, as is the management of small nodules, including whether patients should undergo video-assisted thoracoscopic surgery.

Similarly, clinical experts and policy makers must decide on the optimal screening interval, whether every year or every 2 years, as well as the age at which to stop screening, he noted. And cost-effectiveness will be a critical point.

Workshop attendees from around the world shared current screening practices in their countries. “It’s quite clear that we all have different approaches, but we all have one objective: to identify high-risk individuals early. And we know if we identify them early, successful surgery will actually give them a long life,” Dr. Field said.

“Therefore, we feel that the future is through screening and we need to implement it. At this moment in time, the funding is there within the U.S., we are moving towards implementing it. In Europe, we are still waiting for the NELSON trial, but we are looking at an 18-month or 2-year period where that decision hopefully will be made,” he concluded.

Dr. Field disclosed no relevant conflicts of interest.

DENVER – In its third CT Screening Workshop, the Strategic Screening Advisory Committee of the International Association for the Study of Lung Cancer discussed the finer points of using this technology to screen for lung cancer, including issues such as metrics, quality control, and cost-effectiveness.

“Lung cancer is the major problem of all cancers,” committee chair Dr. John K. Field maintained in press conference at the annual World Conference on Lung Cancer, which was held in conjunction with the workshop. This cancer still causes more deaths than all of those from breast, colon, and prostate cancer combined.

“However, the good news is that the future does lie in early detection,” he said. The National Lung Screening Trial established that low-dose CT screening reduces the risk of lung cancer death by 20% compared with plain chest radiographic screening (N Engl J Med. 2011;365:395-409).

“That was the first time anybody had actually demonstrated such a mortality advantage with anything in lung cancer, so it led to an enormous stage shift in our thinking,” noted Dr. Field, who is also Personal Clinical Chair in Molecular Oncology at the University of Liverpool, England.

In the workshop, committee members reviewed new guidelines on managing screen-detected nodules from the ongoing NELSON (Dutch Belgian Randomised Lung Cancer Screening Trial) (Lancet Oncol. 2014;15:1332-41) and from the British Thoracic Society (Thorax. 2015;70:794-8). Main results from NELSON, as well as from the similar U.K. Lung Cancer Screening Trial, are expected shortly.

“We also looked at quality control for future screening programs. It’s extremely important that if we do have screening in place, that we have the necessary quality control behind it,” Dr. Field asserted.

Another topic discussed was whether CT screening is cost-effective. “Cost-effectiveness is going to be a major issue, especially in Europe,” where policy makers are awaiting results from the two trials before implementing screening, he said. “At this moment in time, it looks as though we will be cost-effective.”

The committee also assessed the potential of lung cancer biomarkers. “If we can actually improve the CT screening by using a particular biomarker, that would help us identify individuals easier. But also, once we undertake the CT, we are sometimes left with a gray situation of nodules that may become malignant but are not large enough to actually undertake any surgical intervention. And if we had a biomarker that would tell us if it was an aggressive tumor, that would be an enormous advantage,” Dr. Field elaborated.

Finally, the committee reviewed the status of national plans for implementing lung cancer CT screening around the world. Implementation is a multistep process requiring clinical experts and policy makers to hammer out a variety of issues, he noted (Lancet. 2013;382:732-41).

These issues include how best to identify individuals at high risk, typically accomplished with the LLP (Liverpool Lung Project) risk model in the United Kingdom and the PLCO (Prostate, Lung, Colorectal, and Ovarian) risk model in the United States. Screening age must also be considered. “In the U.K., our recommendation would probably be 60-75, but in the U.S. it would be 55-80, which came from the U.S. Preventive Services Task Force,” Dr. Field noted.

Another issue is whether nodules identified on CT are better measured by their maximal diameter (used in the National Lung Screening Trial) or their volume (used in the ongoing NELSON and U.K. trials). “There are advantages and disadvantages of both. We feel that volume is the way forward,” he said.

The nature of any subsequent work-up, including whether a biopsy is performed and additional tests, is also a consideration, as is the management of small nodules, including whether patients should undergo video-assisted thoracoscopic surgery.

Similarly, clinical experts and policy makers must decide on the optimal screening interval, whether every year or every 2 years, as well as the age at which to stop screening, he noted. And cost-effectiveness will be a critical point.

Workshop attendees from around the world shared current screening practices in their countries. “It’s quite clear that we all have different approaches, but we all have one objective: to identify high-risk individuals early. And we know if we identify them early, successful surgery will actually give them a long life,” Dr. Field said.

“Therefore, we feel that the future is through screening and we need to implement it. At this moment in time, the funding is there within the U.S., we are moving towards implementing it. In Europe, we are still waiting for the NELSON trial, but we are looking at an 18-month or 2-year period where that decision hopefully will be made,” he concluded.

Dr. Field disclosed no relevant conflicts of interest.

DENVER – In its third CT Screening Workshop, the Strategic Screening Advisory Committee of the International Association for the Study of Lung Cancer discussed the finer points of using this technology to screen for lung cancer, including issues such as metrics, quality control, and cost-effectiveness.

“Lung cancer is the major problem of all cancers,” committee chair Dr. John K. Field maintained in press conference at the annual World Conference on Lung Cancer, which was held in conjunction with the workshop. This cancer still causes more deaths than all of those from breast, colon, and prostate cancer combined.

“However, the good news is that the future does lie in early detection,” he said. The National Lung Screening Trial established that low-dose CT screening reduces the risk of lung cancer death by 20% compared with plain chest radiographic screening (N Engl J Med. 2011;365:395-409).

“That was the first time anybody had actually demonstrated such a mortality advantage with anything in lung cancer, so it led to an enormous stage shift in our thinking,” noted Dr. Field, who is also Personal Clinical Chair in Molecular Oncology at the University of Liverpool, England.

In the workshop, committee members reviewed new guidelines on managing screen-detected nodules from the ongoing NELSON (Dutch Belgian Randomised Lung Cancer Screening Trial) (Lancet Oncol. 2014;15:1332-41) and from the British Thoracic Society (Thorax. 2015;70:794-8). Main results from NELSON, as well as from the similar U.K. Lung Cancer Screening Trial, are expected shortly.

“We also looked at quality control for future screening programs. It’s extremely important that if we do have screening in place, that we have the necessary quality control behind it,” Dr. Field asserted.

Another topic discussed was whether CT screening is cost-effective. “Cost-effectiveness is going to be a major issue, especially in Europe,” where policy makers are awaiting results from the two trials before implementing screening, he said. “At this moment in time, it looks as though we will be cost-effective.”

The committee also assessed the potential of lung cancer biomarkers. “If we can actually improve the CT screening by using a particular biomarker, that would help us identify individuals easier. But also, once we undertake the CT, we are sometimes left with a gray situation of nodules that may become malignant but are not large enough to actually undertake any surgical intervention. And if we had a biomarker that would tell us if it was an aggressive tumor, that would be an enormous advantage,” Dr. Field elaborated.

Finally, the committee reviewed the status of national plans for implementing lung cancer CT screening around the world. Implementation is a multistep process requiring clinical experts and policy makers to hammer out a variety of issues, he noted (Lancet. 2013;382:732-41).

These issues include how best to identify individuals at high risk, typically accomplished with the LLP (Liverpool Lung Project) risk model in the United Kingdom and the PLCO (Prostate, Lung, Colorectal, and Ovarian) risk model in the United States. Screening age must also be considered. “In the U.K., our recommendation would probably be 60-75, but in the U.S. it would be 55-80, which came from the U.S. Preventive Services Task Force,” Dr. Field noted.

Another issue is whether nodules identified on CT are better measured by their maximal diameter (used in the National Lung Screening Trial) or their volume (used in the ongoing NELSON and U.K. trials). “There are advantages and disadvantages of both. We feel that volume is the way forward,” he said.

The nature of any subsequent work-up, including whether a biopsy is performed and additional tests, is also a consideration, as is the management of small nodules, including whether patients should undergo video-assisted thoracoscopic surgery.

Similarly, clinical experts and policy makers must decide on the optimal screening interval, whether every year or every 2 years, as well as the age at which to stop screening, he noted. And cost-effectiveness will be a critical point.

Workshop attendees from around the world shared current screening practices in their countries. “It’s quite clear that we all have different approaches, but we all have one objective: to identify high-risk individuals early. And we know if we identify them early, successful surgery will actually give them a long life,” Dr. Field said.

“Therefore, we feel that the future is through screening and we need to implement it. At this moment in time, the funding is there within the U.S., we are moving towards implementing it. In Europe, we are still waiting for the NELSON trial, but we are looking at an 18-month or 2-year period where that decision hopefully will be made,” he concluded.

Dr. Field disclosed no relevant conflicts of interest.

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.

SEATTLE – Biomarkers may soon join other modalities for the early detection of breast cancer and identification of women at high risk for the disease, Susan L. Neuhausen, Ph.D., told attendees of the Global Biomarkers Consortium.

“There is an urgent need for biomarkers for breast cancer,” she maintained, citing its high prevalence and considerable mortality, coupled with better outcomes and lesser treatment requirements when it is caught early.

“I really think that for a lot of these biomarkers [in development], maybe their best use will be to augment mammographic screening, especially in the short term as they are being developed,” she speculated. Ultimately, “the hope – similar to PSA [prostate-specific antigen], where you can use it to detect cancer as well as use it as a marker of recurrence – is that these biomarkers of early detection will be developed to have the same attributes.”

