AVAHO

Patients with rheumatoid arthritis–associated interstitial lung disease showed increases in overall mortality, respiratory mortality, and cancer mortality, compared with RA patients without interstitial lung disease, based on data from more than 500,000 patients in a nationwide cohort study.

RA-associated interstitial lung disease (RA-ILD) has been associated with worse survival rates as well as reduced quality of life, functional impairment, and increased health care use and costs, wrote Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on the incidence and prevalence of RA-ILD have been inconsistent and large studies are lacking.

In a study published online in Rheumatology, the researchers identified 509,787 RA patients aged 65 years and older from Medicare claims data. The average age of the patients was 72.6 years, and 76.2% were women.

At baseline, 10,306 (2%) of the study population had RA-ILD, and 13,372 (2.7%) developed RA-ILD over an average of 3.8 years’ follow-up per person (total of 1,873,127 person-years of follow-up). The overall incidence of RA-ILD was 7.14 per 1,000 person-years.

Overall mortality was significantly higher among RA-ILD patients than in those with RA alone in a multivariate analysis (38.7% vs. 20.7%; hazard ratio, 1.66).

In addition, RA-ILD was associated with an increased risk of respiratory mortality (HR, 4.39) and cancer mortality (HR, 1.56), compared with RA without ILD. For these hazard regression analyses, the researchers used Fine and Gray subdistribution HRs “to handle competing risks of alternative causes of mortality. For example, the risk of respiratory mortality for patients with RA-ILD, compared with RA without ILD also accounted for the competing risk of cardiovascular, cancer, infection and other types of mortality.”

Case courtesy A.Prof Frank Gaillard, Radiopaedia.org, rID: 12274

In another multivariate analysis, male gender, smoking, asthma, chronic obstructive pulmonary disorder, and medication use (specifically biologic disease-modifying antirheumatic drugs, targeted synthetic DMARDs, and glucocorticoids) were independently associated with increased incident RA-ILD at baseline. However, “the associations of RA-related medications with incident RA-ILD risk should be interpreted with caution since they may be explained by unmeasured factors, including RA disease activity, severity, comorbidities, and prior or concomitant medication use,” the researchers noted.

The study findings were limited by several factors, including the lack of data on disease activity, disease duration, disease severity, and RA-related autoantibodies, the researchers noted. However, the results support data from previous studies and were strengthened by the large sample size and data on demographics and health care use.

“Ours is the first to study the epidemiology and mortality outcomes of RA-ILD using a validated claims algorithm to identify RA and RA-ILD,” and “to quantify the mortality burden of RA-ILD and to identify a potentially novel association of RA-ILD with cancer mortality,” they noted.

The study was supported by an investigator-initiated grant from Bristol-Myers Squibb. Lead author Dr. Sparks disclosed support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. Dr. Sparks also disclosed serving as a consultant to Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer for work unrelated to the current study. Other authors reported research funding from Bristol-Myers Squibb, involvement in a clinical trial funded by Genentech and Bristol-Myers Squibb, and receiving research support to Brigham and Women’s Hospital for other studies from AbbVie, Bayer, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Vertex.

Patients with rheumatoid arthritis–associated interstitial lung disease showed increases in overall mortality, respiratory mortality, and cancer mortality, compared with RA patients without interstitial lung disease, based on data from more than 500,000 patients in a nationwide cohort study.

RA-associated interstitial lung disease (RA-ILD) has been associated with worse survival rates as well as reduced quality of life, functional impairment, and increased health care use and costs, wrote Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on the incidence and prevalence of RA-ILD have been inconsistent and large studies are lacking.

In a study published online in Rheumatology, the researchers identified 509,787 RA patients aged 65 years and older from Medicare claims data. The average age of the patients was 72.6 years, and 76.2% were women.

At baseline, 10,306 (2%) of the study population had RA-ILD, and 13,372 (2.7%) developed RA-ILD over an average of 3.8 years’ follow-up per person (total of 1,873,127 person-years of follow-up). The overall incidence of RA-ILD was 7.14 per 1,000 person-years.

Overall mortality was significantly higher among RA-ILD patients than in those with RA alone in a multivariate analysis (38.7% vs. 20.7%; hazard ratio, 1.66).

In addition, RA-ILD was associated with an increased risk of respiratory mortality (HR, 4.39) and cancer mortality (HR, 1.56), compared with RA without ILD. For these hazard regression analyses, the researchers used Fine and Gray subdistribution HRs “to handle competing risks of alternative causes of mortality. For example, the risk of respiratory mortality for patients with RA-ILD, compared with RA without ILD also accounted for the competing risk of cardiovascular, cancer, infection and other types of mortality.”

Case courtesy A.Prof Frank Gaillard, Radiopaedia.org, rID: 12274

In another multivariate analysis, male gender, smoking, asthma, chronic obstructive pulmonary disorder, and medication use (specifically biologic disease-modifying antirheumatic drugs, targeted synthetic DMARDs, and glucocorticoids) were independently associated with increased incident RA-ILD at baseline. However, “the associations of RA-related medications with incident RA-ILD risk should be interpreted with caution since they may be explained by unmeasured factors, including RA disease activity, severity, comorbidities, and prior or concomitant medication use,” the researchers noted.

The study findings were limited by several factors, including the lack of data on disease activity, disease duration, disease severity, and RA-related autoantibodies, the researchers noted. However, the results support data from previous studies and were strengthened by the large sample size and data on demographics and health care use.

“Ours is the first to study the epidemiology and mortality outcomes of RA-ILD using a validated claims algorithm to identify RA and RA-ILD,” and “to quantify the mortality burden of RA-ILD and to identify a potentially novel association of RA-ILD with cancer mortality,” they noted.

The study was supported by an investigator-initiated grant from Bristol-Myers Squibb. Lead author Dr. Sparks disclosed support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. Dr. Sparks also disclosed serving as a consultant to Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer for work unrelated to the current study. Other authors reported research funding from Bristol-Myers Squibb, involvement in a clinical trial funded by Genentech and Bristol-Myers Squibb, and receiving research support to Brigham and Women’s Hospital for other studies from AbbVie, Bayer, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Vertex.

Patients with rheumatoid arthritis–associated interstitial lung disease showed increases in overall mortality, respiratory mortality, and cancer mortality, compared with RA patients without interstitial lung disease, based on data from more than 500,000 patients in a nationwide cohort study.

RA-associated interstitial lung disease (RA-ILD) has been associated with worse survival rates as well as reduced quality of life, functional impairment, and increased health care use and costs, wrote Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on the incidence and prevalence of RA-ILD have been inconsistent and large studies are lacking.

