AVAHO

Some smokers might not get lung cancer because of their DNA, researchers report in a new study.

These people have genes that help limit mutations to DNA that would turn cells malignant and make them grow into tumors, the researchers say.

Scientists have long suspected that smoking leads to lung cancer by triggering DNA mutations in healthy cells. But it was hard for them to identify the mutations in healthy cells that might help predict future cancer risk, Jan Vijg, PhD, a senior author of the study and researcher at the University School of Medicine, Shanghai, China, said in a statement.

His team used a process called single-cell whole genome sequencing to examine cells lining the lungs of 19 smokers and 14 nonsmokers ranging in age from their pre-teens to their mid-80s. The cells came from patients who had tissue samples collected from their lungs during diagnostic testing unrelated to cancer. The scientists reported their findings in Nature Genetics.

The researchers specifically looked at cells lining the lungs because these cells can survive for years and build up mutations over time that are linked to aging and smoking.

“Of all the lung’s cell types, these are among the most likely to become cancerous,” says Simon Spivack, MD, a senior author of the study and professor at the Albert Einstein College of Medicine, New York.

Smokers had far more gene mutations that can cause lung cancer than nonsmokers, the analysis found.

“This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesized,” says Dr. Spivack. “This is likely one reason why so few nonsmokers get lung cancer, while 10 to 20 percent of lifelong smokers do.”

Among the smokers, people had smoked a maximum of 116 pack-years. A pack-year is the equivalent of smoking one pack a day for a year. The number of mutations detected in smokers’ lung cells increased in direct proportion to the number of pack-years they smoked.

But after 23 pack-years, the lung cells in smokers didn’t appear to add more mutations, the researchers report, suggesting that some people’s genes might make them more likely to fight mutations.

“The heaviest smokers did not have the highest mutation burden,” says Dr. Spivack. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation.”

While it’s possible these findings could one day help doctors come up with better ways to screen for lung cancer and treat the disease, that’s still a long way off. Many more lab tests and larger studies will be needed to better pinpoint which smokers might be more prone to lung cancer and why.

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

Some smokers might not get lung cancer because of their DNA, researchers report in a new study.

These people have genes that help limit mutations to DNA that would turn cells malignant and make them grow into tumors, the researchers say.

Scientists have long suspected that smoking leads to lung cancer by triggering DNA mutations in healthy cells. But it was hard for them to identify the mutations in healthy cells that might help predict future cancer risk, Jan Vijg, PhD, a senior author of the study and researcher at the University School of Medicine, Shanghai, China, said in a statement.

His team used a process called single-cell whole genome sequencing to examine cells lining the lungs of 19 smokers and 14 nonsmokers ranging in age from their pre-teens to their mid-80s. The cells came from patients who had tissue samples collected from their lungs during diagnostic testing unrelated to cancer. The scientists reported their findings in Nature Genetics.

The researchers specifically looked at cells lining the lungs because these cells can survive for years and build up mutations over time that are linked to aging and smoking.

“Of all the lung’s cell types, these are among the most likely to become cancerous,” says Simon Spivack, MD, a senior author of the study and professor at the Albert Einstein College of Medicine, New York.

Smokers had far more gene mutations that can cause lung cancer than nonsmokers, the analysis found.

“This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesized,” says Dr. Spivack. “This is likely one reason why so few nonsmokers get lung cancer, while 10 to 20 percent of lifelong smokers do.”

Among the smokers, people had smoked a maximum of 116 pack-years. A pack-year is the equivalent of smoking one pack a day for a year. The number of mutations detected in smokers’ lung cells increased in direct proportion to the number of pack-years they smoked.

But after 23 pack-years, the lung cells in smokers didn’t appear to add more mutations, the researchers report, suggesting that some people’s genes might make them more likely to fight mutations.

“The heaviest smokers did not have the highest mutation burden,” says Dr. Spivack. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation.”

While it’s possible these findings could one day help doctors come up with better ways to screen for lung cancer and treat the disease, that’s still a long way off. Many more lab tests and larger studies will be needed to better pinpoint which smokers might be more prone to lung cancer and why.

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

Some smokers might not get lung cancer because of their DNA, researchers report in a new study.

These people have genes that help limit mutations to DNA that would turn cells malignant and make them grow into tumors, the researchers say.

Scientists have long suspected that smoking leads to lung cancer by triggering DNA mutations in healthy cells. But it was hard for them to identify the mutations in healthy cells that might help predict future cancer risk, Jan Vijg, PhD, a senior author of the study and researcher at the University School of Medicine, Shanghai, China, said in a statement.

His team used a process called single-cell whole genome sequencing to examine cells lining the lungs of 19 smokers and 14 nonsmokers ranging in age from their pre-teens to their mid-80s. The cells came from patients who had tissue samples collected from their lungs during diagnostic testing unrelated to cancer. The scientists reported their findings in Nature Genetics.

The researchers specifically looked at cells lining the lungs because these cells can survive for years and build up mutations over time that are linked to aging and smoking.

“Of all the lung’s cell types, these are among the most likely to become cancerous,” says Simon Spivack, MD, a senior author of the study and professor at the Albert Einstein College of Medicine, New York.

Smokers had far more gene mutations that can cause lung cancer than nonsmokers, the analysis found.

“This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesized,” says Dr. Spivack. “This is likely one reason why so few nonsmokers get lung cancer, while 10 to 20 percent of lifelong smokers do.”

Among the smokers, people had smoked a maximum of 116 pack-years. A pack-year is the equivalent of smoking one pack a day for a year. The number of mutations detected in smokers’ lung cells increased in direct proportion to the number of pack-years they smoked.

But after 23 pack-years, the lung cells in smokers didn’t appear to add more mutations, the researchers report, suggesting that some people’s genes might make them more likely to fight mutations.

“The heaviest smokers did not have the highest mutation burden,” says Dr. Spivack. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation.”

While it’s possible these findings could one day help doctors come up with better ways to screen for lung cancer and treat the disease, that’s still a long way off. Many more lab tests and larger studies will be needed to better pinpoint which smokers might be more prone to lung cancer and why.

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

In states that adopted Medicaid expansion following the implementation of the Affordable Care Act (ACA), patients with cancer have improved 2-year overall survival rates, compared with patients in states that did not adopt the expansion.

The finding comes from an American Cancer Society study of more than 2 million patients with newly diagnosed cancer, published online in the Journal of the National Cancer Institute.

The analysis also showed that the evidence was strongest for malignancies with poor prognosis such as lung, pancreatic, and liver cancer, and also for colorectal cancer.

Importantly, improvements in survival were larger in non-Hispanic Black patients and individuals residing in rural areas, suggesting there was a narrowing of disparities in cancer survival by race and rurality.

“Our findings provide further evidence of the importance of expanding Medicaid eligibility in all states, particularly considering the economic crisis and health care disruptions caused by the COVID-19 pandemic,” said lead author Xuesong Han, PhD, scientific director of health services research at the American Cancer Society, in a statement. “What’s encouraging is the American Rescue Plan Act of 2021 provides new incentives for Medicaid expansion in states that have yet to increase eligibility.”

The ACA provided states with incentives to expand Medicaid eligibility to all low-income adults under 138% federal poverty level, regardless of parental status.

As of last month, just 12 states have not yet opted for Medicaid expansion, even though the American Rescue Plan Act of 2021 provides new incentives for those remaining jurisdictions. But to date, none of the remaining states have taken advantage of these new incentives.

An interactive map showing the status of Medicare expansion by state is available here. The 12 states that have not adopted Medicare expansion (as of April) are Alabama, Florida, Georgia, Kansas, Mississippi, North Carolina, South Carolina, South Dakota, Tennessee, Texas, Wisconsin, and Wyoming.  

The benefit of Medicaid expansion on cancer outcomes has already been observed in other studies. The first study to show a survival benefit was presented at the 2020 American Society of Clinical Oncology annual meeting. That analysis showed that cancer mortality declined by 29% in states that expanded Medicaid and by 25% in those that did not. The authors also noted that the greatest mortality benefit was observed in Hispanic patients.
 

Improved survival with expansion

In the current paper, Dr. Han and colleagues used population-based cancer registries from 42 states and compared data on patients aged 18-62 years who were diagnosed with cancer in a period of 2 years before (2010-2012) and after (2014-2016) ACA Medicaid expansion. They were followed through Sept. 30, 2013, and Dec. 31, 2017, respectively.

The analysis involved a total of 2.5 million patients, of whom 1.52 million lived in states that adopted Medicaid expansion and compared with 1 million patients were in states that did not.

Patients with grouped by sex, race and ethnicity, census tract-level poverty, and rurality. The authors note that non-Hispanic Black patients and those from high poverty areas and nonmetropolitan areas were disproportionately represented in nonexpansion states. 