Genetic biomarkers

“To me, the current best biomarker is actually a genetic biomarker,” said Dr. Neuhausen, who is the Morris and Horowitz Families Professor in Cancer Etiology and Outcomes Research, Population Sciences, and also coleader of the cancer control and population sciences program, Comprehensive Cancer Center, at the Beckman Research Institute, City of Hope, in Duarte, Calif.

Identifying the breast cancer susceptibility genes BRCA 1 and BRCA 2 paved the way for targeted chemoprevention and prophylactic surgery, which have been highly effective in reducing the incidence of breast cancer as well as ovarian cancer. However, mutations in these genes account for no more than approximately 5% of all breast cancers.

“There has been identification of additional moderate- to high-risk genes, and the strategies that work to prevent cancer in BRCA 1 and 2 carriers are the same that can used for these other high-risk genes,” Dr. Neuhausen noted. For example, mutations of partner and localizer of BRCA2 (PALB2) have been linked to heightened breast cancer risk (N Engl J Med. 2014;371:497-506). Additionally, many companies now offer multigene clinical risk panels.

“The problem or the issue at the current time is that we really don’t know what the risk of cancer in unaffected women who are carrying mutations in these genes is,” she commented. “The good news is there is a large European, United States, and Canadian study that is actually going to be screening for mutations in a total of about 25,000 women, so that similar to what’s been done in BRCA 1 and 2, we will actually have better risk estimates that one can then use for these women.”

A U.S. genome-wide association research effort, the Breast Cancer Surveillance Consortium (BCSC), has thus far identified about 100 loci linked to an increased risk of developing breast cancer, according to Dr. Neuhausen. “On an individual level, these really don’t account for much risk. However, if you combine them, they actually do,” she said.

Applied clinically, a polygenic risk score incorporating 77 single-nucleotide polymorphisms can stratify women into quintiles of risk (J Natl Cancer Inst. 2015;107(5):djv036). Among women without a family history of the disease, lifetime risk ranges from 5.2% for those in the lowest quintile to 16.6% for those in the highest.

Moreover, adding the polygenic risk score to the commonly used BCSC model increases the area under the curve from 0.66 to 0.69 for breast cancer risk prediction. It also results in reclassification of some women, in particular, identifying an additional 3% as having a greater than 3% risk of developing the disease over 5 years. “So this actually does have good discrimination and is something that can be useful moving forward,” Dr. Neuhausen commented.

“We have these low-, moderate-, and high-risk genes, and they really all need to be incorporated into models. There is research ongoing to try to incorporate all of them into models along with lifestyle factors and mammography, family history, that kind of thing,” she said. “But I really think that these genetic markers are very important because rather than early detection, if we can prevent breast cancer, that’s actually the real goal.”

Other biomarkers

A variety of other, nongenetic biomarkers for early breast cancer detection and risk stratification are generally less far along in development, but several have shown promise, according to Dr. Neuhausen.

In the realm of proteomics, a three–amino acid profile detectable in saliva that exploits the hypermetabolic and hypercatabolic nature of cancer was found to have an area under the curve of 0.916 for differentiating women with early breast cancer from unaffected peers (Clin Chim Acta. 2015;447:23-31). “It was only a very small study and they really need to look further, but I think it was an intriguing idea,” she commented.

Infrared spectroscopy of plasma identified a protein fingerprint that had roughly 90% sensitivity and 80% specificity for detecting breast cancer in a cohort that included women with the disease, women with benign breast conditions, and healthy women (BMC Cancer. 2015;15:408). And a pair of proteins in serum—HSP27 and 14-3-3 sigma—accurately distinguished breast cancer cases from controls in a Chinese population (Proteomics. 2003;3:433-9).

One study has suggested how proteomic biomarkers might be integrated with conventional modalities, showing that a five-protein signature in serum (dtectDx Breast, Provista) performed well among women younger than age 50 years for differentiating benign breast lesions from invasive breast cancer in those with a BI-RADS 3 or 4 mammogram (J Clin Oncol. 2014;32(26 Suppl 20). However, the signature had a fairly high false-positive rate, Dr. Neuhausen noted.

As for yet other types of biomarkers, a panel of circulating cell-free methylated DNA of eight tumor suppressor genes was found to have sensitivity and specificity exceeding 90% for differentiating between samples from breast cancer patients and from unaffected women (PLoS One. 2011;6:e16080).MicroRNA profiles of breast cancer have been identified, but findings have generally been inconsistent across studies (Breast Cancer. 2015;7:59-79). Somatic mutations in p53 and PI3KCA, present in about a third of breast cancers, currently have issues when applied to screening. “Those kinds of things are maybe better for determining response to treatment and that kind of thing. Are they ready for early detection? Not really,” Dr. Neuhausen said.

The situation is similar for DNA copy number, although intriguingly, a recent study of a prenatal test looking for fetal copy number aberrations in maternal plasma incidentally discovered maternal cell-free DNA that had copy number changes (JAMA Oncol. 2015 June 5.doi: 10.1001/jamaoncol.2015.1883). Imaging ultimately found various cancers in three women out of about 4,000 tested.

Dr. Neuhausen disclosed that she had no relevant conflicts of interest.

SEATTLE – It’s time to consider an alternative strategy for evaluating new biomarkers that focuses on the predictive information they add, Michael W. Kattan, Ph.D., said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

“In my view, we get too fixated on P values or hazard ratios and odds ratios. Instead, we need to step back and think more about what the goal of any new marker is, and often, it’s to improve our ability to predict a patient outcome,” said Dr. Kattan, professor of medicine, epidemiology, and biostatistics at Case Western Reserve University, Cleveland, and chair of quantitative health sciences at the Cleveland Clinic. “If that’s the case, why not worry more about something like incremental predictive accuracy or incremental predictive ability associated with that new marker, and make our decisions and our modeling steps toward that?”

The long-used, conventional three-step approach to evaluating a new biomarker – assessing its correlation with an established biomarker, its association with an outcome in univariate analysis, and finally its performance in a multivariate analysis (J Natl Cancer Inst. 2003;95:634-5) – has considerable issues, according to Dr. Kattan.

In particular, the multivariate analysis is problematic. “My P value is testing whether my hazard ratio is 1, it’s not per se an improvement in predictive accuracy, which is what I’m going to argue that the new marker should do,” he said. But more concerning is the fact that the hazard ratio is affected by factors the investigators control, such as whether the new biomarker is coded as a continuous or categorical variable, which established biomarkers are included, and any data transformations done.

“At the end of the day, things are getting a little bit subjective because I have a bunch of knobs under my control as the keeper of the data. I can turn all of these knobs, and unfortunately, I don’t have excellent arguments to defend how I would do that, and they may very well affect the [hazard ratio] that has everyone’s attention,” Dr. Kattan elaborated.

Thus, an alternative approach is needed, one that tests the new biomarker as part of a model and addresses the central question of whether it improves predictive accuracy, he maintained. “It’s [comparing] a model of markers that lacks the new marker versus a model of markers that contains the new marker. So it’s a model versus model comparison, it’s not simply looking at the marker in isolation, which is where we get in trouble with the typical way.”

Furthermore, aiming for the most accurate model removes much of the subjectivity of the conventional approach, he added. “Remember, I said there were knobs I could turn that might change the hazard ratio and I didn’t have a good defense for how I would turn these knobs. … Now I do, now I have an explicit goal: I want to have a prediction model that predicts patient outcome as accurately as I can. So whatever I’m doing with my knobs and stuff, that ought to be delivering a more accurate prediction model.”

Dr. Kattan outlined a four-step alternative approach to evaluating new biomarkers. The first step entails calculating the improvement in the concordance index, similar to an area under the receiver operating characteristic (ROC) curve, with the new biomarker. Ideally, that number will increase in a model that contains the marker, indicating an improvement in predictive accuracy.

In the second step, which assesses model calibration, established and new biomarkers are entered into a multivariate model predicting the outcome of interest (Clin Cancer Res. 2004;10:822-4). If the concordance index drops by a clinically significant degree when the new biomarker is omitted, indicating a loss of predictive accuracy, it advances.

The third step is to construct scatterplots comparing results obtained with prediction models of the outcome, say, 10-year progression-free survival, that do and do not contain the new marker, say, surgeon experience with prostatectomy (Cancer. 2009;115:1005-10). If the improvement in accuracy here is clinically significant, the marker again advances.

In the fourth and final step, decision curve analysis, the net benefit is plotted as a function of the threshold for clinical action (Epidemiology. 2010;21:128-38). “This gets at, should I be making clinical decisions based on the prediction model, or should I just treat everyone or treat no one. It’s a way of looking at what the net benefit is of the prediction model across the spectrum of predictions,” Dr. Kattan explained. “So you would first decide what’s my threshold for action … where’s it going to change what I do, and then read upwards [in the plot] and see what the net benefit is.”

Dr. Kattan disclosed that he receives consulting fees from Bayer, Exosome, GlaxoSmithKline, HistoSonics, and Merck.