In a study published online in Rheumatology, the researchers identified 509,787 RA patients aged 65 years and older from Medicare claims data. The average age of the patients was 72.6 years, and 76.2% were women.

At baseline, 10,306 (2%) of the study population had RA-ILD, and 13,372 (2.7%) developed RA-ILD over an average of 3.8 years’ follow-up per person (total of 1,873,127 person-years of follow-up). The overall incidence of RA-ILD was 7.14 per 1,000 person-years.

Overall mortality was significantly higher among RA-ILD patients than in those with RA alone in a multivariate analysis (38.7% vs. 20.7%; hazard ratio, 1.66).

In addition, RA-ILD was associated with an increased risk of respiratory mortality (HR, 4.39) and cancer mortality (HR, 1.56), compared with RA without ILD. For these hazard regression analyses, the researchers used Fine and Gray subdistribution HRs “to handle competing risks of alternative causes of mortality. For example, the risk of respiratory mortality for patients with RA-ILD, compared with RA without ILD also accounted for the competing risk of cardiovascular, cancer, infection and other types of mortality.”

Case courtesy A.Prof Frank Gaillard, Radiopaedia.org, rID: 12274

In another multivariate analysis, male gender, smoking, asthma, chronic obstructive pulmonary disorder, and medication use (specifically biologic disease-modifying antirheumatic drugs, targeted synthetic DMARDs, and glucocorticoids) were independently associated with increased incident RA-ILD at baseline. However, “the associations of RA-related medications with incident RA-ILD risk should be interpreted with caution since they may be explained by unmeasured factors, including RA disease activity, severity, comorbidities, and prior or concomitant medication use,” the researchers noted.

The study findings were limited by several factors, including the lack of data on disease activity, disease duration, disease severity, and RA-related autoantibodies, the researchers noted. However, the results support data from previous studies and were strengthened by the large sample size and data on demographics and health care use.

“Ours is the first to study the epidemiology and mortality outcomes of RA-ILD using a validated claims algorithm to identify RA and RA-ILD,” and “to quantify the mortality burden of RA-ILD and to identify a potentially novel association of RA-ILD with cancer mortality,” they noted.

The study was supported by an investigator-initiated grant from Bristol-Myers Squibb. Lead author Dr. Sparks disclosed support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. Dr. Sparks also disclosed serving as a consultant to Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer for work unrelated to the current study. Other authors reported research funding from Bristol-Myers Squibb, involvement in a clinical trial funded by Genentech and Bristol-Myers Squibb, and receiving research support to Brigham and Women’s Hospital for other studies from AbbVie, Bayer, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Vertex.

It’s been shown that hospitalized cancer patients and those undergoing active treatment are at high risk for severe COVID-19 complications. A new study shows that patients with cancer in remission are at higher risk, too.

For the study, investigators from the University of Pennsylvania, Philadelphia, analyzed 323 patients with SARS-CoV-2 infection in a research database with more than 4,800 patients. About 20% of database patients were Black, but they accounted for almost 65% of the infections, reflecting previous reports of increased risk for COVID among Black people.

A total of 67 of the infected patients had cancer, including 18 patients with active cancer and 49 patients whose cancer was in remission. After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer more than doubled the odds of hospitalization and increased the odds of 30-day mortality nearly sixfold.

Worse outcomes were more strongly associated with active cancer, but patients whose cancer was in remission were also at higher risk than patients who did not have cancer.

It’s not only “patients hospitalized or on treatment ... all oncology patients need to take significant precautions during the pandemic to protect themselves,” senior investigator Kara Maxwell, MD, PhD, hematologist/oncologist and assistant professor at the University of Pennsylvania, said in a press release.

The study was published online on Jan. 21 in JNCI Cancer Spectrum.

The good news is that steps to prevent SARS-CoV-2 infection work, suggests a second report from the University of Pennsylvania. Among 124 cancer patients who underwent outpatient infusions from May to October 2020, not a single one experienced seroconversion over a median of 13 clinical visits. That second study was published on Jan. 16 in medRxiv and is pending peer review.

The zero seroconversion rate likely reflects “the success of transmission mitigation measures within health care facilities,” wrote investigators led by Lova Sun, MD, a hematology/oncology fellow at the University of Pennsylvania.

Like many institutions, the University of Pennsylvania Health System (Penn Medicine) is aggressive in protecting outpatients against the virus, the authors wrote. Among other steps, patients are queried about symptoms and contacts before their office visit, and their temperature is taken when they come in. Masks are worn, check-in is contactless, the number of visitors is limited, and patients who test positive are treated in a separate space.

In addition, patients in the study also reported that they wore masks and practiced social distancing in their daily lives.

Approached for comment, hematologist/oncologist Charles Shapiro, MD, a professor at the Icahn School of Medicine at Mount Sinai and director of translational breast cancer research at Mount Sinai Hospital, both in New York, said he wasn’t surprised that the prevention measures followed at Penn Medicine work. They are very similar to the measures followed at Mount Sinai oncology clinics, and “there’ve been very few COVID cases in our shop,” he added.

The bigger take-home message from both studies is that cancer patients, regardless of their age or if they are in remission, should be prioritized for vaccination against COVID-19, which is the best way to mitigate risk. “I strongly urge my patients to get it” if they can, he said.

The problem in New York is that immunizations are largely limited to people aged 65 years and older. Younger cancer patients are left out, and access has been spotty for all patients. “Vaccine is available one day, then not the next. It’s disheartening,” Dr. Shapiro said in an interview. “Hopefully, with the new administration, this will smooth out,” and the age limit will drop.

The study was supported by the National Institutes of Health, among other organizations. Dr. Lova, Dr. Maxwell, and Dr. Shapiro have disclosed no relevant financial relationships.

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

It’s been shown that hospitalized cancer patients and those undergoing active treatment are at high risk for severe COVID-19 complications. A new study shows that patients with cancer in remission are at higher risk, too.

For the study, investigators from the University of Pennsylvania, Philadelphia, analyzed 323 patients with SARS-CoV-2 infection in a research database with more than 4,800 patients. About 20% of database patients were Black, but they accounted for almost 65% of the infections, reflecting previous reports of increased risk for COVID among Black people.

A total of 67 of the infected patients had cancer, including 18 patients with active cancer and 49 patients whose cancer was in remission. After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer more than doubled the odds of hospitalization and increased the odds of 30-day mortality nearly sixfold.