During the 2-year follow-up period, a total of 453,487 deaths occurred (257,950 in expansion states and 195,537 in nonexpansion states).

Overall, patients in expansion states generally had better survival versus those in nonexpansion states, the authors comment. However, for most cancer types, overall survival improved after the ACA for both groups of states.

The 2-year overall survival increased from 80.6% before the ACA to 82.2% post ACA in expansion states and from 78.7% to 80% in nonexpansion states.

This extrapolated to net increase of 0.44 percentage points in expansion states after adjusting for sociodemographic factors. By cancer site, the net increase was greater for colorectal cancer, lung cancer, non-Hodgkin’s lymphoma, pancreatic cancer, and liver cancer.

For Hispanic patients, 2-year survival also increased but was similar in expansion and nonexpansion states, and little net change was associated with Medicaid expansion.

“Our study shows that the increase was largely driven by improvements in survival for cancer types with poor prognosis, suggesting improved access to timely and effective treatments,” said Dr. Han. “It adds to accumulating evidence of the multiple benefits of Medicaid expansion.”

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

In states that adopted Medicaid expansion following the implementation of the Affordable Care Act (ACA), patients with cancer have improved 2-year overall survival rates, compared with patients in states that did not adopt the expansion.

The finding comes from an American Cancer Society study of more than 2 million patients with newly diagnosed cancer, published online in the Journal of the National Cancer Institute.

The analysis also showed that the evidence was strongest for malignancies with poor prognosis such as lung, pancreatic, and liver cancer, and also for colorectal cancer.

Importantly, improvements in survival were larger in non-Hispanic Black patients and individuals residing in rural areas, suggesting there was a narrowing of disparities in cancer survival by race and rurality.

“Our findings provide further evidence of the importance of expanding Medicaid eligibility in all states, particularly considering the economic crisis and health care disruptions caused by the COVID-19 pandemic,” said lead author Xuesong Han, PhD, scientific director of health services research at the American Cancer Society, in a statement. “What’s encouraging is the American Rescue Plan Act of 2021 provides new incentives for Medicaid expansion in states that have yet to increase eligibility.”

The ACA provided states with incentives to expand Medicaid eligibility to all low-income adults under 138% federal poverty level, regardless of parental status.

As of last month, just 12 states have not yet opted for Medicaid expansion, even though the American Rescue Plan Act of 2021 provides new incentives for those remaining jurisdictions. But to date, none of the remaining states have taken advantage of these new incentives.

An interactive map showing the status of Medicare expansion by state is available here. The 12 states that have not adopted Medicare expansion (as of April) are Alabama, Florida, Georgia, Kansas, Mississippi, North Carolina, South Carolina, South Dakota, Tennessee, Texas, Wisconsin, and Wyoming.  

The benefit of Medicaid expansion on cancer outcomes has already been observed in other studies. The first study to show a survival benefit was presented at the 2020 American Society of Clinical Oncology annual meeting. That analysis showed that cancer mortality declined by 29% in states that expanded Medicaid and by 25% in those that did not. The authors also noted that the greatest mortality benefit was observed in Hispanic patients.
 

Improved survival with expansion

In the current paper, Dr. Han and colleagues used population-based cancer registries from 42 states and compared data on patients aged 18-62 years who were diagnosed with cancer in a period of 2 years before (2010-2012) and after (2014-2016) ACA Medicaid expansion. They were followed through Sept. 30, 2013, and Dec. 31, 2017, respectively.

The analysis involved a total of 2.5 million patients, of whom 1.52 million lived in states that adopted Medicaid expansion and compared with 1 million patients were in states that did not.

Patients with grouped by sex, race and ethnicity, census tract-level poverty, and rurality. The authors note that non-Hispanic Black patients and those from high poverty areas and nonmetropolitan areas were disproportionately represented in nonexpansion states. 

During the 2-year follow-up period, a total of 453,487 deaths occurred (257,950 in expansion states and 195,537 in nonexpansion states).

Overall, patients in expansion states generally had better survival versus those in nonexpansion states, the authors comment. However, for most cancer types, overall survival improved after the ACA for both groups of states.

The 2-year overall survival increased from 80.6% before the ACA to 82.2% post ACA in expansion states and from 78.7% to 80% in nonexpansion states.

This extrapolated to net increase of 0.44 percentage points in expansion states after adjusting for sociodemographic factors. By cancer site, the net increase was greater for colorectal cancer, lung cancer, non-Hodgkin’s lymphoma, pancreatic cancer, and liver cancer.

For Hispanic patients, 2-year survival also increased but was similar in expansion and nonexpansion states, and little net change was associated with Medicaid expansion.

“Our study shows that the increase was largely driven by improvements in survival for cancer types with poor prognosis, suggesting improved access to timely and effective treatments,” said Dr. Han. “It adds to accumulating evidence of the multiple benefits of Medicaid expansion.”

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

In states that adopted Medicaid expansion following the implementation of the Affordable Care Act (ACA), patients with cancer have improved 2-year overall survival rates, compared with patients in states that did not adopt the expansion.

The finding comes from an American Cancer Society study of more than 2 million patients with newly diagnosed cancer, published online in the Journal of the National Cancer Institute.

The analysis also showed that the evidence was strongest for malignancies with poor prognosis such as lung, pancreatic, and liver cancer, and also for colorectal cancer.

Importantly, improvements in survival were larger in non-Hispanic Black patients and individuals residing in rural areas, suggesting there was a narrowing of disparities in cancer survival by race and rurality.

“Our findings provide further evidence of the importance of expanding Medicaid eligibility in all states, particularly considering the economic crisis and health care disruptions caused by the COVID-19 pandemic,” said lead author Xuesong Han, PhD, scientific director of health services research at the American Cancer Society, in a statement. “What’s encouraging is the American Rescue Plan Act of 2021 provides new incentives for Medicaid expansion in states that have yet to increase eligibility.”

The ACA provided states with incentives to expand Medicaid eligibility to all low-income adults under 138% federal poverty level, regardless of parental status.

As of last month, just 12 states have not yet opted for Medicaid expansion, even though the American Rescue Plan Act of 2021 provides new incentives for those remaining jurisdictions. But to date, none of the remaining states have taken advantage of these new incentives.

An interactive map showing the status of Medicare expansion by state is available here. The 12 states that have not adopted Medicare expansion (as of April) are Alabama, Florida, Georgia, Kansas, Mississippi, North Carolina, South Carolina, South Dakota, Tennessee, Texas, Wisconsin, and Wyoming.  

The benefit of Medicaid expansion on cancer outcomes has already been observed in other studies. The first study to show a survival benefit was presented at the 2020 American Society of Clinical Oncology annual meeting. That analysis showed that cancer mortality declined by 29% in states that expanded Medicaid and by 25% in those that did not. The authors also noted that the greatest mortality benefit was observed in Hispanic patients.
 

Improved survival with expansion

In the current paper, Dr. Han and colleagues used population-based cancer registries from 42 states and compared data on patients aged 18-62 years who were diagnosed with cancer in a period of 2 years before (2010-2012) and after (2014-2016) ACA Medicaid expansion. They were followed through Sept. 30, 2013, and Dec. 31, 2017, respectively.

The analysis involved a total of 2.5 million patients, of whom 1.52 million lived in states that adopted Medicaid expansion and compared with 1 million patients were in states that did not.

Patients with grouped by sex, race and ethnicity, census tract-level poverty, and rurality. The authors note that non-Hispanic Black patients and those from high poverty areas and nonmetropolitan areas were disproportionately represented in nonexpansion states. 

During the 2-year follow-up period, a total of 453,487 deaths occurred (257,950 in expansion states and 195,537 in nonexpansion states).

Overall, patients in expansion states generally had better survival versus those in nonexpansion states, the authors comment. However, for most cancer types, overall survival improved after the ACA for both groups of states.

The 2-year overall survival increased from 80.6% before the ACA to 82.2% post ACA in expansion states and from 78.7% to 80% in nonexpansion states.

This extrapolated to net increase of 0.44 percentage points in expansion states after adjusting for sociodemographic factors. By cancer site, the net increase was greater for colorectal cancer, lung cancer, non-Hodgkin’s lymphoma, pancreatic cancer, and liver cancer.

For Hispanic patients, 2-year survival also increased but was similar in expansion and nonexpansion states, and little net change was associated with Medicaid expansion.

“Our study shows that the increase was largely driven by improvements in survival for cancer types with poor prognosis, suggesting improved access to timely and effective treatments,” said Dr. Han. “It adds to accumulating evidence of the multiple benefits of Medicaid expansion.”

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

Laparoscopic surgery can improve long-term overall survival (OS) compared with open surgery for patients with rectal cancer, according to findings from a large meta-analysis.

The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.

“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.

The article was published online in JAMA Network Open.

Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.