SEATTLE – It’s time to consider an alternative strategy for evaluating new biomarkers that focuses on the predictive information they add, Michael W. Kattan, Ph.D., said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

“In my view, we get too fixated on P values or hazard ratios and odds ratios. Instead, we need to step back and think more about what the goal of any new marker is, and often, it’s to improve our ability to predict a patient outcome,” said Dr. Kattan, professor of medicine, epidemiology, and biostatistics at Case Western Reserve University, Cleveland, and chair of quantitative health sciences at the Cleveland Clinic. “If that’s the case, why not worry more about something like incremental predictive accuracy or incremental predictive ability associated with that new marker, and make our decisions and our modeling steps toward that?”

The long-used, conventional three-step approach to evaluating a new biomarker – assessing its correlation with an established biomarker, its association with an outcome in univariate analysis, and finally its performance in a multivariate analysis (J Natl Cancer Inst. 2003;95:634-5) – has considerable issues, according to Dr. Kattan.

In particular, the multivariate analysis is problematic. “My P value is testing whether my hazard ratio is 1, it’s not per se an improvement in predictive accuracy, which is what I’m going to argue that the new marker should do,” he said. But more concerning is the fact that the hazard ratio is affected by factors the investigators control, such as whether the new biomarker is coded as a continuous or categorical variable, which established biomarkers are included, and any data transformations done.

“At the end of the day, things are getting a little bit subjective because I have a bunch of knobs under my control as the keeper of the data. I can turn all of these knobs, and unfortunately, I don’t have excellent arguments to defend how I would do that, and they may very well affect the [hazard ratio] that has everyone’s attention,” Dr. Kattan elaborated.

Thus, an alternative approach is needed, one that tests the new biomarker as part of a model and addresses the central question of whether it improves predictive accuracy, he maintained. “It’s [comparing] a model of markers that lacks the new marker versus a model of markers that contains the new marker. So it’s a model versus model comparison, it’s not simply looking at the marker in isolation, which is where we get in trouble with the typical way.”

Furthermore, aiming for the most accurate model removes much of the subjectivity of the conventional approach, he added. “Remember, I said there were knobs I could turn that might change the hazard ratio and I didn’t have a good defense for how I would turn these knobs. … Now I do, now I have an explicit goal: I want to have a prediction model that predicts patient outcome as accurately as I can. So whatever I’m doing with my knobs and stuff, that ought to be delivering a more accurate prediction model.”

Dr. Kattan outlined a four-step alternative approach to evaluating new biomarkers. The first step entails calculating the improvement in the concordance index, similar to an area under the receiver operating characteristic (ROC) curve, with the new biomarker. Ideally, that number will increase in a model that contains the marker, indicating an improvement in predictive accuracy.

In the second step, which assesses model calibration, established and new biomarkers are entered into a multivariate model predicting the outcome of interest (Clin Cancer Res. 2004;10:822-4). If the concordance index drops by a clinically significant degree when the new biomarker is omitted, indicating a loss of predictive accuracy, it advances.

The third step is to construct scatterplots comparing results obtained with prediction models of the outcome, say, 10-year progression-free survival, that do and do not contain the new marker, say, surgeon experience with prostatectomy (Cancer. 2009;115:1005-10). If the improvement in accuracy here is clinically significant, the marker again advances.

In the fourth and final step, decision curve analysis, the net benefit is plotted as a function of the threshold for clinical action (Epidemiology. 2010;21:128-38). “This gets at, should I be making clinical decisions based on the prediction model, or should I just treat everyone or treat no one. It’s a way of looking at what the net benefit is of the prediction model across the spectrum of predictions,” Dr. Kattan explained. “So you would first decide what’s my threshold for action … where’s it going to change what I do, and then read upwards [in the plot] and see what the net benefit is.”

Dr. Kattan disclosed that he receives consulting fees from Bayer, Exosome, GlaxoSmithKline, HistoSonics, and Merck.

SEATTLE – It’s time to consider an alternative strategy for evaluating new biomarkers that focuses on the predictive information they add, Michael W. Kattan, Ph.D., said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

“In my view, we get too fixated on P values or hazard ratios and odds ratios. Instead, we need to step back and think more about what the goal of any new marker is, and often, it’s to improve our ability to predict a patient outcome,” said Dr. Kattan, professor of medicine, epidemiology, and biostatistics at Case Western Reserve University, Cleveland, and chair of quantitative health sciences at the Cleveland Clinic. “If that’s the case, why not worry more about something like incremental predictive accuracy or incremental predictive ability associated with that new marker, and make our decisions and our modeling steps toward that?”

The long-used, conventional three-step approach to evaluating a new biomarker – assessing its correlation with an established biomarker, its association with an outcome in univariate analysis, and finally its performance in a multivariate analysis (J Natl Cancer Inst. 2003;95:634-5) – has considerable issues, according to Dr. Kattan.

In particular, the multivariate analysis is problematic. “My P value is testing whether my hazard ratio is 1, it’s not per se an improvement in predictive accuracy, which is what I’m going to argue that the new marker should do,” he said. But more concerning is the fact that the hazard ratio is affected by factors the investigators control, such as whether the new biomarker is coded as a continuous or categorical variable, which established biomarkers are included, and any data transformations done.

“At the end of the day, things are getting a little bit subjective because I have a bunch of knobs under my control as the keeper of the data. I can turn all of these knobs, and unfortunately, I don’t have excellent arguments to defend how I would do that, and they may very well affect the [hazard ratio] that has everyone’s attention,” Dr. Kattan elaborated.

Thus, an alternative approach is needed, one that tests the new biomarker as part of a model and addresses the central question of whether it improves predictive accuracy, he maintained. “It’s [comparing] a model of markers that lacks the new marker versus a model of markers that contains the new marker. So it’s a model versus model comparison, it’s not simply looking at the marker in isolation, which is where we get in trouble with the typical way.”

Furthermore, aiming for the most accurate model removes much of the subjectivity of the conventional approach, he added. “Remember, I said there were knobs I could turn that might change the hazard ratio and I didn’t have a good defense for how I would turn these knobs. … Now I do, now I have an explicit goal: I want to have a prediction model that predicts patient outcome as accurately as I can. So whatever I’m doing with my knobs and stuff, that ought to be delivering a more accurate prediction model.”

Dr. Kattan outlined a four-step alternative approach to evaluating new biomarkers. The first step entails calculating the improvement in the concordance index, similar to an area under the receiver operating characteristic (ROC) curve, with the new biomarker. Ideally, that number will increase in a model that contains the marker, indicating an improvement in predictive accuracy.

In the second step, which assesses model calibration, established and new biomarkers are entered into a multivariate model predicting the outcome of interest (Clin Cancer Res. 2004;10:822-4). If the concordance index drops by a clinically significant degree when the new biomarker is omitted, indicating a loss of predictive accuracy, it advances.

The third step is to construct scatterplots comparing results obtained with prediction models of the outcome, say, 10-year progression-free survival, that do and do not contain the new marker, say, surgeon experience with prostatectomy (Cancer. 2009;115:1005-10). If the improvement in accuracy here is clinically significant, the marker again advances.

In the fourth and final step, decision curve analysis, the net benefit is plotted as a function of the threshold for clinical action (Epidemiology. 2010;21:128-38). “This gets at, should I be making clinical decisions based on the prediction model, or should I just treat everyone or treat no one. It’s a way of looking at what the net benefit is of the prediction model across the spectrum of predictions,” Dr. Kattan explained. “So you would first decide what’s my threshold for action … where’s it going to change what I do, and then read upwards [in the plot] and see what the net benefit is.”

Dr. Kattan disclosed that he receives consulting fees from Bayer, Exosome, GlaxoSmithKline, HistoSonics, and Merck.

SEATTLE – “Biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia,” Dr. Hemant K. Roy said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

A better, personalized strategy for screening the population is needed given the current limitations of colonoscopy, he said. “Unfortunately, we know that the endoscopic capacity and funding are really inadequate to perform colonoscopy on the entire average at-risk population, which is greater than 100 million Americans over the age of 50. Juxtaposed with this is the fact that most screenings by colonoscopy are negative for a significant lesion.

“In retrospect, most colonoscopies are squandered if you just look at colonoscopy as a cancer prevention tool. The solution may be a better risk stratification tool, to develop a prescreen that can detect patients most likely to benefit from colonoscopy,” he said.

Biomarker tests

Numerous colorectal cancer biomarkers are being evaluated in various physiologic compartments, according to Dr. Roy, professor of medicine and chief of the section of gastroenterology, Boston University Medical Center. The development of these biomarkers is complicated by several factors, such as the heterogeneity of the neoplasia and the large number of mutations found in this cancer.

Most of those being investigated for screening are still in the earlier phases of development. One now on the market is a blood test for methylated SEPT9 (ColoVantage). Its sensitivity is 48% for colorectal cancer but only 11% for advanced adenomas (Gut. 2014 Feb;63(2):317-25). “This represents a small step forward, but it is available,” Dr. Roy said.

Among other promising blood tests is the microRNA MiR-21 assay. This assay was found to have an area under the curve of 0.92 for the detection of colorectal cancer and 0.81 for the detection of adenomas (J Natl Cancer Inst. 2013 Jun 19;105(12):849-59).

A stool DNA test on the market (Cologuard) outperformed the fecal immunochemical test (FIT) for detecting colon cancer, with a sensitivity of 92% and a specificity of 87% (N Engl J Med. 2014 Apr 3;370(14):1287-97). But the sensitivity was only 42% for advanced adenomas. “This is our real target, and this is a problem, especially as the Cologuard test, while good, is expensive at about $500 a test,” he said.