Worse outcomes were more strongly associated with active cancer, but patients whose cancer was in remission were also at higher risk than patients who did not have cancer.

It’s not only “patients hospitalized or on treatment ... all oncology patients need to take significant precautions during the pandemic to protect themselves,” senior investigator Kara Maxwell, MD, PhD, hematologist/oncologist and assistant professor at the University of Pennsylvania, said in a press release.

The study was published online on Jan. 21 in JNCI Cancer Spectrum.

The good news is that steps to prevent SARS-CoV-2 infection work, suggests a second report from the University of Pennsylvania. Among 124 cancer patients who underwent outpatient infusions from May to October 2020, not a single one experienced seroconversion over a median of 13 clinical visits. That second study was published on Jan. 16 in medRxiv and is pending peer review.

The zero seroconversion rate likely reflects “the success of transmission mitigation measures within health care facilities,” wrote investigators led by Lova Sun, MD, a hematology/oncology fellow at the University of Pennsylvania.

Like many institutions, the University of Pennsylvania Health System (Penn Medicine) is aggressive in protecting outpatients against the virus, the authors wrote. Among other steps, patients are queried about symptoms and contacts before their office visit, and their temperature is taken when they come in. Masks are worn, check-in is contactless, the number of visitors is limited, and patients who test positive are treated in a separate space.

In addition, patients in the study also reported that they wore masks and practiced social distancing in their daily lives.

Approached for comment, hematologist/oncologist Charles Shapiro, MD, a professor at the Icahn School of Medicine at Mount Sinai and director of translational breast cancer research at Mount Sinai Hospital, both in New York, said he wasn’t surprised that the prevention measures followed at Penn Medicine work. They are very similar to the measures followed at Mount Sinai oncology clinics, and “there’ve been very few COVID cases in our shop,” he added.

The bigger take-home message from both studies is that cancer patients, regardless of their age or if they are in remission, should be prioritized for vaccination against COVID-19, which is the best way to mitigate risk. “I strongly urge my patients to get it” if they can, he said.

The problem in New York is that immunizations are largely limited to people aged 65 years and older. Younger cancer patients are left out, and access has been spotty for all patients. “Vaccine is available one day, then not the next. It’s disheartening,” Dr. Shapiro said in an interview. “Hopefully, with the new administration, this will smooth out,” and the age limit will drop.

The study was supported by the National Institutes of Health, among other organizations. Dr. Lova, Dr. Maxwell, and Dr. Shapiro have disclosed no relevant financial relationships.

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

It’s been shown that hospitalized cancer patients and those undergoing active treatment are at high risk for severe COVID-19 complications. A new study shows that patients with cancer in remission are at higher risk, too.

For the study, investigators from the University of Pennsylvania, Philadelphia, analyzed 323 patients with SARS-CoV-2 infection in a research database with more than 4,800 patients. About 20% of database patients were Black, but they accounted for almost 65% of the infections, reflecting previous reports of increased risk for COVID among Black people.

A total of 67 of the infected patients had cancer, including 18 patients with active cancer and 49 patients whose cancer was in remission. After adjusting for demographics, smoking status, and comorbidities, a diagnosis of cancer more than doubled the odds of hospitalization and increased the odds of 30-day mortality nearly sixfold.

Worse outcomes were more strongly associated with active cancer, but patients whose cancer was in remission were also at higher risk than patients who did not have cancer.

It’s not only “patients hospitalized or on treatment ... all oncology patients need to take significant precautions during the pandemic to protect themselves,” senior investigator Kara Maxwell, MD, PhD, hematologist/oncologist and assistant professor at the University of Pennsylvania, said in a press release.

The study was published online on Jan. 21 in JNCI Cancer Spectrum.

The good news is that steps to prevent SARS-CoV-2 infection work, suggests a second report from the University of Pennsylvania. Among 124 cancer patients who underwent outpatient infusions from May to October 2020, not a single one experienced seroconversion over a median of 13 clinical visits. That second study was published on Jan. 16 in medRxiv and is pending peer review.

The zero seroconversion rate likely reflects “the success of transmission mitigation measures within health care facilities,” wrote investigators led by Lova Sun, MD, a hematology/oncology fellow at the University of Pennsylvania.

Like many institutions, the University of Pennsylvania Health System (Penn Medicine) is aggressive in protecting outpatients against the virus, the authors wrote. Among other steps, patients are queried about symptoms and contacts before their office visit, and their temperature is taken when they come in. Masks are worn, check-in is contactless, the number of visitors is limited, and patients who test positive are treated in a separate space.

In addition, patients in the study also reported that they wore masks and practiced social distancing in their daily lives.

Approached for comment, hematologist/oncologist Charles Shapiro, MD, a professor at the Icahn School of Medicine at Mount Sinai and director of translational breast cancer research at Mount Sinai Hospital, both in New York, said he wasn’t surprised that the prevention measures followed at Penn Medicine work. They are very similar to the measures followed at Mount Sinai oncology clinics, and “there’ve been very few COVID cases in our shop,” he added.

The bigger take-home message from both studies is that cancer patients, regardless of their age or if they are in remission, should be prioritized for vaccination against COVID-19, which is the best way to mitigate risk. “I strongly urge my patients to get it” if they can, he said.

The problem in New York is that immunizations are largely limited to people aged 65 years and older. Younger cancer patients are left out, and access has been spotty for all patients. “Vaccine is available one day, then not the next. It’s disheartening,” Dr. Shapiro said in an interview. “Hopefully, with the new administration, this will smooth out,” and the age limit will drop.

The study was supported by the National Institutes of Health, among other organizations. Dr. Lova, Dr. Maxwell, and Dr. Shapiro have disclosed no relevant financial relationships.

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

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining an EGFR inhibitor with a pair of checkpoint inhibitors can produce “promising” activity in certain patients with colorectal cancer (CRC), according to an investigator from a phase 2 trial.

The trial was designed to test the combination of panitumumab, ipilimumab, and nivolumab in patients with previously treated, unresectable and/or metastatic, microsatellite stable or mismatch repair–proficient CRC without mutations in KRAS, NRAS, or BRAF.

Among 49 evaluable patients treated with the triplet, 35% had a partial response at 12 weeks of follow-up, which met the trial’s primary response endpoint, according to investigator Michael S. Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“Though toxicities were, of course, observed, they were consistent overall with the expected adverse event profiles of anti-EGFR therapy and combination ipilimumab and nivolumab. Correlative studies are ongoing to identify potential biomarkers of response,” Dr. Lee said when presenting the trial results at the 2021 Gastrointestinal Cancers Symposium (Abstract 7).