In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.

Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.

In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).

However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).

These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).

The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.

“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”

No outside funding source was noted. The authors have disclosed no relevant financial relationships.

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

Laparoscopic surgery can improve long-term overall survival (OS) compared with open surgery for patients with rectal cancer, according to findings from a large meta-analysis.

The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.

“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.

The article was published online in JAMA Network Open.

Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.

In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.

Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.

In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).

However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).

These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).

The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.

“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”

No outside funding source was noted. The authors have disclosed no relevant financial relationships.

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

Laparoscopic surgery can improve long-term overall survival (OS) compared with open surgery for patients with rectal cancer, according to findings from a large meta-analysis.

The estimated 5-year OS rate for patients who underwent laparoscopic surgery was 76.2%, vs. 72.7% for those who had open surgery.

“The survival benefit of laparoscopic surgery is encouraging and supports the routine use of laparoscopic surgery for adult patients with rectal cancer in the era of minimally invasive surgery,” wrote the authors, led by Leping Li, MD, of the department of gastrointestinal surgery, Shandong (China) Provincial Hospital.

The article was published online in JAMA Network Open.

Surgery is an essential component in treating rectal cancer, but the benefits of laparoscopic vs. open surgery are not clear. Over the past 15 years, randomized clinical trials (RCTs) have shown comparable long-term outcomes for laparoscopic and open surgery. However, in most meta-analyses that assessed the evidence more broadly, researchers used an “inappropriate” method for the pooled analysis. Dr. Li and colleagues wanted to perform their own meta-analysis to more definitively understand whether the evidence on long-term outcomes supports or opposes the use of laparoscopic surgery for rectal cancer.

In the current study, the authors conducted an individual participant data meta-analysis using time-to-event data and focused on the long-term survival outcomes after laparoscopic or open surgery for adult patients with rectal cancer.

Ten articles involving 12 RCTs and 3,709 participants were included. In these, 2,097 patients were randomly assigned to undergo laparoscopic surgery, and 1,612 were randomly assigned to undergo open surgery. The studies covered a global population, with participants from Europe, North America, and East Asia.

In a one-stage analysis, the authors found that disease-free survival was slightly better among patients who underwent laparoscopic surgery, but the results were statistically similar (hazard ratio [HR], 0.92; P = .26).

However, when it came to OS, those who had undergone laparoscopic surgery fared significantly better (HR, 0.85; P = .02).

These results held up in the two-stage analysis for both disease-free survival (HR, 0.92; P = .25) and OS (HR, 0.85; P = .02). A sensitivity analyses conducted with large RCTs yielded similar pooled effect sizes for disease-free survival (HR, 0.91; P = .20) and OS (HR, 0.84; P = .03).

The authors highlighted several reasons why laparoscopic surgery may be associated with better survival. First, the faster recovery from the minimally invasive procedure could allow patients to begin adjuvant therapy earlier. In addition, the reduced stress responses and higher levels of immune function among patients undergoing minimally invasive surgery may contribute to a long-term survival advantage.

“These findings address concerns regarding the effectiveness of laparoscopic surgery,” the authors wrote. However, “further studies are necessary to explore the specific mechanisms underlying the positive effect of laparoscopic surgery on OS.”

No outside funding source was noted. The authors have disclosed no relevant financial relationships.

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

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

Infertile men may be twice as likely to develop invasive breast cancer as those without fertility issues, according to new research funded by the charity Breast Cancer Now and published in Breast Cancer Research. The study is one of the largest ever into male breast cancer, enabling the team to show a highly statistically significant association.  

A link with infertility had been suspected, since parity markedly reduces the risk of female breast cancer; there are known genetic links in both sexes, and a high risk of both breast cancer and infertility among men with Klinefelter syndrome, suggesting some sex hormone-related involvement. However, the rarity of breast cancer in men – with an annual incidence of about 370 cases and 80 deaths per year in the United Kingdom – meant that past studies were necessarily small and yielded mixed results.

“Compared with previous studies, our study of male breast cancer is large,” said study coauthor Michael Jones, PhD, of the division of genetics and epidemiology at the Institute of Cancer Research (ICR) in London. “It was carried out nationwide across England and Wales and was set in motion more than 15 years ago. Because of how rare male breast cancer is, it took us over 12 years to identify and interview the nearly 2,000 men with breast cancer who were part of this study.”

The latest research is part of the wider Breast Cancer Now Male Breast Cancer Study, launched by the charity in 2007. For the new study, the ICR team interviewed 1,998 males living in England and Wales who had been diagnosed with breast cancer between 2005 and 2017. All were aged under 80 but most 60 or older at diagnosis; 92% of their tumors were invasive, and almost all were estrogen receptor positive (98.5% of those with known status).

Their responses were compared with those of a control group of 1,597 men without breast cancer, matched by age at diagnosis and geographic region, recruited from male non-blood relatives of cases and from husbands of women participating in the Generations cohort study of breast cancer etiology.
 

Raised risk with history of male infertility

Overall, 112 cases (5.6%) and 80 controls (5.0%) reported that they had had infertility problems for which they or their partner had consulted a doctor or infertility clinic. This represented a raised odds ratio of 1.29 (95% confidence interval, 0.94-1.77), which was statistically not significant. However, when analyzed by outcome of the infertility consultation, there was a significant and more than doubled risk of breast cancer among men who were diagnosed as the source of the couple’s infertility (OR = 2.03 [1.18-3.49]), whereas this was not the case among men whose partner was the source (OR = 0.86 [0.51-1.45]) or for whom no source was identified (OR = 1.26 [0.71-2.24]).

In addition, proportionately fewer cases (1,615, or 80.8%) compared with controls (1,423, or 89.1%) had fathered any children, also giving a statistically significantly raised risk of breast cancer for men with no biological children (OR = 1.50 [1.21-1.86], P < .001), “congruent with infertility as a risk factor,” the authors said. The risk was statistically significant for invasive tumors but not for the much smaller number of in situ tumors.

Analysis by number of children showed a decreasing risk with increasing numbers of children, with a highly significant (P < .001) inverse trend where zero was included as a value, but a borderline significant trend (P = .04) if it was not. The team noted that number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se.

Baseline demographic factors were adjusted for in the risk analyses, and results were not materially changed by sensitivity analyses adjusting additionally for alcohol consumption, smoking, liver disease, and family history of breast cancer. The association also largely remained after exclusion of patients with other preexisting potential confounders including severe obesity and testicular abnormalities, and was consistent irrespective of HER-2 status (there were too few ER-negative tumors to analyze results by ER status).
 

Potential underlying factors

“The causes of breast cancer in men are largely unknown, partly because it is rare and partly because previous studies have been small,” Dr. Jones said. “The evidence presented in our study suggests that the association of infertility and breast cancer should be confirmed with further research, and future investigations are needed into the potential underlying factors, such as hormone imbalances.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, told this news organization: “Overall, there isn’t strong evidence that infertility is a risk factor for male breast cancer. This study helps to shed light onto a cancer type that is sadly still not very well understood, but much more research is needed to say that infertility is a risk factor for male breast cancer.”

She added that although male breast cancer is a rare condition, it’s still important for men to be aware of what looks and feels normal for them, and to be encouraged to seek medical advice if something is not quite right.

A spokesperson for Breast Cancer UK told this news organization: “[We] believe it’s important to understand what leads to breast cancer in men as well as women and that high quality, long-term studies such as this will help with this understanding.

The findings are consistent with an earlier study that found that U.S. men who have never fathered children are at higher risk of breast cancer. This new long-term U.K. study provides strong evidence, which supports this finding.  

“As the authors note, the biological reasons are unclear, but may be associated with altered hormone levels. The ratio of circulating levels of estrogen and androgens (e.g. testosterone) is crucial in healthy functioning of breast tissue. Disruption to this, for example as a result of damage to testes, may affect both fertility and breast cancer risk.

“It is also possible that external factors, such as exposure to certain endocrine (hormone) disrupting chemicals (EDCs), which affect sex hormones, may also affect both fertility and breast cancer risk.

“More studies into breast cancer in men are needed to help us understand better all the risk factors associated with this disease including both hormonal factors and chemical exposures.”

Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now, said: “Research has discovered different treatments directed at some features of breast cancer in women; however, breast cancer is not as well understood for men. This is why Breast Cancer Now funds the Male Breast Cancer Study, which looks at what might cause the disease in men. Discovering a link between infertility and male breast cancer is a step towards us understanding male breast cancer and how we could find more ways to diagnose and treat men – and possibly women – with this devastating disease.”

A version of this article first appeared on Medscape UK.

More than 70% of cancer patients do not know that they are at greater risk of deep vein thrombosis (DVT) than the general population. It is up to their physician to discuss this with them.

This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.

A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.

“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.

It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.

In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.

“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.