Fecal microRNA biomarkers have also shown some promise, with a pair found to perform well for differentiating individuals with advanced adenomas and cancers from unaffected peers (Cancer Epidemiol Biomarkers Prev. 2010 Jul;19(7):1766-74). “While this needs to be repeated, it has some potential,” Dr. Roy commented.

Tissue tests exploit the fact that, in general, the entire large intestine is exposed to the same genetic and environmental influences. “The corollary is that we can potentially look in the rectum or at other lesions in the colon and predict risk throughout the colon,” he explained.

Promising tissue biomarkers include nanoarchitectural changes in endoscopically normal-appearing rectal mucosa that appear to reflect the risk of carcinogenesis throughout the colon (Cancer Res. Jun 1;72(11):2720-7) and microsatellite instability, which can be used as part of an algorithm to identify Lynch syndrome (Gastroenterology. Aug;147(2):502-26).

Clinical applications

“Our long-term goal is to take the general population and find these biomarkers, to narrow down our conventional cancer-screening group,” Dr. Roy explained. An additional goal is developing noninvasive tests that are more acceptable to patients than colonoscopy.

Although a randomized trial showed colonoscopy performs better than FIT at detecting advanced adenomas among patients who actually undergo screening, the difference is attenuated among all patients offered screening, likely due in part to poorer compliance with colonoscopy (N Engl J Med. 2012 Feb 23;366(8):697-706).

“You could say, we should do colonoscopy on everyone [eligible], and I’m a gastroenterologist, so that would make me very happy,” Dr. Roy commented. “But if we can’t get people to undergo the test, and with the costs associated with it and the really very small number of people in whom we actually find a significant polyp, we need a better strategy. And that is where I think a biomarker approach is going to be very helpful.”

He predicted risk-stratified use of screening tests in the future. “I think [we will see] a combination approach, with the highest-risk patients going directly to colonoscopy and the lowest-risk patients getting less sensitive biomarker-based tests,” he said.

Biomarkers may also be applied clinically to help inform colorectal cancer chemoprevention, for example, by identifying patients most likely to benefit from aspirin therapy and by helping to assess whether the dose should be altered, according to Dr. Roy. To this end, research on tissue biomarkers suggests that aspirin’s risk-reducing benefit is limited to individuals with higher 15-PDGH expression in normal colonic mucosa (Sci Transl Med. 2014 Apr 23;6(233):233re2).

Dr. Roy disclosed that he receives a salary from NanoCytomics, and has an ownership interest in American BioOptics, NanoCytomics, and Pegasus Biosolutions.

SEATTLE – “Biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia,” Dr. Hemant K. Roy said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

A better, personalized strategy for screening the population is needed given the current limitations of colonoscopy, he said. “Unfortunately, we know that the endoscopic capacity and funding are really inadequate to perform colonoscopy on the entire average at-risk population, which is greater than 100 million Americans over the age of 50. Juxtaposed with this is the fact that most screenings by colonoscopy are negative for a significant lesion.

“In retrospect, most colonoscopies are squandered if you just look at colonoscopy as a cancer prevention tool. The solution may be a better risk stratification tool, to develop a prescreen that can detect patients most likely to benefit from colonoscopy,” he said.

Biomarker tests

Numerous colorectal cancer biomarkers are being evaluated in various physiologic compartments, according to Dr. Roy, professor of medicine and chief of the section of gastroenterology, Boston University Medical Center. The development of these biomarkers is complicated by several factors, such as the heterogeneity of the neoplasia and the large number of mutations found in this cancer.

Most of those being investigated for screening are still in the earlier phases of development. One now on the market is a blood test for methylated SEPT9 (ColoVantage). Its sensitivity is 48% for colorectal cancer but only 11% for advanced adenomas (Gut. 2014 Feb;63(2):317-25). “This represents a small step forward, but it is available,” Dr. Roy said.

Among other promising blood tests is the microRNA MiR-21 assay. This assay was found to have an area under the curve of 0.92 for the detection of colorectal cancer and 0.81 for the detection of adenomas (J Natl Cancer Inst. 2013 Jun 19;105(12):849-59).

A stool DNA test on the market (Cologuard) outperformed the fecal immunochemical test (FIT) for detecting colon cancer, with a sensitivity of 92% and a specificity of 87% (N Engl J Med. 2014 Apr 3;370(14):1287-97). But the sensitivity was only 42% for advanced adenomas. “This is our real target, and this is a problem, especially as the Cologuard test, while good, is expensive at about $500 a test,” he said.

Fecal microRNA biomarkers have also shown some promise, with a pair found to perform well for differentiating individuals with advanced adenomas and cancers from unaffected peers (Cancer Epidemiol Biomarkers Prev. 2010 Jul;19(7):1766-74). “While this needs to be repeated, it has some potential,” Dr. Roy commented.

Tissue tests exploit the fact that, in general, the entire large intestine is exposed to the same genetic and environmental influences. “The corollary is that we can potentially look in the rectum or at other lesions in the colon and predict risk throughout the colon,” he explained.

Promising tissue biomarkers include nanoarchitectural changes in endoscopically normal-appearing rectal mucosa that appear to reflect the risk of carcinogenesis throughout the colon (Cancer Res. Jun 1;72(11):2720-7) and microsatellite instability, which can be used as part of an algorithm to identify Lynch syndrome (Gastroenterology. Aug;147(2):502-26).

Clinical applications

“Our long-term goal is to take the general population and find these biomarkers, to narrow down our conventional cancer-screening group,” Dr. Roy explained. An additional goal is developing noninvasive tests that are more acceptable to patients than colonoscopy.

Although a randomized trial showed colonoscopy performs better than FIT at detecting advanced adenomas among patients who actually undergo screening, the difference is attenuated among all patients offered screening, likely due in part to poorer compliance with colonoscopy (N Engl J Med. 2012 Feb 23;366(8):697-706).

“You could say, we should do colonoscopy on everyone [eligible], and I’m a gastroenterologist, so that would make me very happy,” Dr. Roy commented. “But if we can’t get people to undergo the test, and with the costs associated with it and the really very small number of people in whom we actually find a significant polyp, we need a better strategy. And that is where I think a biomarker approach is going to be very helpful.”

He predicted risk-stratified use of screening tests in the future. “I think [we will see] a combination approach, with the highest-risk patients going directly to colonoscopy and the lowest-risk patients getting less sensitive biomarker-based tests,” he said.

Biomarkers may also be applied clinically to help inform colorectal cancer chemoprevention, for example, by identifying patients most likely to benefit from aspirin therapy and by helping to assess whether the dose should be altered, according to Dr. Roy. To this end, research on tissue biomarkers suggests that aspirin’s risk-reducing benefit is limited to individuals with higher 15-PDGH expression in normal colonic mucosa (Sci Transl Med. 2014 Apr 23;6(233):233re2).

Dr. Roy disclosed that he receives a salary from NanoCytomics, and has an ownership interest in American BioOptics, NanoCytomics, and Pegasus Biosolutions.

SEATTLE – “Biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia,” Dr. Hemant K. Roy said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

A better, personalized strategy for screening the population is needed given the current limitations of colonoscopy, he said. “Unfortunately, we know that the endoscopic capacity and funding are really inadequate to perform colonoscopy on the entire average at-risk population, which is greater than 100 million Americans over the age of 50. Juxtaposed with this is the fact that most screenings by colonoscopy are negative for a significant lesion.

“In retrospect, most colonoscopies are squandered if you just look at colonoscopy as a cancer prevention tool. The solution may be a better risk stratification tool, to develop a prescreen that can detect patients most likely to benefit from colonoscopy,” he said.

Biomarker tests

Numerous colorectal cancer biomarkers are being evaluated in various physiologic compartments, according to Dr. Roy, professor of medicine and chief of the section of gastroenterology, Boston University Medical Center. The development of these biomarkers is complicated by several factors, such as the heterogeneity of the neoplasia and the large number of mutations found in this cancer.

Most of those being investigated for screening are still in the earlier phases of development. One now on the market is a blood test for methylated SEPT9 (ColoVantage). Its sensitivity is 48% for colorectal cancer but only 11% for advanced adenomas (Gut. 2014 Feb;63(2):317-25). “This represents a small step forward, but it is available,” Dr. Roy said.

Among other promising blood tests is the microRNA MiR-21 assay. This assay was found to have an area under the curve of 0.92 for the detection of colorectal cancer and 0.81 for the detection of adenomas (J Natl Cancer Inst. 2013 Jun 19;105(12):849-59).

A stool DNA test on the market (Cologuard) outperformed the fecal immunochemical test (FIT) for detecting colon cancer, with a sensitivity of 92% and a specificity of 87% (N Engl J Med. 2014 Apr 3;370(14):1287-97). But the sensitivity was only 42% for advanced adenomas. “This is our real target, and this is a problem, especially as the Cologuard test, while good, is expensive at about $500 a test,” he said.

Fecal microRNA biomarkers have also shown some promise, with a pair found to perform well for differentiating individuals with advanced adenomas and cancers from unaffected peers (Cancer Epidemiol Biomarkers Prev. 2010 Jul;19(7):1766-74). “While this needs to be repeated, it has some potential,” Dr. Roy commented.