Immune activation?

The rationale for adding panitumumab to immune checkpoint inhibitors comes, in part, from a trial published in 2014 in The Lancet Oncology. The trial showed that panitumumab was noninferior to cetuximab. Panitumumab was associated with a 22% response rate in patients with KRAS wild-type, metastatic CRC that was refractory to chemotherapy. Progression-free survival (PFS) and overall survival (OS) were similar between the treatment arms.

In addition, in mouse models of RAS wild-type CRC, treatment with an anti-EGFR antibody induced immunogenic cell death.

“Moreover, translational studies of tumor biopsies from patients who were treated with the anti-EGFR antibody cetuximab showed that responders had significant increases in T-cell infiltration and cytolytic activity within tumors after starting treatment,” Dr. Lee said.

In the latter studies, tumor samples taken at the time of disease progression also showed increased expression of immune checkpoint inhibitor pathways, including PD-L1, the primary target of nivolumab, and CTLA-4, the primary target of ipilimumab.

“Given this, we hypothesized that combining anti–PD-1 and anti–CTLA-4 antibodies with anti-EGFR therapy would be synergistic,” Dr. Lee said.

Single-arm study

Investigators enrolled patients with unresectable and/or metastatic CRC in the trial. All patients had disease that was KRAS, NRAS, and BRAF wild-type, and they had either microsatellite stability or proficient mismatch repair. Patients also had to have received one or two prior lines of therapy, not including an anti-EGFR agent.

The patients received panitumumab at 6 mg/kg IV every 2 weeks, nivolumab at 240 mg IV every 2 weeks, and ipilimumab at 1 mg/kg IV every 6 weeks.

Of all 56 patients enrolled, 28 (50%) had tumors in the left colon, 3 (5%) had tumors in the right colon, 2 (4%) had tumors in the transverse colon, 16 (29%) had rectal tumors, and 7 (13%) were not specified.

As noted before, 49 patients were evaluable, and the trial met its primary endpoint of responses in at least 17 patients (35%) at 12 weeks. All were partial responses.

Of the remaining patients, 21 (43%) had stable disease, and 11 (22%) had disease progression. Of the latter group, five patients did not have documented radiographic progression at 12 weeks, but they discontinued therapy before restaging because of unequivocal clinical progression.

The best response rate (confirmed and unconfirmed) at any time was 41%.

At a median follow-up of 12.1 months, the median PFS was 5.7 months. The OS data were not mature at the time of data cutoff. However, the median OS was 27 months.

There were two deaths on study, one from myocarditis possibly related to the study treatment, and one from colonic perforation, which was deemed unlikely to be treatment related.

Grade 3 or 4 adverse events included hypomagnesemia (n = 6), acneiform rash (n = 6), increased lipase (n = 5), increased amylase (n = 4), alanine aminotransferase elevation (n = 3), aspartate aminotransferase elevation (n = 3), diarrhea (n = 3), hyophosphatemia (n = 3), and maculopapular rash (n = 3).

‘Disappointing PFS’

In the question and answer session following the presentation, moderator Michael J. Hall, MD, of Fox Chase Cancer Center in Philadelphia, asked whether the response rate seen with the addition of panitumumab was what the investigators expected, independent of the dual–checkpoint inhibitor therapy, and “with the relatively disappointing PFS you saw, what are the plans moving forward with this regimen?”

“These are great questions and thoughts I’ve had as well,” Dr. Lee replied.

He noted that studies of other anti-EGFR and checkpoint inhibitor combinations have had relatively low response rates, and his group’s study was conducted with “an effort to try and get over this immune-cold environment that we know exists in the tumor microenvironment,” he said.

Dr. Lee also acknowledged that the response rate may have been slightly higher than that seen in other studies because of the preponderance of left colon tumors, which are generally more amenable to systemic therapy.

Regarding PFS, Dr. Lee said the analyses of durability of response are still ongoing, and the median PFS was better than that seen in a trial of single-agent panitumumab in a similar population.

The current study was funded by Amgen and Bristol Myers Squibb. Dr. Lee disclosed institutional research funding from the companies, consulting/advising for Pfizer, and travel expenses from Genentech/Roche. Dr. Hall disclosed relationships with Ambry Genetics, AstraZeneca, Caris Life Sciences, Foundation Medicine, InVitae, and Myriad Genetics. He also shares a patent with several Fox Chase investigators for a novel method to investigate hereditary CRC genes.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

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

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

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

The combination of liothyronine (LT₃) with levothyroxine (LT₄) for the treatment of hypothyroidism shows no evidence of any increased risk of breast cancer in a large, long-term study, contrary to concerns raised in some prior trials.

“An increasing number of patients ask their physicians for a prescription of combination therapy, often causing tensions. Thus, the question of whether combination therapy does any harm to patients is crucial,” say Tereza Planck, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues, in their article published online Jan. 5 in Thyroid.

“Our data provide reassuring evidence regarding the risk of cancer and mortality,” they stress.

Asked to comment, Caroline T. Nguyen, MD, agrees that the study results are welcome in light of some previous evidence.

“The findings of these [prior] studies were concerning as they suggested an association between T₃ and breast cancer, breast cancer-specific mortality, and poorer prognosis with potential estrogen-like activity of T₃ on the estrogen receptor,” Dr. Nguyen of the division of endocrinology, diabetes & metabolism at Keck Medical Center of University of Southern California, Los Angeles, told this news organization.

“Therefore, the findings of this paper provide some reassurance, which is important because, as the paper states, the use of T₃ is becoming increasingly common.”
 

Many patients with hypothyroidism opt to add liothyronine

Although the standard treatment for hypothyroidism, levothyroxine, increases free thyroxine (T₄) to high-normal levels, it may potentially lower triiodothyronine (T₃) to relatively low levels. There is speculation that the imbalance in a subset of patients could explain why some fail to have an adequate reduction of symptoms with levothyroxine alone.

To offset the effect, some add liothyronine (a synthetic version of T₃) to levothyroxine treatment as so-called “combination therapy.” However, a long-term study conducted in Scotland showed a borderline significant increase in breast cancer risk with the combination, raising concern.

To further investigate, Dr. Planck and coauthors used Swedish adult population data, identifying 575,461 individuals who had made at least three purchases of thyroid hormone therapy between July 2005 and December 2017, and had no history of breast cancer at the time of their first prescription.