“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
 

Poor understanding

One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.

Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.

When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.

Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.

The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
 

The Italian situation

The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.

The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).

The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.

Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.

In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
 

Which way forward?

“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.

The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.

So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.

“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.

Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.

The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.

Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.

“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.

This article was translated from Univadis Italy.

More than 70% of cancer patients do not know that they are at greater risk of deep vein thrombosis (DVT) than the general population. It is up to their physician to discuss this with them.

This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.

A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.

“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.

It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.

In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.

“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.

“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
 

Poor understanding

One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.

Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.

When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.

Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.

The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
 

The Italian situation

The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.

The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).

The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.

Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.

In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
 

Which way forward?

“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.

The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.

So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.

“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.

Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.

The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.

Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.

“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.

This article was translated from Univadis Italy.

More than 70% of cancer patients do not know that they are at greater risk of deep vein thrombosis (DVT) than the general population. It is up to their physician to discuss this with them.

This link is explained by the authors of an article in Cancer Treatment and Research Communications that reports results of a survey carried out by the European Cancer Patient Coalition (ECPC). “The aim of this pan-European patient survey was to assess patient awareness and knowledge about cancer-associated thrombosis (CAT), including risk factors, signs and symptoms, and interventions, to better prevent and treat CAT,” write the authors. “The idea was to create a sort of starting point for subsequent communication and information strategies and for comparing the results of any action taken in this area,” they add.

A roundtable discussion that included oncology healthcare professionals, policymakers, and patient advocates was convened to discuss and review the evidence regarding their ongoing concerns of excessive CAT-associated morbidity and mortality, as well as patients’ desire for greater CAT awareness.

“These discussions demonstrated that very little change had occurred over the years and that greater knowledge about CAT was still needed across the spectrum of healthcare practitioners and patients, particularly regarding primary and secondary prevention of thrombosis,” the authors write.

It was from this starting point that the idea for the pan-European survey was born. The ECPC, widely viewed as the “unified voice of cancer patients across Europe,” led the survey. This survey spanned six countries (France, Germany, Greece, Italy, United Kingdom, and Spain) and involved 1,365 patients and caregivers. The ECPC survey result was originally released at World Thrombosis Day in late 2018.

In an interview, Anna Falanga, MD, the main author of the article and professor of hematology at the University of Milan-Bicocca, Italy, reviewed the results and explained how to improve knowledge of CAT among patients with cancer.

“Data support that up to 20% of patients with cancer will experience venous thromboembolism (VTE), which is approximately 4–5 times higher than the general population,” said Dr. Falanga, who is also chief of the department of immunohematology and transfusion medicine and the Thrombosis and Hemostasis Center at the Hospital Papa Giovanni XXIII, in Bergamo, Italy.

“We have known about the link between thrombosis and cancer since the 19th century, but it has taken until midway through the last century for our level of understanding and awareness of the problem to reach its current level. Initially, this was limited to fundamental research, with large advances in our understanding of the mechanisms of the link between the two; it has only been more recently that we have had clinical studies that have piqued the interest of healthcare professionals, who were previously uninterested in the topic,” she said.
 

Poor understanding

One piece of data stands out from the European survey: Nearly three quarters of respondents (72%) said that before taking part in the survey, they were not aware that people with cancer have a higher-than-normal risk of developing thrombosis. “We asked participants to rate their overall understanding of CAT on a scale of 1 (low) to 10 (high), with the average (mean) score obtained being 4.1. Only 21% of patients gave a rating of 7 or above (high understanding). The average rating was very similar in the different countries surveyed,” write the authors. They note that the survey also assessed how much participants had learned about the topic from their physicians.

Approximately 35% of patients were made aware of CAT either immediately before or at the time of their cancer diagnosis. Of particular concern, one quarter (26%) of respondents (the largest proportion) noted that they first became aware of CAT when they suffered a blood clot. The average rating was very similar in the different countries surveyed. “Let us not forget that cancer and cancer treatments themselves cause a number of side effects, some of which can be very serious, so in some ways, a clot might be seen as a minor problem. Yet, in reality, it isn’t. It is a significant cause of death and disease in cancer patients,” said Dr. Falanga.

When discussing prevention, most respondents (87%) said they were aware that taking a walk could reduce their risk. Slightly fewer were aware that stopping smoking could reduce their risk (75%), and even fewer were aware that keeping hydrated (63%) and stretching their legs (55%) could reduce their risk.

Symptoms of CAT appeared to be relatively well known; 73% of survey participants indicated that they were aware that swelling in the foot, ankle, or leg could be a sign of DVT, and 71% indicated that shortness of breath could be a sign of pulmonary embolism (PE). “Other symptoms, however, were less well known, with just over half (57%) of participants being aware that pain, cramping, and tenderness could be a sign of DVT. About one third (33%) knew that irregular heartbeat could be a sign of PE. These results varied between countries,” according to the authors.

The survey highlighted that just over a third of respondents said that they were currently using anticoagulants, although almost all (96%) knew that anticoagulants could be used to effectively treat thrombosis. Only 41% of those using anticoagulants said they had been told about any possible side effects.
 

The Italian situation

The report containing the full results of the European survey goes even further, since, in addition to its overall results, it also gives information about individual countries.

The data from Italy, which are based on 246 persons, show that only 27% of patients and caregivers were aware of the increased risk of thrombosis after a cancer diagnosis. This figure is in line with the overall results of the survey, although the average score of the 10-point scale was lower for the Italy cohort (3.3/10 vs 4.1/10).

The results are more variable in terms of knowledge of risk factors. Most respondents (89%) said that they were aware of the risks related to inactivity. Just over half (52%), however, said that they were aware of the risks related to radiotherapy. Nevertheless, 75% of participants knew about the risks relating to cancer surgery and chemotherapy. “To all intents and purposes, all types of cancer drug can significantly affect the risk of developing a clot. And this is also the case for more modern types of treatment, such as immunotherapy,” said Dr. Falanga.

Most respondents reported that they got information about cancer-associated thrombosis verbally, usually from their hospital doctor (11%). Some respondents (6%) said that they found out about it from their own research, usually online. Almost 1 in 4 patients (24%) in Italy said that they first became aware of CAT when they suffered a blood clot. Answers to questions about knowledge of symptoms show that 58% of Italian patients and caregivers know that swelling of the lower limbs can be a symptom of DVT, and the same percentage knows that shortness of breath might indicate PE.

In terms of preventive action, the picture in Italy is somewhat variable: 74% of participants were aware of the importance of walking, but far fewer knew about the need to stop smoking (57%) and stretch the legs (35%). Of the 41% of Italians who were also taking an anticoagulant drug, 53% said that they knew about the possible side effects of such medication.
 

Which way forward?

“The high rate of CAT suggests that, despite the clinical evidence and clear guideline recommendations for patients with cancer, CAT prevention and recognition remain low among healthcare professionals,” the authors write.

The results of the ECPC survey further confirm those of previous studies, highlighting patients’ lack of knowledge about CAT and the need for more in-depth discussions between physician and patient.

So, what can be done? As highlighted by previous studies, “patients’ experiences are an education in themselves, particularly for the oncology care team,” the authors write. “Once the patient has a thrombosis, the opportunity for thrombosis prevention, which should be the most crucial focus of the care clinics (surgical, oncology, and palliative care), is gone,” they add.

“Oncology professionals, as well as other members of the patient’s care team (eg, internists, surgeons, nurses), need to perform better, at every stage of the patient’s cancer pathway, to ensure patients are aware of CAT and their individual risk to develop a blood clot,” said Dr. Falanga. She explained that in this group, it is the general practitioner who is the first contact. “These professionals are on the front line of the battle; they are among the first healthcare workers given the chance to suspect a clot and should, therefore, be fully aware of the increased risk in oncology patients,” she reiterated.

Experts agree on the fact that a multidisciplinary approach is of utmost importance in this context: the different roles in the team must be clear. “It is also fundamental to establish who does what in terms of educating and informing the patient,” said Dr. Falanga.

The researchers also put forward an example of a successful initiative: the Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTE-PACC) program. The initiative was developed by experts from the University of Vermont and was described in a recent article in JCO Oncology Practice.

Numerous resources are available online to help physicians talk to their patients and explain the risks linked to CAT along the continuum of cancer care. Among them is a resource titled, “Cancer Associated Thrombosis (CAT): Be Clot Conscious,” which can be found on the ECPC’s website.

“We have a collective responsibility using the ECPC patient survey as a baseline to inform patients with cancer on how to identify signs and symptoms of CAT to enable faster diagnosis and treatment,” the authors conclude.

This article was translated from Univadis Italy.

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

An injection of bupivacaine following Mohs micrographic surgery procedures that have notable postsurgical pain significantly reduces pain scores and, importantly, use of postsurgical narcotics, a randomized trial shows.