Tissue tests exploit the fact that, in general, the entire large intestine is exposed to the same genetic and environmental influences. “The corollary is that we can potentially look in the rectum or at other lesions in the colon and predict risk throughout the colon,” he explained.

Promising tissue biomarkers include nanoarchitectural changes in endoscopically normal-appearing rectal mucosa that appear to reflect the risk of carcinogenesis throughout the colon (Cancer Res. Jun 1;72(11):2720-7) and microsatellite instability, which can be used as part of an algorithm to identify Lynch syndrome (Gastroenterology. Aug;147(2):502-26).

Clinical applications

“Our long-term goal is to take the general population and find these biomarkers, to narrow down our conventional cancer-screening group,” Dr. Roy explained. An additional goal is developing noninvasive tests that are more acceptable to patients than colonoscopy.

Although a randomized trial showed colonoscopy performs better than FIT at detecting advanced adenomas among patients who actually undergo screening, the difference is attenuated among all patients offered screening, likely due in part to poorer compliance with colonoscopy (N Engl J Med. 2012 Feb 23;366(8):697-706).

“You could say, we should do colonoscopy on everyone [eligible], and I’m a gastroenterologist, so that would make me very happy,” Dr. Roy commented. “But if we can’t get people to undergo the test, and with the costs associated with it and the really very small number of people in whom we actually find a significant polyp, we need a better strategy. And that is where I think a biomarker approach is going to be very helpful.”

He predicted risk-stratified use of screening tests in the future. “I think [we will see] a combination approach, with the highest-risk patients going directly to colonoscopy and the lowest-risk patients getting less sensitive biomarker-based tests,” he said.

Biomarkers may also be applied clinically to help inform colorectal cancer chemoprevention, for example, by identifying patients most likely to benefit from aspirin therapy and by helping to assess whether the dose should be altered, according to Dr. Roy. To this end, research on tissue biomarkers suggests that aspirin’s risk-reducing benefit is limited to individuals with higher 15-PDGH expression in normal colonic mucosa (Sci Transl Med. 2014 Apr 23;6(233):233re2).

Dr. Roy disclosed that he receives a salary from NanoCytomics, and has an ownership interest in American BioOptics, NanoCytomics, and Pegasus Biosolutions.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – Recent developments in the field of melanoma may help clinicians refine their approach to this disease, according to Dr. Suraj S. Venna, a dermatologist and medical director of the Inova Melanoma and Skin Cancer Center in Fairfax, Va. He discussed several key studies and guideline revisions at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Sentinel node biopsy for thin melanomas

Guidance regarding staging of and use of sentinel lymph node (SLN) biopsy in cases of thin melanomas, those no more than 1 mm thick, is in flux, and these gray areas pose challenges to management.

In its seventh edition of the TNM Staging System published in 2010, the American Joint Committee on Cancer started incorporating mitotic rate to substage T1 melanomas, according to Dr. Venna. Those having a mitotic rate of at least 1 mitosis/mm² are now categorized as T1b. Yet, even within this subset, there is a spectrum of 10-year survival according to mitotic rate (J Clin Oncol. 2011;29:2199-205). Also, the association of mitotic rate with regional nodal metastasis is unclear.

Therefore, “T1b is not an automatic recommendation for lymph node biopsy,” he said. Decisions about SLN in patients with such tumors should consider all available clinical and pathologic factors.

The National Comprehensive Cancer Network has also revised its guidelines in this area. In 2011, they advised that SLN could be discussed and considered in stage IA melanomas with various high-risk features and in selected stage IB melanomas based on mitotic rate and thickness.

But in their 2015 update, they gave priority to lesion depth. “What they say is other than Breslow depth, there remains little consensus regarding the significance of ulceration, mitotic rate, or lymphovascular invasion,” Dr. Venna elaborated. Now, SLN biopsy can be considered on a case-by-case basis for stage 1A melanomas that are thicker or have uncertain microstaging, and can be discussed and offered for thicker stage 1B melanomas with ulceration or an elevated mitotic rate.

“At the end of the day, when we are all in our multidisciplinary clinics trying to talk to patients about this, these are nuances that really cause a lot of angst for us and the patient in terms of making decisions,” commented Dr. Venna.

“Acknowledge the prognostic gap in the T1b cohort and that not all T1b melanomas are created equal. We all anticipate that molecular techniques may better identify who among that thin group may benefit from lymph node testing,” Dr. Venna said.

Screening strategies

Population-based screening for melanoma and other skin cancers remains controversial, and this practice is generally limited to areas of the world having high incidence, according to Dr. Venna. Germany was the first country to implement a nationwide program, starting in 2008.

“There is evidence that screening may lead to the prevention of a substantial proportion of melanoma deaths,” he maintained. However, the U.S. National Cancer Institute’s position is that current evidence is inadequate and population-based screening has potential drawbacks such as overdiagnosis.

In the meantime, many opportunities to detect melanoma during routine medical care may be missed, according to Dr. Venna; for example, auscultating a patients’ heart or lungs without pulling up their shirt may miss truncal lesions. “Use every opportunity to screen the patient – that’s opportunistic screening,” he recommended.

He also endorsed listening to patients’ concerns and balancing their requests with judicious removal of lesions, as a large share of melanomas are self-detected. In one study of note, 9 of 166 lesions removed and found to be melanoma were removed only to reassure the patient (Arch Dermatol. 2005;141:434-8).

Barriers to and imperatives for early detection

Data suggest that access to specialist care is problematic for the early detection of melanoma. In a survey of dermatologists, the median wait time for an appointment was 8 days for botulinum toxin type A (Botox) injections, compared with 26 days for evaluation of a suspicious mole (J Am Acad Dermatol. 2007;57:985-9).

“The concern of course is a delay in diagnosis and the fact that the nondermatologists will have an opportunity likely to capture melanoma before we do,” Dr. Venna commented.

Imperatives for early detection include not only better outcomes but also reduced costs, given the hefty price tag of novel targeted therapies being used to treat advanced disease, he noted.

A recent phase III trial found that progression-free survival in advanced melanoma was roughly two to four times longer with the combination of the targeted agents nivolumab (Opdivo) and ipilimumab (Yervoy) than with either agent alone (ASCO 2015, Abstract LBA1). But a discussion touching on costs noted that for the average-weight American, this combination would run about $300,000 annually (ASCO 2015, Saltz L).

Risk and protective factors

New data have implicated medications used to treat erectile dysfunction (ED) as a risk factor for melanoma, raising concern given their widespread use, Dr. Venna said.

A cohort study found that melanoma risk was 84% higher with recent use of sildenafil (Viagra) and 92% higher with ever use (JAMA Intern Med. 2014;174:964-70). But the absolute number of excess cases was fairly small.

A case-control study looking at all types of ED drugs found that receipt of a single prescription was associated with a 32% higher risk of melanoma (JAMA. 2015;313:2449-55). Use increased risk of in situ and stage I melanoma, but not more advanced disease. There was no difference between short- and long-acting agents.

“Prospective studies with clearly defined inclusions and exclusions are needed, with dosing in particular,” Dr. Venna summed up. “There appears to be a modest association, but it certainly is not enough to call for widespread discontinuation. In the patients who are on these drugs, it’s good to document [use] until we have more clarity about the biologic effects of this ultimately.”

A study using dietary surveys and having an average follow-up of more than a decade showed that coffee drinkers had a 20% lower risk of melanoma relative to nondrinkers (J Natl Cancer Inst. 2015 Jan 20;107(2)). But benefit was significant only among the subset drinking at least 4 cups a day.

“It’s premature to advise coffee intake based on this paper, although it does build upon an earlier Norwegian study from the 1990s which showed a similar trend,” Dr. Venna said. “At the end of the day, these data are intriguing, but obviously there are a lot of side effects of trying to consume 4 cups of coffee a day, so further study is certainly warranted.”

Dr. Venna disclosed that he had no relevant conflicts of interest.

SEATTLE – A new biomarker for bronchial epithelium that helps identify smokers with suspicious lesions who have lung cancer is now ready for clinical use. And one for nasal epithelium that could be used for screening may not be far behind.

“There is clearly a critical unmet need to develop molecular biomarkers to address some of the challenges that we now face since we have instituted CT screening for lung cancer,” Dr. Avi Spira said at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Although the National Lung Screening Trial established that annual chest CT among high-risk current and former smokers reduces their risk of death from lung cancer (N Engl J Med. 2011;365:395-409), the vast majority of those who screen positive do not have lung cancer. Also, screening only patients who meet criteria set by the trial will pick up less than half of all lung cancers in the United States.

“That leads to two critical unmet needs for molecular biomarkers in the so-called post–National Lung Screening Trial era,” said Dr. Spira, professor of medicine, pathology and laboratory medicine, and bioinformatics; chief of the division of computational biomedicine; and director of the translational bioinformatics program, Clinical and Translational Science Institute, all at Boston University.

“The first is … we desperately need molecular biomarkers that can distinguish a benign nodule found on CT versus a malignant one,” he said. “The second and arguably longer-term biomarker that we need is to distinguish which smokers would benefit from CT screening annually.”