Among the individuals, 11,147 had made at least three purchases of LT₃, including combinations with LT₄. LT₄-only users were an average age of 54.4 years, and the average age of those who also took LT₃ was 44.7 years.

Over a median follow-up of 8.1 years, there was no significantly increased risk of breast cancer among women treated with LT₃ plus LT₄ versus LT₄ alone (hazard ratio, 0.93), after adjusting for differences in age, sex, previous thyroid cancer, previous other cancer, use of antithyroid preparations, use of sex hormones, and dose.

Further evaluation of women as well as men showed those treated with LT₃ also had no increased incidence of any cancer (HR, 0.97).

In dose-adjusted models, LT₃ treatment did, surprisingly, appear to have a protective effect in terms of all-cause mortality (HR, 0.69) and any cancer mortality (HR, 0.78) for men and women.

However, the implications of these latter results remain uncertain, first author Dr. Planck said in an interview.

“We think the data on reduced mortality should be interpreted with caution, as we only observe the differences in the models adjusting for dose,” she noted.

 

LT3 treatment still considered ‘experimental’

Despite the dramatic increase in LT₃ prescribing in recent years noted by the authors, as many as five systematic reviews/meta-analyses have shown no superiority of combination therapy over LT₄ alone in terms of hypothyroid symptoms, quality of life, or patient preference.

As a result, many international guidelines still consider the combination-treatment approach to be experimental.

Other trials that have raised concerns about the combination include previous large, prospective Swedish studies that have linked higher endogenous T₃ levels to breast cancer in postmenopausal women.

As for the mechanism, some small experimental studies have suggested an estrogenlike effect whereby T₃ could enhance the proliferation of breast cancer cells.

On a broader level, thyroid hormones, in general, have been extensively studied in cancer research as possibly promoting cancer cell proliferation in a variety of cancer types.

However, the current findings should lay some of those concerns to rest, Dr. Planck reiterated: “Our data provide reassuring evidence regarding the risk of cancer and mortality.”

“We did not identify any increase in breast cancer incidence, any cancer incidence, all-cause mortality, any cancer mortality, or breast cancer mortality between individuals using LT₃ and LT₄ treatment.”

The authors and Nguyen have reported no relevant financial relationships.

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

The COVID-19 pandemic led to a drastic reduction in lung cancer screening, but the rate of decline was similar between Whites and non-Whites and between rural and nonrural populations. All groups saw their rates of lung cancer screening (LCS) return to near prepandemic levels by June 2020, according to a new analysis of two academic and two community imaging sites in North Carolina.

The study was led by Louise Henderson, PhD, of the Lineberger Comprehensive Cancer Center, and M. Patricia Rivera, MD, FCCP, of the department of medicine, division of pulmonary disease and critical care medicine, both at the University of North Carolina at Chapel Hill. The findings appeared online in Chest.

“I am [not] surprised by the decline, but I am certainly reassured,” Abbie Begnaud, MD, FCCP, said in an interview. Dr. Begnaud is assistant professor of medicine at the University of Minnesota, Minneapolis. She was not involved in the study.

The COVID-19 pandemic led to a drastic reduction in lung cancer screening, but the rate of decline was similar between Whites and non-Whites and between rural and nonrural populations. All groups saw their rates of lung cancer screening (LCS) return to near prepandemic levels by June 2020, according to a new analysis of two academic and two community imaging sites in North Carolina.

The study was led by Louise Henderson, PhD, of the Lineberger Comprehensive Cancer Center, and M. Patricia Rivera, MD, FCCP, of the department of medicine, division of pulmonary disease and critical care medicine, both at the University of North Carolina at Chapel Hill. The findings appeared online in Chest.

“I am [not] surprised by the decline, but I am certainly reassured,” Abbie Begnaud, MD, FCCP, said in an interview. Dr. Begnaud is assistant professor of medicine at the University of Minnesota, Minneapolis. She was not involved in the study.

The COVID-19 pandemic led to a drastic reduction in lung cancer screening, but the rate of decline was similar between Whites and non-Whites and between rural and nonrural populations. All groups saw their rates of lung cancer screening (LCS) return to near prepandemic levels by June 2020, according to a new analysis of two academic and two community imaging sites in North Carolina.

The study was led by Louise Henderson, PhD, of the Lineberger Comprehensive Cancer Center, and M. Patricia Rivera, MD, FCCP, of the department of medicine, division of pulmonary disease and critical care medicine, both at the University of North Carolina at Chapel Hill. The findings appeared online in Chest.

“I am [not] surprised by the decline, but I am certainly reassured,” Abbie Begnaud, MD, FCCP, said in an interview. Dr. Begnaud is assistant professor of medicine at the University of Minnesota, Minneapolis. She was not involved in the study.

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

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

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

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

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


 

Arguing that melanoma is overdiagnosed

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

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

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

Furthermore, overdiagnosis could contribute to unnecessary intervention.

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

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

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

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

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

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

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

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

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

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

Taking issue with some of the arguments

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

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

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

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

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

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

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

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

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

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

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

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

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


 

Arguing that melanoma is overdiagnosed

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

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

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

Furthermore, overdiagnosis could contribute to unnecessary intervention.

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

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

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

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

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

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

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

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

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

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

Taking issue with some of the arguments

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

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

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

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

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

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

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

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

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

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

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

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

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


 

Arguing that melanoma is overdiagnosed

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

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

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

Furthermore, overdiagnosis could contribute to unnecessary intervention.

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

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

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

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

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

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

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

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

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

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

Taking issue with some of the arguments

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

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

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

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

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

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

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

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

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Preliminary data suggest that a certain pattern of gut microbes may be useful in predicting which patients with advanced gastric cancer are likely to benefit from treatment with the immunotherapy nivolumab.

Researchers have demonstrated bacterial invasion of the epithelial cell pathway in the gut microbiome and suggest that this could potentially become a novel biomarker.

“In addition, we found gastric cancer–specific gut microbiome predictive of responses to immune checkpoint inhibitors,” said study author Yu Sunakawa, MD, PhD, an associate professor in the department of clinical oncology at St. Marianna University, Kawasaki, Japan.

Dr. Sunakawa presented the study’s results at the 2021 Gastrointestinal Cancers Symposium.

The gut microbiome holds great interest as a potential biomarker for response. Previous studies suggested that it may hold the key to immunotherapy responses. The concept has been demonstrated in several studies involving patients with melanoma, but this is the first study in patients with gastric cancer.