“Single-dose, in-office bupivacaine administration immediately following reconstructions known to be high risk for pain reduces postoperative narcotic use and acute pain during the time period when our patients have the highest levels of pain,” said first author Vanessa B. Voss, MD, of the University of Missouri–Columbia, who presented the findings at the annual meeting of the American College of Mohs Surgery.

Dr. Vanessa Voss

“It was well tolerated, there were no adverse effects, and we recommend the consideration of using this in Mohs micrographic surgery reconstructions that are at the highest risk for pain,” she said.

Recent research has shown that Mohs micrographic surgeons have the highest rates of opioid prescribing of all dermatologists, with about 11% of patients undergoing a Mohs procedure prescribed the drugs for postoperative use, Dr. Voss explained.

Yet, with the ongoing opioid epidemic and even short courses of postoperative opioids placing patients at risk for addiction, the pressure is on to find alternative, nonaddictive strategies for the treatment of acute postoperative pain.

Bupivacaine is commonly used intraoperatively with other types of surgeries to reduce postoperative pain, with a favorable duration of action lasting up to 7 hours, compared with just 2-3 hours with lidocaine. And while its use in Mohs surgery is typically also intraoperative, along with lidocaine, the unique postoperative treatment approach in Mohs surgery has not been well studied, Dr. Voss noted.

To investigate, Dr. Voss and colleagues conducted the prospective, multicenter randomized trial, enrolling 174 patients undergoing Mohs micrographic surgery for skin cancer.

Patients were receiving complex flap reconstructions that have been specifically designated in an American Academy of Dermatology position statement to be high risk for pain following Mohs surgeries, and hence, more likely to involve prescriptions for opioids. These include reconstruction flaps of the scalp, ear, nose or lip, a wedge repair of the ear or lip, or a Mustarde cheek rotation flap.

The mean age of the patients was about 69 years, and about 65% were male. The two groups had no significant differences in demographics, tumor types, or repairs. They were randomized to receive either local injections of bupivacaine 0.5% (with no epinephrine) or placebo with sterile saline injection immediately following the procedure, with the total amount of injection standardized and dependent upon the flap surface area, ranging from 2.5 to 5 cm³.

For postoperative pain, all patients were prescribed acetaminophen 1,000 mg alternating with ibuprofen 400 mg, and tramadol, with instructions to only use tramadol as needed for breakthrough pain.

The reported use of narcotic analgesics by participants was significantly higher among those receiving placebo versus bupivacaine in the first 24 hours following surgery (odds ratio, 2.18; P = .03), as well as in the second 24 hours (OR, 2.18; P = .08) and at 48 hours combined (OR, 2.58; P < .01).

Those in the bupivacaine group also reported lower average pain scores, on a scale of 0-10, during the first 8-hour interval (mean difference, 1.6; P < .001). Importantly, overall, reports of pain medication use and the percentage of patients reporting pain under control were similar between groups, despite lower opioid use in the bupivacaine group.

“The percentage of patients reporting their pain to be under control was similar at all time intervals in both groups, so this means the bupivacaine group had their pain well-controlled despite fewer narcotics, with significant reductions in opioid use,” Dr. Voss noted.

Bupivacaine, though generally regarded as safe, has a reputation for being the most cardiotoxic of the local anesthetic agents; however, there were no such side effects reported in the study. Dr. Voss said the likely explanation is the use of low doses.

“In our study, we had no cardiotoxic effects when using up to 5 cc of 0.5%, which equates to 25 mg per patient,” she explained. This is considered a “very low dose,” since the maximum in the Food and Drug Administration pamphlet for local infiltration is 175 mg per patient every 3 hours, “yet is sufficient for reducing pain/narcotic use.”

She added that “surgeons must be careful to avoid accidental intravascular injection, which could increase risks of systemic toxicity, but this is very rare in the reconstruction settings described.”

Overall, the study suggests a potentially beneficial and unique nonopioid approach that is currently lacking for Mohs procedures associated with a high level of pain. “These findings offer a very effective intervention to reduce postoperative opioid use in this subset of patients,” Dr. Voss told this news organization. “There is not any other intervention that I am aware of to address this, although further study into other long-acting anesthetics may demonstrate similar effects.”

Dr. Justin J. Leitenberger

Commenting on the study, Justin J. Leitenberger, MD, session moderator, said that these “data could be impactful for reducing pain as well as the need for opioid medication after dermatologic surgery, both of which would be significant for our patients and public health outcomes.”

Among the challenges in treating pain following Mohs surgeries is that “every patient has a different pain threshold and expectation after surgery,” said Dr. Leitenberger, assistant professor of medicine and dermatology and codirector of dermatologic surgery, Mohs micrographic surgery, and laser and cosmetic surgery at Oregon Health & Science University, Portland.

“Patients undergoing larger repairs in tense areas of skin can experience increased pain and require prescription pain medication,” he said. “Bupivacaine, in this study, shows promise to provide longer lasting pain control from the surgical appointment and easier bridging to nonopioid pain control.”

Regarding the potential cardiotoxicities associated with the drug, Dr. Leitenberger agreed that the risks are low, and added that many surgeons have, in fact, switched to full use of bupivacaine, as opposed to combination with lidocaine, apparently without problems. “This is a small dose locally to the area after a procedure and I agree that the risks are minuscule,” he said.

“Of note, during national lidocaine shortages over the past few years, many practices transitioned to exclusive use of bupivacaine for the entire Mohs procedure, and [anecdotally], this transition did not result in toxicities that were reported,” Dr. Leitenberger said.

GW Medical Faculty Associates

Commenting further, Vishal Patel, MD, assistant professor of dermatology and hematology/oncology at George Washington University and director of cutaneous oncology at the GW Cancer Center, both in Washington, also agreed that the benefits appear important. “The benefit from using bupivacaine is encouraging on multiple levels,” he said in an interview.

“Given all that we know about opioids and their negative side effect profile as well as their limited help in cutaneous surgery pain control, the use of long-acting anesthetics is an innovative and reasonable approach to provide pain control in the immediate postoperative window when patients tend to have the most pain,” said Dr. Patel, who is also director of dermatologic surgery at George Washington University.

“After this window, acetaminophen and ibuprofen, which have been shown when used in tandem in an alternating schedule to be superior to opioids, provides an effective pain regimen,” he said. “For larger and more pain-sensitive patients, this appears to be a promising combination.”

Dr. Voss, Dr. Leitenberger, and Dr. Patel have reported no relevant financial relationships.

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

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.

The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.

“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.

“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.

The study was published online in the Journal of Clinical Oncology.

Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.

TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.

After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).

Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.

In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).

The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.

The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.

Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

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

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

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

Long-term treatment with clozapine is associated with a small but significant risk of hematological malignancies in individuals with schizophrenia, new research shows.

Investigators found long-term clozapine use of more than 5 years was linked to a 2.7-fold increased risk of hematological malignancies in a dose-dependent manner, compared with other antipsychotics.

Karolinska Institute

An unresolved issue

Clozapine is more effective than other antipsychotics for managing symptoms and suicidal behavior in schizophrenia, with the lowest mortality, compared with other antipsychotics, but its use is restricted in many countries, the researchers note.  

Reports of nine deaths associated with clozapine use – eight due to agranulocytosis and one due to leukemia – in southwestern Finland in 1975 resulted in worldwide withdrawal of the drug. In 1990, clozapine was relaunched with stipulations for strict blood count control. The cumulative incidence of clozapine-induced agranulocytosis or severe neutropenia is estimated at about 0.9%.

Several small studies from Australia, Denmark, and the United States, and a large pharmacovigilance study, suggest that clozapine treatment might be associated with an increased risk of hematological malignancies.

“Previous studies have suggested a possible risk of hematological malignancies associated with clozapine, but due to methodological issues, the question had remained unsettled,” said Dr. Tiihonen. 

Finland has among the highest rates of clozapine use in the world, where 20% of schizophrenia cases are treated with the drug. In most other countries, clozapine use is less than half of that, in Finland largely because of agranulocytosis concerns.

To examine the risk of hematological malignancies associated with long-term use of clozapine and other antipsychotics, the investigators conducted a large prospective case-control and cohort study that used data from Finnish national registers and included all patients with schizophrenia.

“Unlike previous studies, we employed prospectively gathered data from a nationwide cohort [including all patients with schizophrenia], had a long follow-up time, and studied the dose-response of the risk of hematological malignancies,” Dr. Tiihonen noted.

The nested case-control study was constructed by individually matching cases of lymphoid and hematopoietic tissue malignancy and pairing them with up to 10 matched controls with schizophrenia but without cancer.

Inclusion criteria were restricted to malignancies diagnosed on a histological basis. Individuals outside the ages of 18-85 years were excluded, as were those with a previous malignancy. Analyses were done using conditional logistic regression adjusted for comorbid conditions.
 