Much of his team’s research in this area builds on the concept of field of injury. “The idea here is if you smoke, even though lung cancer tends to develop deep within the parenchyma of your lung, all of the epithelial cells that line your respiratory tract have genomic alterations that reflect the presence of that cancer,” Dr. Spira explained. Thus, profiling epithelial cells anywhere in the airway could be used for early detection and risk assessment.

He and his colleagues developed a 23-gene signature for use on bronchial epithelial cells. The biomarker was validated in the Airway Epithelium Gene Expression In the Diagnosis of Lung Cancer (AEGIS) 1 and 2 trials among 639 current and former smokers undergoing bronchoscopy for suspicious nodules seen on CT.

With 1 year of follow-up, biomarker sensitivity was 88%-89%, while specificity was 47% (N Engl J Med. 2015;373:243-251). “However the negative predictive value, which is really what drives the clinical utility of this test, is above 90%. And that’s what we believe will drive physicians to use the test – [determining] who can they avoid sending for an unnecessary [biopsy] procedure,” Dr. Spira said. Bronchoscopy alone had sensitivity of about 75%, but bronchoscopy combined with the gene signature had sensitivity of 97%.

Subgroup analyses showed the biomarker had superior sensitivity for detecting lung cancer when lesions measured no more than 3 cm or were located in the lung periphery, and when patients had early-stage disease. In addition, it performed similarly well across different types of tumors.

Of special note, among patients whose pretest probability of cancer fell in the intermediate range (10%-60%), bronchoscopy had an 83% nondiagnostic rate, but the biomarker had 88% sensitivity and a 91% negative predictive value. “That means if you have a nondiagnostic bronchoscopy in a patient who is at intermediate pretest risk for disease, a negative gene expression test would mean there is a less than 10% chance this is cancer. That’s where a physician might feel, okay, I don’t have to go on and do a biopsy, I can watch that patient serially with CT scans of the chest,” Dr. Spira said.

The biomarker test is now clinically available (Percepta, manufactured by Veracyte). “I think it’s exciting because it’s the first of what I believe are many molecular biomarkers that are going to be emerging in the clinical space for the early detection of lung cancer,” he said.

“The multimillion dollar question is why are we seeing gene expression changes in normal-appearing cells so far away from where the tumor arises? We don’t have the full answer to that yet, but based on the genes that are changing, we have developed some hypotheses,” Dr. Spira said.

Some of the down-regulated genes are involved in antioxidant and DNA repair pathways, suggesting that the smokers who ultimately get cancer have less of a protective response to smoking. And some of the up-regulated genes include ones in the PI3 kinase signaling pathway.

“I would argue that what we are seeing in the proximal airway isn’t necessarily reflecting the presence of the cancer but the susceptibility, and that’s a really important distinguishing factor because then perhaps the test could be used as a screening tool,” Dr. Spira maintained.

As not all smokers at elevated risk for lung cancer will undergo bronchoscopy, one of the investigators’ future goals is to move biomarker testing to a less invasive site. They are currently focusing on the nose, using nasal epithelium collected by brushings from the inferior turbinate.

An analysis of nasal epithelium collected at the time of bronchoscopy in the AEGIS trials has shown that a 200-gene signature performs well for distinguishing between patients with and without lung cancer, Dr. Spira reported. Furthermore, the changes in gene expression profile in the nose were similar to those seen in the bronchus.

Such a biomarker might have best clinical utility in two other settings, he proposed. The first would be in patients having nodules that are clearly not accessible by bronchoscopy, in which case the biomarker would be applied for diagnosis. The second would be in smokers being seen for routine annual exams, in which case it would be used to identify those who should have CT surveillance.

“We are hopeful that the nasal epithelium can serve as a less invasive surrogate for the bronchus and ultimately allow us to move airway profiling into the screening setting for lung cancer in the longer term,” he concluded.

Dr. Spira disclosed that he receives intellectual property rights and consulting fees from, and has an ownership interest in, Veracyte Inc.

SEATTLE – A new biomarker for bronchial epithelium that helps identify smokers with suspicious lesions who have lung cancer is now ready for clinical use. And one for nasal epithelium that could be used for screening may not be far behind.

“There is clearly a critical unmet need to develop molecular biomarkers to address some of the challenges that we now face since we have instituted CT screening for lung cancer,” Dr. Avi Spira said at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Although the National Lung Screening Trial established that annual chest CT among high-risk current and former smokers reduces their risk of death from lung cancer (N Engl J Med. 2011;365:395-409), the vast majority of those who screen positive do not have lung cancer. Also, screening only patients who meet criteria set by the trial will pick up less than half of all lung cancers in the United States.

“That leads to two critical unmet needs for molecular biomarkers in the so-called post–National Lung Screening Trial era,” said Dr. Spira, professor of medicine, pathology and laboratory medicine, and bioinformatics; chief of the division of computational biomedicine; and director of the translational bioinformatics program, Clinical and Translational Science Institute, all at Boston University.

“The first is … we desperately need molecular biomarkers that can distinguish a benign nodule found on CT versus a malignant one,” he said. “The second and arguably longer-term biomarker that we need is to distinguish which smokers would benefit from CT screening annually.”

Much of his team’s research in this area builds on the concept of field of injury. “The idea here is if you smoke, even though lung cancer tends to develop deep within the parenchyma of your lung, all of the epithelial cells that line your respiratory tract have genomic alterations that reflect the presence of that cancer,” Dr. Spira explained. Thus, profiling epithelial cells anywhere in the airway could be used for early detection and risk assessment.

He and his colleagues developed a 23-gene signature for use on bronchial epithelial cells. The biomarker was validated in the Airway Epithelium Gene Expression In the Diagnosis of Lung Cancer (AEGIS) 1 and 2 trials among 639 current and former smokers undergoing bronchoscopy for suspicious nodules seen on CT.

With 1 year of follow-up, biomarker sensitivity was 88%-89%, while specificity was 47% (N Engl J Med. 2015;373:243-251). “However the negative predictive value, which is really what drives the clinical utility of this test, is above 90%. And that’s what we believe will drive physicians to use the test – [determining] who can they avoid sending for an unnecessary [biopsy] procedure,” Dr. Spira said. Bronchoscopy alone had sensitivity of about 75%, but bronchoscopy combined with the gene signature had sensitivity of 97%.

Subgroup analyses showed the biomarker had superior sensitivity for detecting lung cancer when lesions measured no more than 3 cm or were located in the lung periphery, and when patients had early-stage disease. In addition, it performed similarly well across different types of tumors.

Of special note, among patients whose pretest probability of cancer fell in the intermediate range (10%-60%), bronchoscopy had an 83% nondiagnostic rate, but the biomarker had 88% sensitivity and a 91% negative predictive value. “That means if you have a nondiagnostic bronchoscopy in a patient who is at intermediate pretest risk for disease, a negative gene expression test would mean there is a less than 10% chance this is cancer. That’s where a physician might feel, okay, I don’t have to go on and do a biopsy, I can watch that patient serially with CT scans of the chest,” Dr. Spira said.

The biomarker test is now clinically available (Percepta, manufactured by Veracyte). “I think it’s exciting because it’s the first of what I believe are many molecular biomarkers that are going to be emerging in the clinical space for the early detection of lung cancer,” he said.

“The multimillion dollar question is why are we seeing gene expression changes in normal-appearing cells so far away from where the tumor arises? We don’t have the full answer to that yet, but based on the genes that are changing, we have developed some hypotheses,” Dr. Spira said.

Some of the down-regulated genes are involved in antioxidant and DNA repair pathways, suggesting that the smokers who ultimately get cancer have less of a protective response to smoking. And some of the up-regulated genes include ones in the PI3 kinase signaling pathway.

“I would argue that what we are seeing in the proximal airway isn’t necessarily reflecting the presence of the cancer but the susceptibility, and that’s a really important distinguishing factor because then perhaps the test could be used as a screening tool,” Dr. Spira maintained.

As not all smokers at elevated risk for lung cancer will undergo bronchoscopy, one of the investigators’ future goals is to move biomarker testing to a less invasive site. They are currently focusing on the nose, using nasal epithelium collected by brushings from the inferior turbinate.

An analysis of nasal epithelium collected at the time of bronchoscopy in the AEGIS trials has shown that a 200-gene signature performs well for distinguishing between patients with and without lung cancer, Dr. Spira reported. Furthermore, the changes in gene expression profile in the nose were similar to those seen in the bronchus.

Such a biomarker might have best clinical utility in two other settings, he proposed. The first would be in patients having nodules that are clearly not accessible by bronchoscopy, in which case the biomarker would be applied for diagnosis. The second would be in smokers being seen for routine annual exams, in which case it would be used to identify those who should have CT surveillance.

“We are hopeful that the nasal epithelium can serve as a less invasive surrogate for the bronchus and ultimately allow us to move airway profiling into the screening setting for lung cancer in the longer term,” he concluded.

Dr. Spira disclosed that he receives intellectual property rights and consulting fees from, and has an ownership interest in, Veracyte Inc.

SEATTLE – A new biomarker for bronchial epithelium that helps identify smokers with suspicious lesions who have lung cancer is now ready for clinical use. And one for nasal epithelium that could be used for screening may not be far behind.

“There is clearly a critical unmet need to develop molecular biomarkers to address some of the challenges that we now face since we have instituted CT screening for lung cancer,” Dr. Avi Spira said at a joint meeting of the Global Biomarkers Consortium and World Cutaneous Malignancies Congress.