Nivolumab monotherapy has been shown to provide a survival benefit with a manageable safety profile in previously treated patients with gastric cancer or gastroesophageal junction (GEJ) cancer, Dr. Sunakawa noted. However, fewer than half of patients responded to therapy.

“The disease control rate was about 40%, and many patients did not experience any tumor degradation,” he said. “About 60% of the patients did not respond to nivolumab as a late-line therapy.”

In the observational/translational DELIVER trial, investigators enrolled 501 patients with recurrent or metastatic adenocarcinoma of the stomach or GEJ. The patients were recruited from 50 sites in Japan.

The primary endpoint was the relationship between the genomic pathway in the gut microbiome and efficacy of nivolumab and whether there was progressive disease or not at the first evaluation, as determined in accordance with Response Evaluation Criteria in Solid Tumors criteria.

Genomic data were measured by genome shotgun sequence at a central laboratory. Biomarkers were analyzed by Wilcoxon rank sum test in the first 200 patients, who constituted the training cohort. The top 30 biomarker candidates were validated in the last 300 patients (the validation cohort) using the Bonferroni method.

Clinical and genomic data were available for 437 patients (87%). Of this group, 180 constituted the training cohort, and 257, the validation cohort.

The phylogenetic composition of common bacterial taxa was similar for both cohorts.

In the training cohort, 62.2% of patients had progressive disease, as did 53.2% in the validation cohort. The microbiome was more diverse among the patients who did not have progressive disease than among those who did have progressive disease.

The authors noted that, although there was no statistically significant pathway to be validated for a primary endpoint using the Bonferroni method, bacterial invasion of epithelial cells in the KEGG pathway was associated with clinical outcomes in both the training cohort (P = .057) and the validation cohort (P = .014). However, these pathways were not significantly associated with progressive disease after Bonferroni correction, a conservative test that adjusts for multiple comparisons.

An exploratory analysis of genus showed that Odoribacter and Veillonella species were associated with tumor response to nivolumab in both cohorts.

Dr. Sunakawa noted that biomarker analyses are ongoing. The researchers are investigating the relationships between microbiome and survival times, as well as other endpoints.
 

Still some gaps

In a discussion of the study, Jonathan Yeung, MD, PhD, of Princess Margaret Cancer Center, Toronto, congratulated the investigators on their study, noting that “the logistical hurdles must have been tremendous to obtain these data.”

However, Dr. Yeung pointed out some limitations and gaps in the data that were presented. For example, he found that the ratio of the training set to the validation set was unusual. “The training set is usually larger and usually an 80/20 ratio,” he said. “In their design, the validation set is larger, and I’m quite curious about their rationale.

“The conclusion of the study is that a more diverse microbiome was observed in patients with a tumor response than in those without a response,” he continued, “but they don’t actually show the statistical test used to make this conclusion. There is considerable overlap between the groups, and more compelling data are needed to make that conclusion.”

Another limitation was the marked imbalance in the number of patients whose condition responded to nivolumab in comparison with those whose condition did not (20 vs. 417 patients). This could have affected the statistical power of the study.

But overall, Dr. Yeung congratulated the authors for presenting a very impressive dataset. “The preliminary data are very interesting, and I look forward to the final results,” he said.

The study was funded by Ono Pharmaceutical and Bristol-Myers Squibb, which markets nivolumab. Dr. Sunakawa has received honoraria from Bayer Yakuhin, Bristol-Myers Squibb Japan, Chugai, Kyowa Hakko Kirin, Lilly Japan, Nippon Kayaku, Sanofi, Taiho, Takeda, and Yakult Honsha. He has held a consulting or advisory role for Bristol-Myers Squibb Japan, Daiichi Sankyo, and Takeda and has received research funding from Chugai Pharma, Daiichi Sankyo, Lilly Japan, Sanofi, Taiho Pharmaceutical, and Takeda. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

New guidelines issued jointly by four major international hematology groups focus on the management of patients with von Willebrand disease (VWD), the most common bleeding disorder in the world.

The evidence-based guidelines, published in Blood Advances, were developed in collaboration by the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. They outline key recommendations spanning the care of patients with a broad range of therapeutic needs.

“We addressed some of the questions that were most important to the community, but certainly there are a lot of areas that we couldn’t cover” said coauthor Veronica H. Flood, MD, of the Medical College of Wisconsin in Milwaukee.

The guidelines process began with a survey sent to the von Willebrand disease community, including patients, caregivers, nurses, physicians, and scientists. The respondents were asked to prioritize issues that they felt should be addressed in the guidelines.

“Interestingly, some of the issues were the same between patients and caregivers and physicians, and some were different, but there were obviously some areas that we just couldn’t cover,” she said in an interview.

One of the areas of greatest concern for respondents was bleeding in women, and many of the recommendations include specific considerations for management of gynecologic and obstetric patients, Dr. Flood said.

“We also tried to make the questions applicable to as many patients with von Willebrand disease as possible,” she added.

Some of the questions, such as recommendation 1, regarding prophylaxis, are geared toward management of patients with severe disease, while others, such as recommendations for treatment of menstrual bleeding, are more suited for patients with milder VWD.

All of the recommendations in the guidelines are “conditional” (suggested), due to very low certainty in the evidence of effects, the authors noted.
 

Prophylaxis

The guidelines suggest long-term prophylaxis for patients with a history of severe and frequent bleeds, with periodic assessment of the need for prophylaxis.

Desmopressin

For those patients who may benefit from the use of desmopressin, primarily those with type 1 VWD, and who have a baseline von Willebrand factor (VWF) level below 0.30 IU/mL, the panel issued a conditional recommendation for a desmopressin trial with treatment based on the patient’s results compared with not performing a trial and treating with tranexamic acid or factor concentrate. The guidelines also advise against treating with desmopressin in the absence of a trial. In a section of “good practice statements,” the guidelines indicate that using desmopressin in patients with type 2B VWD is generally contraindicated, because of the risk of thrombocytopenia as a result of increased platelet binding. In addition, desmopressin is generally contraindicated in patients with active cardiovascular disease, patients with seizure disorders, patients less than 2 years old, and patients with type 1C VWD in the setting of surgery.

Antithrombotic therapy

The guideline panelists conditionally recommend antithrombotic therapy with either antiplatelet agents or anticoagulants, with an emphasis on reassessing bleeding risk throughout the course of treatment.

An accompanying good practice statement calls for individualized assessments of risks and benefits of specific antithrombotic therapies by a multidisciplinary team including hematologists, cardiovascular specialists, and the patient.
 