Patient education, vigilant monitoring

The case-control analysis was based on 516 patients with a first-time diagnosis of lymphoid and hematopoietic tissue malignancy from 2000-2017 and diagnosed after first diagnosis of schizophrenia.

Of these, 102 patients were excluded because of a diagnosis with no histological basis, five were excluded because of age, and 34 for a previous malignancy, resulting in 375 patients with malignancies matched with 10 controls for a total of 3,743 study participants.

Of the 375 patients with hematological malignancies (305 had lymphoma, 42 leukemia, 22 myeloma, six unspecified) in 2000-2017, 208 (55%) were men and 167 (45%) were women. Ethnicity data were not available.

Compared with non-use of clozapine, clozapine use was associated with increased odds of hematological malignancies in a dose-response manner (adjusted odds ratio, 3.35; 95% confidence interval, 2.22-5.05] for ≥ 5,000 defined daily dose cumulative exposure (P < .0001).

Exposure to other antipsychotic medications was not associated with increased odds of hematological malignancies. A complementary analysis showed that the clozapine-related risk increase was specific to hematological malignancies only.

Over 17 years follow-up of the base cohort, 37 deaths occurred due to hematological malignancy among patients exposed to clozapine in 26 patients with ongoing use at the time they were diagnosed with malignancy and in 11 patients who did not use clozapine at the exact time of their cancer diagnosis. Only three deaths occurred due to agranulocytosis, the investigators report.

The use of a nationwide registry for the study makes it “unlikely” that there were any undiagnosed/unreported malignancies, the researchers note. This, plus the “robust dose-response finding, and additional analysis showing no substantial difference in odds of other cancers between users of clozapine versus other antipsychotics suggest the association is causal, and not attributable to surveillance bias,” they write.

These findings, the investigators note, suggest patients taking clozapine and their caregivers need to be educated about the signs of hematological malignancies. Furthermore, they call for mental health providers to be “vigilant” in monitoring for potential signs and symptoms of hematological malignancy in patients taking the drug.
 

A ‘vital’ medication

Commenting on the findings, Stephen Marder, MD, professor of psychiatry and biobehavioral sciences and vice chair of the department of psychiatry at UCLA, noted the link between clozapine and agranulocytosis.

UCLA

“Clozapine has been previously associated with agranulocytosis. Over the years that seemed to be the main concern of clinicians. The monitoring system for agranulocytosis has been a burden on the system and for patients, but not really a significant cause for concern with the safety of the drug,” said Dr. Marder, who is also director of the VISN 22 Mental Illness Research, Education and Clinical Center for the Department of Veterans Affairs and director of the section on psychosis at the UCLA Neuropsychiatric Institute.

In fact, he noted recent research, including studies from this group that used large databases from Finland, which showed that clozapine was actually associated with a lower mortality risk than other antipsychotics.

The fact that the study showed prolonged use of clozapine at high doses was associated with a “very small” risk of hematological abnormalities does not undermine its standing as “the most effective antipsychotic [that is] associated with a lower risk of death,” said Dr. Marder.

“On the other hand,” he added, “it does suggest that clinicians should tell patients about it and, when they review the blood monitoring, they look at things beyond the neutrophil count” that may suggest malignancy.

“Clozapine has a vital role as the most effective antipsychotic drug and the only drug that has an indication for treatment-resistant schizophrenia and schizophrenia associated with suicidality,” said Dr. Marder.

The study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital and by the Academy of Finland. Dr. Tiihonen and Dr. Marder have reported no relevant financial relationships.

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

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

New results from a phase 3 clinical trial may shut the door on the addition of progressive death–1 or PD–ligand 1 inhibitors to the combination of BRAF and MEK inhibitors for the treatment of BRAF V600–mutated melanoma.

The approach seemed promising, given the efficacy of PD-1 and PD-L1 inhibitors in metastatic melanoma, and the relatively short response times to BRAF and MEK inhibitors could potentially be supplemented by longer response times associated with PD-1 and PD-L1 inhibitors. The two categories also have different mechanisms of action and nonoverlapping toxicities, which led to an expectation that the combination would be well tolerated.

But the new study joins two previous randomized, controlled trials that also failed to show much clinical benefit. IMspire150 assigned BRAF V600–mutated melanoma patients to vemurafenib and cobimetinib plus the anti–PD-L1 antibody atezolizumab or placebo. The treatment arm had a small benefit in progression-free survival (hazard ratio, 0.78), which led to Food and Drug Administration approval of the combination, though there was no significant difference when the two cohorts were assessed by an independent review committee. The KEYNOTE-022 trial examined dabrafenib plus trametinib with or without the anti–PD-1 antibody pembrolizumab, and found no difference in investigator-assessed progression free survival.

The new study was published in the Journal of Clinical Oncology. In an accompanying editorial, Margaret K. Callahan, MD, PhD, of Memorial Sloan Kettering Cancer Center, and Paul B. Chapman, MD, of Weill Cornell Medicine, both in New York, speculated that the toxicity of the triplet combination might explain the latest failure, since patients in the triplet arm had more treatment interruptions and dose reductions than the doublet arm (32% received full-dose dabrafenib vs. 54% in the doublet arm), which may have undermined efficacy.

Citing the fact that there are now three randomized, controlled trials with discouraging results, “we believe that there are sufficient data now to be confident that the addition of anti–PD-1 or anti–PD-L1 antibodies to combination RAFi [RAF inhibitors] plus MEKi [MEK inhibitors] is not associated with a significant clinical benefit and should not be studied further in melanoma.

Moreover, “there is some evidence of harm,” the editorial authors wrote. “As the additional toxicity of triplet combination limited the delivery of combination RAFi plus MEKi therapy in COMBI-I. Focus should turn instead to optimizing doses and schedules of combination RAFi plus MEKi and checkpoint inhibitors, developing treatment strategies to overcome resistance to these therapies, and determining how best to sequence combination RAFi plus MEKi therapy and checkpoint inhibitors. Regarding the latter point, there are several sequential therapy trials currently underway in previously untreated patients with BRAF V600–mutated melanoma.”

In the study, patients were randomized to receive dabrafenib and trametinib plus the anti–PD receptor–1 antibody spartalizumab or placebo. After a median follow-up of 27.2 months, mean progression-free survival was 16.2 months in the spartalizumab arm and 12.0 months in the placebo arm (HR, 0.82; P = .042). The spartalizumab group had a 69% objective response rate versus 64% in the placebo group. 55% of the spartalizumab group experienced grade 3 or higher treatment-related adverse events, compared with 33% in the placebo group.

“These results do not support broad use of first-line immunotherapy plus targeted therapy combination, but they provide additional data toward understanding the optimal application of these therapeutic classes in patients with BRAF V600–mutant metastatic melanoma,” the authors of the study wrote.

The study was funded by F Hoffmann–La Roche and Genentech. Dr. Callahan has been employed at Bristol-Myers Squibb, Celgene, and Kleo Pharmaceuticals. Dr. Callahan has consulted for or advised AstraZeneca, Moderna Therapeutics, Merck, and Immunocore. Dr. Chapman has stock or ownership interest in Rgenix; has consulted for or advised Merck, Pfizer, and Black Diamond Therapeutics; and has received research funding from Genentech.

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.

The ability to find and target specific biomarkers in the DNA of advanced cancers is rapidly changing options and outcomes for patients with locally advanced and metastatic solid tumors. This strategy is the basis for precision oncology, defined here as using predictive biomarkers from tumor and/or germline sequencing to guide therapies. This article focuses specifically on the use of DNA sequencing to find those biomarkers and provides guidance about which test is optimal in a specific situation, as well as interpretation of the results. We emphasize the identification of biomarkers that provide adult patients with advanced solid tumors access to therapies that would not be an option had sequencing not been performed and that have the potential for significant clinical benefit. The best approach is to have an expert team with experience in precision oncology to assist in the interpretation of results.

Which test?

Deciding what test of the array of assays available to use and which tissue to test can be overwhelming, and uncertainty may prevent oncology practitioners from ordering germline or somatic sequencing. For the purposes of this article, we will focus on DNA sequencing for inherited/germline alterations (including mutations, copy number changes, or fusions), which may inform treatment, or alterations that arise in the process of carcinogenesis and tumor evolution (somatic alterations in tumor DNA). This focus is not meant to exclude any specific test but to focus on DNA-based tests in patients with locally advanced or metastatic malignancy.