Although the National Lung Screening Trial established that annual chest CT among high-risk current and former smokers reduces their risk of death from lung cancer (N Engl J Med. 2011;365:395-409), the vast majority of those who screen positive do not have lung cancer. Also, screening only patients who meet criteria set by the trial will pick up less than half of all lung cancers in the United States.

“That leads to two critical unmet needs for molecular biomarkers in the so-called post–National Lung Screening Trial era,” said Dr. Spira, professor of medicine, pathology and laboratory medicine, and bioinformatics; chief of the division of computational biomedicine; and director of the translational bioinformatics program, Clinical and Translational Science Institute, all at Boston University.

“The first is … we desperately need molecular biomarkers that can distinguish a benign nodule found on CT versus a malignant one,” he said. “The second and arguably longer-term biomarker that we need is to distinguish which smokers would benefit from CT screening annually.”

Much of his team’s research in this area builds on the concept of field of injury. “The idea here is if you smoke, even though lung cancer tends to develop deep within the parenchyma of your lung, all of the epithelial cells that line your respiratory tract have genomic alterations that reflect the presence of that cancer,” Dr. Spira explained. Thus, profiling epithelial cells anywhere in the airway could be used for early detection and risk assessment.

He and his colleagues developed a 23-gene signature for use on bronchial epithelial cells. The biomarker was validated in the Airway Epithelium Gene Expression In the Diagnosis of Lung Cancer (AEGIS) 1 and 2 trials among 639 current and former smokers undergoing bronchoscopy for suspicious nodules seen on CT.

With 1 year of follow-up, biomarker sensitivity was 88%-89%, while specificity was 47% (N Engl J Med. 2015;373:243-251). “However the negative predictive value, which is really what drives the clinical utility of this test, is above 90%. And that’s what we believe will drive physicians to use the test – [determining] who can they avoid sending for an unnecessary [biopsy] procedure,” Dr. Spira said. Bronchoscopy alone had sensitivity of about 75%, but bronchoscopy combined with the gene signature had sensitivity of 97%.

Subgroup analyses showed the biomarker had superior sensitivity for detecting lung cancer when lesions measured no more than 3 cm or were located in the lung periphery, and when patients had early-stage disease. In addition, it performed similarly well across different types of tumors.

Of special note, among patients whose pretest probability of cancer fell in the intermediate range (10%-60%), bronchoscopy had an 83% nondiagnostic rate, but the biomarker had 88% sensitivity and a 91% negative predictive value. “That means if you have a nondiagnostic bronchoscopy in a patient who is at intermediate pretest risk for disease, a negative gene expression test would mean there is a less than 10% chance this is cancer. That’s where a physician might feel, okay, I don’t have to go on and do a biopsy, I can watch that patient serially with CT scans of the chest,” Dr. Spira said.

The biomarker test is now clinically available (Percepta, manufactured by Veracyte). “I think it’s exciting because it’s the first of what I believe are many molecular biomarkers that are going to be emerging in the clinical space for the early detection of lung cancer,” he said.

“The multimillion dollar question is why are we seeing gene expression changes in normal-appearing cells so far away from where the tumor arises? We don’t have the full answer to that yet, but based on the genes that are changing, we have developed some hypotheses,” Dr. Spira said.

Some of the down-regulated genes are involved in antioxidant and DNA repair pathways, suggesting that the smokers who ultimately get cancer have less of a protective response to smoking. And some of the up-regulated genes include ones in the PI3 kinase signaling pathway.

“I would argue that what we are seeing in the proximal airway isn’t necessarily reflecting the presence of the cancer but the susceptibility, and that’s a really important distinguishing factor because then perhaps the test could be used as a screening tool,” Dr. Spira maintained.

As not all smokers at elevated risk for lung cancer will undergo bronchoscopy, one of the investigators’ future goals is to move biomarker testing to a less invasive site. They are currently focusing on the nose, using nasal epithelium collected by brushings from the inferior turbinate.

An analysis of nasal epithelium collected at the time of bronchoscopy in the AEGIS trials has shown that a 200-gene signature performs well for distinguishing between patients with and without lung cancer, Dr. Spira reported. Furthermore, the changes in gene expression profile in the nose were similar to those seen in the bronchus.

Such a biomarker might have best clinical utility in two other settings, he proposed. The first would be in patients having nodules that are clearly not accessible by bronchoscopy, in which case the biomarker would be applied for diagnosis. The second would be in smokers being seen for routine annual exams, in which case it would be used to identify those who should have CT surveillance.

“We are hopeful that the nasal epithelium can serve as a less invasive surrogate for the bronchus and ultimately allow us to move airway profiling into the screening setting for lung cancer in the longer term,” he concluded.

Dr. Spira disclosed that he receives intellectual property rights and consulting fees from, and has an ownership interest in, Veracyte Inc.

SEATTLE – When it comes to managing osteoarthritis, clinicians can use their interactions with patients to tap into a powerful placebo effect, according to Dr. Paul Dieppe, a professor of health and well-being at the University of Exeter, England.

“I am particularly excited to have the opportunity to talk to you about a phenomenology that I think is amongst the most important within medicine and an area that those of us interested in osteoarthritis could really exploit,” he said at the World Congress on Osteoarthritis. “We don’t have a treatment that’s better than placebo, so let’s use placebo.”

In the clinical trial context, the placebo effect – the response seen from giving a sham or dummy treatment, or in essence, doing nothing – has an effect size of about 0.5 for alleviating pain and stiffness from osteoarthritis (Ann. Rheum. Dis. 2008;67:1716-23). “That’s an effect size which is quite a lot bigger than the effect size of most of the standard interventions that we use, be they drug therapy, physical therapy, whatever. It’s not as big as joint replacement, although there we don’t have the appropriate data. But it is bigger than pretty much everything else. So ‘nothing’ is efficacious,” Dr. Dieppe commented.

On the other hand, effectiveness in the real-world setting is unknown and would require large pragmatic trials or Big Data analyses using registries. “But I think the effectiveness of ‘nothing’ is much, much greater than its efficacy in the very artificial circumstance of a clinical trial,” he said, a viewpoint based on his experience both as a clinician and as a patient with knee osteoarthritis.

“I prefer to call [the placebo effect] a healing response, and I’m not trying to be provocative using that term because I think we do have innate healing abilities in our bodies. I think that’s an evolutionary demand, and good interactions can activate that,” Dr. Dieppe maintained.

Compelling evidence suggests that healing does indeed work (Explore [NY] 2015;11:11-23). “We think that it’s mediated by focused attention with good intention of sensitive people,” he said. “Maybe that’s what a lot of you as therapists are actually doing. Maybe that is the basis of much of what we call the placebo effect.”

Clinicians should also be aware of the nocebo effect, what Dr. Dieppe referred to as the placebo effect’s evil twin, as it can negatively influence outcomes and is stronger (Am. J. Med. 2015;128:126-9). “The fact is that doing nothing ... can and often does make our patients much worse. This is most likely to occur when one or both people in a consultation are feeling unsafe or anxious. ... A lot of what we do in modern health care seems designed to make people anxious and to make them worse,” he elaborated at the meeting, which was sponsored by the Osteoarthritis Research Society International.

Many of the leading theories about the placebo and nocebo effects postulate that they relate to factors such as expectations or the release or blockage of natural endorphins. “These theories are basically saying that this is all about what’s going on in the brain of the patient,” Dr. Dieppe commented. “I think that’s wrong. ... It’s missing the point, completely, because the point is that this is about the quality of interactions between individuals. We are social beings, we are evolved as social beings, and our social interactions control a lot of what happens to us, not only psychologically but physiologically.”

He pointed to theories that instead focus on interactions, such as one pertaining to the concept of validation and invalidation (J. Clin. Psychol. 2006;62:459-80). “This theory goes beyond empathy and compassion, which are the usual sort of things evoked in this context, because you can be empathic and compassionate as much as you like, but if the patient in front of you doesn’t know you are being empathic or compassionate, then it’s no use at all. So validation, invalidation is more about have you successfully communicated that empathy and compassion to the other person or not. If you have, the person feels validated, they feel you genuinely do understand them, and you do genuinely care about them. If they are invalidated, they feel you haven’t understood them, and you don’t really care.” He added, “It depends very much on your behavior, as much as on what you say. Communication specialists tell us that 80% of communication to people is nonverbal.”

Another relevant theory here is the polyvagal theory of social interaction, which proposes that in addition to being hardwired for a fight or flight response, the autonomic nervous system is hardwired for a nurturing response (Cleve. Clin. J. Med. 2009;76 Suppl 2:S86-S90). Activation of this response has a calming physiologic effect and influences how messages are heard. “This nurturing response … is linked to communication strategies, so that you have to feel safe to be able to communicate well with another person,” Dr. Dieppe noted.

Taken together, these theories on interactions help explain “how we can make people better, how we can make people worse with ‘nothing,’ ” he maintained. “Of course, it’s not nothing – it’s the totality of our behavior with another person, and it’s crucial. And it can, in extreme cases, positively activate the innate healing response, or it can, as we often do sadly in clinical practice, activate an invalidation, fight-or-flight response, and make everything a lot worse.”

“There are colossal implications about how we behave when we are with patients,” Dr. Dieppe concluded. “I think basically, it’s just about our ability to be present for another human being in a nonjudgmental way. And that’s difficult, but that’s what we need to be able to do.”