Major surgery

This section includes a recommendation for targeting both factor VIII and VWF activity levels to a minimum of 50 IU/mL for at least 3 days after surgery, and a suggestion against using factor VIII target levels alone.

Minor surgery/invasive procedures

The panelists suggest increasing VWF activity levels to a minimum of 0.50 IU/mL with desmopressin or factor concentrate with the addition of tranexamic acid over raising VWF levels to at least 0.50 IU/mL with desmopressin or factor concentrate alone.

In addition, the panelists suggest “giving tranexamic acid alone over increasing VWF activity levels to a minimum threshold of 0.50 IU/mL with any intervention in patients with type 1 VWD with baseline VWF activity levels of 0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures.”
 

Heavy menstrual bleeding

In women with heavy menstrual bleeding who do not plan to conceive, the panel suggests either combined hormonal therapy or levonorgestrel-releasing intrauterine system, or tranexamic acid over desmopressin.

In women who wish to conceive, the panel suggests using tranexamic acid over desmopressin.
 

Neuraxial anesthesia during labor

For women in labor for whom neuraxial anesthesia is considered, the guidelines suggest targeting a VWF activity level from 0.50 to 1.50 IU/mL over targeting a level above 1.50 IU/mL.

Postpartum management

“The guideline panel suggests the use of tranexamic acid over not using it in women with type 1 VWD or low VWF levels (and this may also apply to types 2 and 3 VWD) during the postpartum period,” the guidelines say.

An accompanying good practice statement says that tranexamic acid can be provided orally or intravenously. The oral dose is 25 mg/kg three times daily for 10-14 days, or longer if blood loss remains heavy.

Dr. Flood said that the guidelines were developed under the assumption that they would apply to care of patients in regions with a high or moderately high degree of clinical resources.

“We recognize that this eliminates a great deal of the globe, and our hope is that ASH and the other sponsoring organizations are going to let us revise this and do a version for lower-resourced settings,” she said.

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

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

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

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

For the second year in a row, mortality from cancer has fallen in the United States, driven largely by reductions in the incidence of, and death from, non–small cell lung cancer (NSCLC) in men and women, according to a new report from the American Cancer Society.

The study was published online Jan. 12 in CA: A Cancer Journal for Clinicians.

“Mortality rates are a better indicator of progress against cancer than incidence or survival because they are less affected by biases resulting from changes in detection practices,” wrote the authors, led by Rebecca Siegel, MPH, American Cancer Society, Atlanta.  

“The overall drop of 31% as of 2018 [since the early 1990s] translates to an estimated 3,188,500 fewer cancer deaths (2,170,700 in men and 1,017,800 in women) than what would have occurred if mortality rates had remained at their peak,” the researchers added.

Lung cancer accounted for 46% of the total decline in cancer mortality in the past 5 years, with a record, single-year drop of 2.4% between 2017 and 2018.

The recent and rapid reductions in lung cancer mortality reflect better treatments for NSCLC, the authors suggested. For example, survival rates at 2 years have increased from 34% for patients diagnosed with NSCLC between 2009 and 2010 to 42% for those diagnosed during 2015 and 2016 – an absolute gain of 5%-6% in survival odds for every stage of diagnosis.

On a more somber note, the authors warned that COVID-19 is predicted to have a negative impact on both the diagnosis and outcomes of patients with cancer in the near future.  

“We anticipate that disruptions in access to cancer care in 2020 will lead to downstream increases in advanced stage diagnoses that may impede progress in reducing cancer mortality rates in the years to come,” Ms. Siegel said in a statement.
 

New cancer cases

The report provides an estimated number of new cancer cases and deaths in 2021 in the United States (nationally and state-by-state) based on the most current population-based data for cancer incidence through 2017 and for mortality through 2018. “An estimated 608,570 Americans will die from cancer in 2021, corresponding to more than 1600 deaths per day,” Ms. Siegel and colleagues reported.

The greatest number of deaths are predicted to be from the most common cancers: Lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women, they added. However, the mortality rates for all four cancers are continuing to fall.

As of 2018, the death rate from lung cancer had dropped by 54% among males and by 30% among females over the past few decades, the investigators noted.

Mortality from female breast cancer has dropped by 41% since 1989; by 52% for prostate cancer since 1993; and by 53% and 59% for colorectal cancer for men (since 1980) and women (since 1969), respectively.

“However, in recent years, mortality declines have slowed for breast cancer and [colorectal cancer] and have halted for prostate cancer,” the researchers noted.

In contrast, the pace of the annual decline in lung cancer mortality doubled among men from 3.1% between 2009 and 2013 to 5.5% between 2014 and 2018, and from 1.8% to 4.4% among women during the same time intervals.
 

Increase in incidence at common sites

Despite the steady progress in mortality for most cancers, “rates continue to increase for some common sites,” Ms. Siegel and colleagues reported.

For example, death rates from uterine corpus cancer have accelerated from the late 1990s at twice the pace of the increase in its incidence. Death rates also have increased for cancers of the oral cavity and pharynx – although in this cancer, increases in mortality parallel an increase in its incidence. 

“Pancreatic cancer death rates [in turn] continued to increase slowly in men ... but remained stable in women, despite incidence [rates] rising by about 1% per year in both sexes,” the authors observed.

Meanwhile, the incidence of cervical cancer, although declining for decades overall, is increasing for patients who present with more distant-stage disease as well as cervical adenocarcinoma, both of which are often undetected by cytology.

“These findings underscore the need for more targeted efforts to increase both HPV [human papillomavirus] vaccination among all individuals aged [26 and younger] and primary HPV testing or HPV/cytology co-testing every 5 years among women beginning at age 25,” the authors emphasized.

On a more positive note, the long-term increase in mortality from liver cancer has recently slowed among women and has stabilized among men, they added.

Once again, disparities in both cancer occurrence and outcomes varied considerably between racial and ethnic groups. For example, cancer is the leading cause of death in people who are Hispanic, Asian American, and Alaska Native. Survival rates at 5 years for almost all cancers are still higher for White patients than for Black patients, although the disparity in cancer mortality between Black persons and White persons has declined to 13% from a peak of 33% in 1993.

Geographic disparities in cancer mortality rates still prevail; the rates are largest for preventable cancers such as lung and cervical cancer, for which mortality varies by as much as fivefold across states.

And although cancer remains the second most common cause of death among children, death rates from cancer have continuously declined over time among both children and adolescents, largely the result of dramatic declines in death rates from leukemia in both age groups.