Germline Testing

Germline testing is the sequencing of inherited DNA in noncancerous cells to find alterations that may play a role in the development of cancers and are actionable in some cases. Germline alterations can inform therapeutic decisions, predict future cancer risk, and provide information that can help family members to better manage their risks of malignancy. Detailed discussions of the importance of germline testing to inform cancer surveillance, risk-reducing interventions, and the testing of relatives to determine who carries inherited alterations (cascade testing) is extremely important with several advantages and is covered in a number of excellent reviews elsewhere.^1-3 Testing of germline DNA in patients with a metastatic malignancy can provide treatment options otherwise not available for patients, particularly for BRCA1/2 and Lynch syndrome–related cancers. Recent studies have shown that 10 to 15% of patients with advanced malignancies of many types have a pathogenic germline alteration.^4,5

Germline DNA is usually acquired from peripheral blood, a buccal swab, or saliva collection and is therefore readily available. This is advantageous because it does not require a biopsy to identify relevant alterations. Germline testing is also less susceptible to the rare situations in which artifacts occur in formalin-fixed tissues and obscure relevant alterations.

The cost of germline testing varies, but most commercial vendor assays for germline testing are significantly less expensive than the cost of somatic testing. The disadvantages include the inability of germline testing to find any alterations that arise solely in tumor tissue and the smaller gene panels included in germline testing as compared to somatic testing panels. Other considerations relate to the inherited nature of pathogenic germline variants and its implications for family members that may affect the patient’s psychosocial health and potentially change the family dynamics.

Deciding who is appropriate for germline testing and when to perform the testing should be individualized to the patient’s wishes and disease status. Treatment planning may be less complicated if testing has been performed and germline status is known. In some cases urgent germline testing is indicated to inform pending procedures and/or surgical decisions for risk reduction, including more extensive tissue resection, such as the removal of additional organs or contralateral tissue. A minor point regarding germline testing is that the DNA of patients with hematologic malignancies may be difficult to sequence because of sample contamination by the circulating malignancy. For this reason, most laboratories will not accept peripheral blood or saliva samples for germline testing in patients with active hematologic malignancies; they often require DNA from another source such as fibroblasts from a skin biopsy or cells from a muscle biopsy. Germline testing is recommended for all patients with metastatic prostate cancer, as well as any patient with any stage of pancreatic cancer or ovarian cancer and patients with breast cancer diagnosed at age ≤ 45 years. More detailed criteria for who is appropriate for germline testing outside of these groups can be found in the appropriate National Comprehensive Cancer Network (NCCN) guidelines.^6-8 In patients with some malignancies such as prostate and pancreatic cancer, approximately half of patients who have a BRCA-related cancer developed that malignancy because of a germline BRCA alteration.^9-11 Testing germline DNA is therefore an easy way to quickly find almost half of all targetable alterations with a treatment approved by the US Food and Drug Administration (FDA) and at low cost, with the added benefit of providing critical information for families who may be unaware that members carry a relevant pathogenic germline alteration. In those families, cascade testing can provide surveillance and intervention strategies that can be lifesaving.

A related and particularly relevant question is when should a result found on a somatic testing panel prompt follow-up germline testing? Some institutions have algorithms in place to automate referral for germline testing based on specific genetic criteria.¹² Excellent reviews are available that outline the following considerations in more detail.¹³ Typically, somatic testing results that would trigger follow-up germline testing would be truncating or deleterious or likely deleterious mutations per germline datasets in high-risk genes associated with highly penetrant autosomal dominant conditions (BRCA1, BRCA2, PALB2, MLH1, MSH2, and MSH6), selected moderate-risk genes (BRIP1, RAD51C, and RAD51D), and specific variants with a high probability of being germline because they are common germline founder mutations. Although the actionability and significance of specific genes remains a matter of some discussion, generally finding a somatic pathogenic sequencing result included in the 59-gene list of the American College of Medical Genetics and Genomics (ACMG) guidelines would be an indication for germline testing. Another indication for germline testing would be finding genes with germline mutations for which the NCCN has specific management guidelines, or the presence of alterations consistent with known founder mutations.¹⁴ When a patient’s tumor has microsatellite instability or is hypermutated (defined as > 10 mutations per megabase), a search for germline alterations is warranted given that about 15% of these patients with these tumors carry a Lynch syndrome gene.¹⁵ Genes that are commonly found as somatic alterations alone (eg, TP53 or APC) are generally not an indication for germline testing unless family history is compelling.

Although some clinicians use the variant allele fraction in the somatic sequencing report to decide whether to conduct germline testing, this approach is suboptimal, as allele fraction may be confounded by assay conditions and a high allele fraction may be found in pure tumors with loss of heterozygosity (LOH) of the other allele. There is also evidence that for a variety of reasons, somatic sequencing panels do not always detect germline alterations in somatic tissues.¹⁶ Reasons for this may include discordance between the genes being tested in the germline vs the somatic panel, technical differences such as interference of formalin-fixed paraffin-embedded (FFPE) artifact with detecting the germline variant, lack of expertise in germline variant interpretation among laboratories doing tumor-only sequencing, and, in rare cases, large deletions in tumor tissue masking a germline point mutation.

Variant Interpretation of Germline Testing

A general understanding of the terminology used for germline variant interpretation allows for the ordering health care practitioner (HCP) to provide the best quality care and an appreciation for the limitations of current molecular testing. Not all variants are associated with disease; the clinical significance of a genetic variant falls on a spectrum. The criteria for determining pathogenicity differ between molecular laboratories, but most are influenced by the standards and guidelines set forth by the ACMG.¹⁴ The clinical molecular laboratory determines variant classification, and a detailed discussion is beyond the scope of this primer. In brief, variant classification is based on evidence of varying strength in different categories including population data, computational and predictive data, functional data, segregation data, de novo data, allelic data, and information from various databases. The ACMG has proposed a 5-tiered classification system, by which most molecular laboratories adhere to in their genetic test reports (Table 1).¹⁴

Pathogenic and likely pathogenic variants are clinically actionable, whereas variants of uncertain significance (VUS) require additional data and/or functional studies before making clinical decisions. Depending on the clinical context and existing supporting evidence, it may be prudent to continue monitoring for worsening or new signs of disease in patients with one or more VUS while additional efforts are underway to understand the variant’s significance.

Somatic Testing

Testing of somatic (tumor) tissue is critical and is the approach most commonly taken in medical oncology (Table 2). Somatic testing may be performed on primary tumor, metastatic biopsy, or circulating tumor DNA (ctDNA, also referred to as cell-free DNA [cfDNA]), with each having its own advantages and disadvantages. Primary tumor tissue is appropriate for testing when the alteration is generally truncal, that is, present at the time that the tumor developed and would be expected to be carried through the evolution of the tumor because of a critical role in carcinogenesis and maintenance of the malignant phenotype. Examples include BRCA1/2, and many tyrosine kinase mutations. Somatic testing at diagnosis is part of standard of care for many malignancies, including adenocarcinoma of the lung, colon cancer, melanoma, and others.^17-19 Testing for specific genes or comprehensive genomic profiling will depend on the tumor histology, stage, and payer coverage.

The advantages of primary tumor are that it is usually in hand as a diagnostic biopsy, acquisition is standard of care, and several targetable alterations are truncal, defined as driver mutations present at the time of tumor development. Also, the potential that the tumor arose in the background of a predisposing germline alteration can be suggested by sequencing primary tumor as discussed above. Moreover, sequencing the primary tumor can be done at any time unless the biopsy sample is considered too old or degraded (per specific platform requirements). The information gained can be used to anticipate additional treatment options that are relevant when patients experience disease progression. Disadvantages include the problem that primary specimens may be old or have limited tumor content, both of which increase the likelihood that sequencing will not be technically successful.

Alterations that are targetable and arise as a result of either treatment pressure or clonal evolution are considered evolutionary. If evolutionary alterations are the main focus for sequencing, then metastasis biopsy or ctDNA are better choices. The advantages of a metastasis biopsy are that tissue is contemporary, tumor content may be higher than in primary tumor, and both truncal and evolutionary alterations can be detected.

For specific tumors, continued analysis of evolving genomic alterations can play a critical role in management. In non–small cell lung cancer (NSCLC), somatic testing is conducted again at progression on repeat biopsies to evaluate for emerging resistance mutations. In epidermal growth factor receptor (EGFR)–mutated lung cancer, the resistance mutation, exon 20 p.T790M (point mutation), can present in patients after treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKI). Even in patients who are treated with the third-generation EGFR TKI osimertinib that can treat T790M-mutated lung cancer, multiple possible evolutionary mutations can occur at progression, including other EGFR mutations, MET/HER2 amplification, and BRAF V600E, to name a few.²⁰ Resistance mechanisms develop due to treatment selection pressure and the molecular heterogeneity seen in lung cancer.

Disadvantages for metastatic biopsy include the inability to safely access a metastatic site, the time considerations for preauthorization and arrangement of biopsy, and a lower-than-average likelihood of successful sequencing from sites such as bone.^21,22 In addition, there is some concern that a single metastatic site may not capture all relevant alterations for multiple reasons, including tumor heterogeneity.