SEATTLE – When it comes to managing osteoarthritis, clinicians can use their interactions with patients to tap into a powerful placebo effect, according to Dr. Paul Dieppe, a professor of health and well-being at the University of Exeter, England.

“I am particularly excited to have the opportunity to talk to you about a phenomenology that I think is amongst the most important within medicine and an area that those of us interested in osteoarthritis could really exploit,” he said at the World Congress on Osteoarthritis. “We don’t have a treatment that’s better than placebo, so let’s use placebo.”

In the clinical trial context, the placebo effect – the response seen from giving a sham or dummy treatment, or in essence, doing nothing – has an effect size of about 0.5 for alleviating pain and stiffness from osteoarthritis (Ann. Rheum. Dis. 2008;67:1716-23). “That’s an effect size which is quite a lot bigger than the effect size of most of the standard interventions that we use, be they drug therapy, physical therapy, whatever. It’s not as big as joint replacement, although there we don’t have the appropriate data. But it is bigger than pretty much everything else. So ‘nothing’ is efficacious,” Dr. Dieppe commented.

On the other hand, effectiveness in the real-world setting is unknown and would require large pragmatic trials or Big Data analyses using registries. “But I think the effectiveness of ‘nothing’ is much, much greater than its efficacy in the very artificial circumstance of a clinical trial,” he said, a viewpoint based on his experience both as a clinician and as a patient with knee osteoarthritis.

“I prefer to call [the placebo effect] a healing response, and I’m not trying to be provocative using that term because I think we do have innate healing abilities in our bodies. I think that’s an evolutionary demand, and good interactions can activate that,” Dr. Dieppe maintained.

Compelling evidence suggests that healing does indeed work (Explore [NY] 2015;11:11-23). “We think that it’s mediated by focused attention with good intention of sensitive people,” he said. “Maybe that’s what a lot of you as therapists are actually doing. Maybe that is the basis of much of what we call the placebo effect.”

Clinicians should also be aware of the nocebo effect, what Dr. Dieppe referred to as the placebo effect’s evil twin, as it can negatively influence outcomes and is stronger (Am. J. Med. 2015;128:126-9). “The fact is that doing nothing ... can and often does make our patients much worse. This is most likely to occur when one or both people in a consultation are feeling unsafe or anxious. ... A lot of what we do in modern health care seems designed to make people anxious and to make them worse,” he elaborated at the meeting, which was sponsored by the Osteoarthritis Research Society International.

Many of the leading theories about the placebo and nocebo effects postulate that they relate to factors such as expectations or the release or blockage of natural endorphins. “These theories are basically saying that this is all about what’s going on in the brain of the patient,” Dr. Dieppe commented. “I think that’s wrong. ... It’s missing the point, completely, because the point is that this is about the quality of interactions between individuals. We are social beings, we are evolved as social beings, and our social interactions control a lot of what happens to us, not only psychologically but physiologically.”

He pointed to theories that instead focus on interactions, such as one pertaining to the concept of validation and invalidation (J. Clin. Psychol. 2006;62:459-80). “This theory goes beyond empathy and compassion, which are the usual sort of things evoked in this context, because you can be empathic and compassionate as much as you like, but if the patient in front of you doesn’t know you are being empathic or compassionate, then it’s no use at all. So validation, invalidation is more about have you successfully communicated that empathy and compassion to the other person or not. If you have, the person feels validated, they feel you genuinely do understand them, and you do genuinely care about them. If they are invalidated, they feel you haven’t understood them, and you don’t really care.” He added, “It depends very much on your behavior, as much as on what you say. Communication specialists tell us that 80% of communication to people is nonverbal.”

Another relevant theory here is the polyvagal theory of social interaction, which proposes that in addition to being hardwired for a fight or flight response, the autonomic nervous system is hardwired for a nurturing response (Cleve. Clin. J. Med. 2009;76 Suppl 2:S86-S90). Activation of this response has a calming physiologic effect and influences how messages are heard. “This nurturing response … is linked to communication strategies, so that you have to feel safe to be able to communicate well with another person,” Dr. Dieppe noted.

Taken together, these theories on interactions help explain “how we can make people better, how we can make people worse with ‘nothing,’ ” he maintained. “Of course, it’s not nothing – it’s the totality of our behavior with another person, and it’s crucial. And it can, in extreme cases, positively activate the innate healing response, or it can, as we often do sadly in clinical practice, activate an invalidation, fight-or-flight response, and make everything a lot worse.”

“There are colossal implications about how we behave when we are with patients,” Dr. Dieppe concluded. “I think basically, it’s just about our ability to be present for another human being in a nonjudgmental way. And that’s difficult, but that’s what we need to be able to do.”

SEATTLE – When it comes to managing osteoarthritis, clinicians can use their interactions with patients to tap into a powerful placebo effect, according to Dr. Paul Dieppe, a professor of health and well-being at the University of Exeter, England.

“I am particularly excited to have the opportunity to talk to you about a phenomenology that I think is amongst the most important within medicine and an area that those of us interested in osteoarthritis could really exploit,” he said at the World Congress on Osteoarthritis. “We don’t have a treatment that’s better than placebo, so let’s use placebo.”

In the clinical trial context, the placebo effect – the response seen from giving a sham or dummy treatment, or in essence, doing nothing – has an effect size of about 0.5 for alleviating pain and stiffness from osteoarthritis (Ann. Rheum. Dis. 2008;67:1716-23). “That’s an effect size which is quite a lot bigger than the effect size of most of the standard interventions that we use, be they drug therapy, physical therapy, whatever. It’s not as big as joint replacement, although there we don’t have the appropriate data. But it is bigger than pretty much everything else. So ‘nothing’ is efficacious,” Dr. Dieppe commented.

On the other hand, effectiveness in the real-world setting is unknown and would require large pragmatic trials or Big Data analyses using registries. “But I think the effectiveness of ‘nothing’ is much, much greater than its efficacy in the very artificial circumstance of a clinical trial,” he said, a viewpoint based on his experience both as a clinician and as a patient with knee osteoarthritis.

“I prefer to call [the placebo effect] a healing response, and I’m not trying to be provocative using that term because I think we do have innate healing abilities in our bodies. I think that’s an evolutionary demand, and good interactions can activate that,” Dr. Dieppe maintained.

Compelling evidence suggests that healing does indeed work (Explore [NY] 2015;11:11-23). “We think that it’s mediated by focused attention with good intention of sensitive people,” he said. “Maybe that’s what a lot of you as therapists are actually doing. Maybe that is the basis of much of what we call the placebo effect.”

Clinicians should also be aware of the nocebo effect, what Dr. Dieppe referred to as the placebo effect’s evil twin, as it can negatively influence outcomes and is stronger (Am. J. Med. 2015;128:126-9). “The fact is that doing nothing ... can and often does make our patients much worse. This is most likely to occur when one or both people in a consultation are feeling unsafe or anxious. ... A lot of what we do in modern health care seems designed to make people anxious and to make them worse,” he elaborated at the meeting, which was sponsored by the Osteoarthritis Research Society International.

Many of the leading theories about the placebo and nocebo effects postulate that they relate to factors such as expectations or the release or blockage of natural endorphins. “These theories are basically saying that this is all about what’s going on in the brain of the patient,” Dr. Dieppe commented. “I think that’s wrong. ... It’s missing the point, completely, because the point is that this is about the quality of interactions between individuals. We are social beings, we are evolved as social beings, and our social interactions control a lot of what happens to us, not only psychologically but physiologically.”

He pointed to theories that instead focus on interactions, such as one pertaining to the concept of validation and invalidation (J. Clin. Psychol. 2006;62:459-80). “This theory goes beyond empathy and compassion, which are the usual sort of things evoked in this context, because you can be empathic and compassionate as much as you like, but if the patient in front of you doesn’t know you are being empathic or compassionate, then it’s no use at all. So validation, invalidation is more about have you successfully communicated that empathy and compassion to the other person or not. If you have, the person feels validated, they feel you genuinely do understand them, and you do genuinely care about them. If they are invalidated, they feel you haven’t understood them, and you don’t really care.” He added, “It depends very much on your behavior, as much as on what you say. Communication specialists tell us that 80% of communication to people is nonverbal.”

Another relevant theory here is the polyvagal theory of social interaction, which proposes that in addition to being hardwired for a fight or flight response, the autonomic nervous system is hardwired for a nurturing response (Cleve. Clin. J. Med. 2009;76 Suppl 2:S86-S90). Activation of this response has a calming physiologic effect and influences how messages are heard. “This nurturing response … is linked to communication strategies, so that you have to feel safe to be able to communicate well with another person,” Dr. Dieppe noted.

Taken together, these theories on interactions help explain “how we can make people better, how we can make people worse with ‘nothing,’ ” he maintained. “Of course, it’s not nothing – it’s the totality of our behavior with another person, and it’s crucial. And it can, in extreme cases, positively activate the innate healing response, or it can, as we often do sadly in clinical practice, activate an invalidation, fight-or-flight response, and make everything a lot worse.”

“There are colossal implications about how we behave when we are with patients,” Dr. Dieppe concluded. “I think basically, it’s just about our ability to be present for another human being in a nonjudgmental way. And that’s difficult, but that’s what we need to be able to do.”