The study authors have disclosed no relevant financial relationships.

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

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.

A combination of biomarkers identifies patients with luminal early breast cancer who can safely skip chemotherapy after surgery, results from the ADAPT HR+/HER2– trial suggest.

The findings were reported at the 2020 San Antonio Breast Cancer Symposium.

“In early luminal breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in patients with one to three involved lymph nodes, is still unclear,” noted principal investigator Nadia Harbeck, MD, PhD, of the University of Munich.

Successive trials have used nodal status, genomic risk scores, and response to preoperative therapy to home in on subsets of women for whom this practice is safe.

The ADAPT HR+/HER2– trial is a phase 3 trial that enrolled 5,625 patients with luminal (hormone receptor–positive, HER2-negative) early breast cancer who were candidates for adjuvant chemotherapy based on conventional criteria.

The trial combined a static biomarker – Oncotype Dx recurrence score (RS) in the baseline core biopsy – and a dynamic biomarker – Ki-67 response to a 3-week course of preoperative endocrine therapy – to personalize adjuvant therapy.

At SABCS 2020, Dr. Harbeck reported results for 2,290 patients having zero to three involved lymph nodes: 868 patients with RS 0-11 and 1,422 patients with RS 12-25 who had a response to brief preoperative endocrine therapy (a Ki-67 fraction ≤10% at surgery). All were treated with endocrine therapy alone as adjuvant therapy.
 

Similar outcomes

The median follow-up was 60 months. The 5-year rate of invasive disease–free survival was 93.9% for the group with RS 0-11 and 92.6% for the group with RS 12-25 and a response to the preoperative endocrine therapy.

The study met its primary endpoint, as the lower limit of the 95% confidence interval for the difference between groups of –3.3% fell just within the predefined margin of –3.3% or less for noninferiority (P = .05).

The groups also had similarly “excellent” distant disease–free survival (96.3% for RS 0-11 and 95.6% for RS 12-25; P = .247) and overall survival (98.0% for RS 0-11 and 97.3% for RS 12-25; P = .160), Dr. Harbeck reported.

The similar distant disease–free survival was consistent regardless of whether women were younger or older than 50 years and regardless of whether women had involved nodes or not.

In multivariate analysis, women had greater risk of distant disease–free survival events if they had three positive lymph nodes versus zero to two (hazard ratio, 3.40) or a pathologic T stage of 2-4 versus 0-1 (HR, 2.24), whereas risk fell with increasing baseline progesterone receptor expression (HR, 0.92).

“Neither patient age nor study arm were prognostic factors for patient outcome,” Dr. Harbeck noted.

In stratified analysis, the negative impact of having three positive nodes was seen only in the group with RS 12-25 and response to preoperative endocrine therapy, suggesting this subgroup may not be good candidates for omission of chemotherapy, she said.
 

Applying results to practice

“In luminal early breast cancer, the following patients – irrespective of their age – can safely be treated by endocrine therapy alone: patients with zero to three involved lymph nodes and recurrence score 0-11, and those with limited nodal burden (zero to two lymph nodes), recurrence score 12-25, and endocrine response after short preoperative endocrine therapy,” Dr. Harbeck summarized.

“Oncotype Dx testing can spare chemotherapy for the majority of patients with up to three involved lymph nodes. Dynamic Ki-67 response testing is feasible in clinical routine and complements baseline risk assessment to define patient selection for therapy deescalation or escalation,” she added.

The investigators have used the trial’s data to develop an algorithm for predicting the probability of response to short-course preoperative endocrine therapy that is available free of charge online (www.enrep.info).

“This may support everyday clinical decision-making in luminal early breast cancer; for example, whether to start a short period of preoperative endocrine therapy at all, and whether to rely on adjuvant endocrine therapy alone, but also in times like these, whether it’s safe to delay surgery by putting patients on prolonged preoperative endocrine therapy if surgical resources are scarce,” Dr. Harbeck commented.

Her clinic is now recruiting patients for the ADAPT Cycle trial, which is testing an endocrine-based approach with a CDK4/6 inhibitor versus chemotherapy in patients who are not candidates for adjuvant endocrine therapy alone. Therefore, all eligible patients receive the short course of endocrine therapy up front as the standard.

“But if you don’t have a trial, what are you going to do on Monday morning? Please let your patient know whether her tumor is endocrine responsive by doing this 3-week preoperative endocrine therapy,” Dr. Harbeck recommended. “It’s easy to do, you can schedule your surgeries better, and in patients with up to three lymph nodes, it helps with your decision-making, not just in the postmenopausal patients but also in the premenopausal patients, regarding whether they can forgo chemotherapy.”

Findings in context

More than 75% of ADAPT patients with RS 12-25 had a response to short-course endocrine therapy, noted invited discussant Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Conn.

“This implies that the endocrine challenge is not informative for most patients,” he said, adding that a related question is whether the 25% of patients who did not have a response and were therefore given chemotherapy benefited from that therapy.

Dr. Pusztai cautioned that, among patients in the group with RS 12-25 who had a response to preoperative endocrine therapy, certain subgroups were fairly or very small: those aged 50 years or younger (330 patients) and those with two or three positive nodes (75 and 22 patients, respectively).

And collective findings of the similar but much larger TAILORx trial and RxPONDER trial (also reported at SABCS 2020) do suggest a benefit of chemotherapy in younger women, regardless of the number of positive nodes.

“Selection of [estrogen receptor]–positive patients with zero to three lymph nodes for adjuvant chemotherapy currently should be based on age and baseline recurrence score or a similar validated molecular assay,” Dr. Pusztai recommended. “TAILORx results guide us in regard to the use of the recurrence score in node-negative patients with a recurrence score of less than 26, and the recently presented RxPONDER results provide evidence for the use of recurrence score in patients with one to three positive nodes with a recurrence score in the range of 0-26. Both of these trials showed benefit in younger women from adjuvant chemotherapy.”

The ADAPT trial was sponsored by Roche, Genomic Health/Exact Sciences, Celgene, Bayer, Teva, and Amgen. Dr. Harbeck disclosed relationships with Agendia, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Merck, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Samsung, Sandoz, and Seattle Genetics. Dr. Pusztai disclosed relationships with AstraZeneca, Athenex, Almac, Bristol-Myers Squibb, Biotheranostics, Clovis, Daiichi, Eisai, Genentech, H2Bio, H3 Biomedicine, Immunomedics, Merck, Novartis, Pfizer, Pieris, Radius Health, Syndax, and Seattle Genetics,.