Selecting the Tissue

Deciding on the tissue to analyze is a critical part of the decision process (Table 3). If the primary tumor tissue is old the likelihood of productive sequencing is lower, although age alone is not the only consideration and the methods of fixation may be just as relevant.

For prostate cancer in particular, the ability to successfully sequence primary tumor tissue decreases as the amount of tumor decreases in low-volume biopsies such as prostate needle biopsies. Generally, if tumor content is < 10% of the biopsy specimen, then sequencing is less likely to be productive.²⁵ Also, if the alteration of interest is not known to be truncal, then a relevant target might be missed by sequencing tissue that does not reflect current biology. Metastasis biopsy may be the most appropriate tissue, particularly if this specimen has already been acquired. As above, a metastasis biopsy may have a higher tumor content, and it should reflect relevant biology if it is recent. However, bone biopsies have a relatively low yield for successful sequencing, so a soft tissue lesion (eg, liver or lymph node metastasis) is generally preferred.

The inability to safely access tissue is often a consideration. Proximity to vital structures such as large blood vessels or the potential for significant morbidity in the event of a complication (liver or lung biopsies, particularly in patients on anticoagulation medications) may make the risk/benefit ratio too high. The inability to conduct somatic testing has been reported to often be due to inadequate tissue sampling.²⁶ ctDNA is an attractive alternative but should typically be drawn when a tumor is progressing with a reasonable tumor burden that is more likely to be shedding DNA. Performing ctDNA analysis in patients without obvious radiographic metastasis or in patients whose tumor is under good control is unlikely to produce interpretable results.

Interpreting the Results

The intent of sequencing tumor tissue is to identify alterations that are biologically important and may provide a point of therapeutic leverage. However, deciding which alterations are relevant is not always straightforward. For example, any normal individual genome contains around 10,000 missense variants, hundreds of insertion/deletion variants, and dozens of protein-truncating variants. Distinguishing these alterations, which are part of the individual, from those that are tumor-specific and have functional significance can be difficult in the absence of paired sequencing of both normal and tissue samples.

Specific Alterations

Although most commercial vendors provide important information in sequencing reports to assist oncology HCPs in deciding which alterations are relevant, the reports are not always clear. In many cases the report will specifically indicate whether the alteration has been reported previously as pathogenic or benign. However, some platforms will report alterations that are not known to be drivers of tumor biology. It is critical to be aware that if variants are not reported as pathogenic, they should not be assumed to be pathogenic simply because they are included in the report. Alterations more likely to be drivers of relevant biology are those that change gene and protein structure and include frameshift (fs*), nonsense (denoted by sequence ending in “X” or “*”), or specific fusions or insertions/deletions (indel) that occur in important domains of the gene.

For some genes, only specific alterations are targetable and not all alterations have the same effect on protein function. Although overexpression of certain genes and proteins are actionable (eg, HER2), amplification of a gene does not necessarily indicate that it is targetable. In NSCLC, specific alterations convey sensitivity to targeted therapies. For example, in EGFR-mutated NSCLC, the sensitizing mutations to EGFR TKIs are exon19 deletions and exon 21 L858R point mutations (the most common mutations), as well as less common mutations found in exon 18-21. Exon 20 mutations, however, are not responsive to EGFR TKIs with a few exceptions.²⁷ Patients who have tumors that do not harbor a sensitizing EGFR mutation should not be treated with an EGFR TKI. In a variety of solid tumors, gene fusions of the NTRK 1/2/3, act as oncogenic drivers. The chromosomal fusion events involving the carboxy-terminal kinase domain of TRK and upstream amino-terminal partners lead to overexpression of the chimeric proteins tropomyosin receptor kinase (TRK) A/B/C, resulting in constitutively active, ligand-independent downstream signaling. In patients with NTRK 1/2/3 gene fusions, larotrectinib and entrectinib, small molecule inhibitors to TRK, have shown antitumor activity.^28,29 No alterations beyond these fusions are known to be targetable.

Allele Fraction

Knowing the fraction (or proportion) of the alteration of interest in the sequenced tissue relative to the estimated tumor content can assist in decision making. Not all platforms will provide this information, which is referred to as mutation allele fraction (MAF) or variant allele fraction (VAF), but sometimes will provide it on request. Platforms will usually provide an estimate of the percent tumor in the tissue being sampled if it is from a biopsy. If the MAF is around 50% in the sequenced tissue (including ctDNA), then there is a reasonable chance that it is a germline variant. However, there are nuances as germline alterations in some genes, such as BRCA1/2, can be accompanied by loss of the other allele of the gene (LOH). In that case, if most of the circulating DNA is from tumor, then the MAF can be > 50%.

If there are 2 alterations of the same gene with MAF percentages that are each half of the total percent tumor, there is a high likelihood of biallelic alteration. These sorts of paired alterations or one mutation with apparent LOH or copy loss would again indicate a high likelihood that the alteration is in fact pathogenic and a relevant driver. Not all pathogenic alterations have to be biallelic to be driver mutations but in BRCA1/2, or mismatch repair deficiency genes, the presence of biallelic alterations increases the likelihood of their being pathogenic.

Tumors that are hypermutated—containing sometimes hundreds of mutations per megabyte of DNA—can be particularly complicated to interpret, because the likelihood increases that many of the alterations are a function of the hypermutation and not a driver mutation. This is particularly important when there are concurrent mutations in mismatch repair genes and genes, such as BRCA1/2. If the tumor is microsatellite instability high or hypermutated, concurrent BRCA1/2 alterations are often passengers as the tumors rarely have coexisting “signatures” suggesting that they have a true deficiency in homologous recombination.³⁰ Large genes such as BRCA1/2 have microsatellite tracts that are prone to frameshift mutations as a result of microsatellite instability, and such mutations in this context are typically subclonal and not drivers. In hypermutated tumors, the likelihood is significantly decreased that any of the mutations other than mismatch repair deficiency or polymerase genes are targetable drivers.

Confounders

In some situations, interpretation can be particularly challenging. For example, several alterations for which there are FDA on-label indications (such as ATM or BRCA2) can be detected in ctDNA that may not be due to the tumor but to CHIP. CHIP represents hematopoietic clones that are dysplastic as a result of exposure to DNA-damaging agents (eg, platinum chemotherapy) or as a result of aging and arise when mutations in hematopoietic stem cells provide a competitive advantage.³¹ The most common CHIP clones that can be detected are DNMT3A, ASXL1, or TET2; because these alterations are not targetable, their importance lies primarily in whether patients have evidence of hematologic abnormality, which might represent an evolving hematopoietic disorder. Because CHIP alterations can overlap with somatic alterations for which FDA-approved drugs exist, such as ATM or CHEK2 (olaparib for prostate cancer) and BRCA2 (poly-ADP-ribose polymerase inhibitors in a range of indications) there is concern that CHIP might result in patient harm from inappropriate treatment of CHIP rather than the tumor, with no likelihood that the treatment would affect the tumor, causing treatment delays.³² General considerations for deciding whether an alteration represents CHIP include excluding alteration in which the VAF is < 1% and when the VAF in the alteration of interest is < 20% of the estimated tumor fraction in the sample. Exceptions to this are found in patients with true myelodysplasia or chronic lymphocytic leukemia, in whom the VAF can be well over 50% because of circulating tumor burden. The only way to be certain that an alteration detected on ctDNA reflects tumor rather than CHIP is to utilize an assay with matched tumor-normal sequencing.

Resources for Assistance

For oncology HCPs, perhaps the best resource to help in selecting and interpreting the appropriate testing is through a dedicated molecular oncology tumor board and subject matter experts who contribute to those tumor boards. In the US Department of Veterans Affairs, the national precision oncology program and its affiliated clinical services, such as the option to order a national consultation and molecular tumor board education, are easily accessible to all HCPs (www.cancer.va.gov). Many commercial vendors provide support to assist with questions of interpretation and to inform clinical decision-making. Other resources that can assist with deciding whether an alteration is pathogenic include extensive curated databases such as ClinVar (www.ncbi.nlm.nih.gov/clinvar) and the Human Genetic Mutation Database (www.hgmd.cf.ac.uk/ac/index.php) for germline alterations or COSMIC (cancer.sanger.ac.uk/cosmic) for somatic alterations. OncoKB (www.oncokb.org) is a resource for assistance in defining levels of evidence for the use of agents to target specific alterations and to assist in assigning pathogenicity to specific alterations. Additional educational resources for training in genomics and genetics are also included in the Appendix.

The rapid growth in technology and ability to enhance understanding of relevant tumor biology continues to improve the therapeutic landscape for men and women dealing with malignancy and our ability to find targetable genetic alterations with the potential for meaningful clinical benefit.

Acknowledgments

Dedicated to Neil Spector.