AVAHO

Abiraterone and enzalutamide showed identical survival outcomes when used as first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC), according to a new study using US Department of Veterans Affairs (VA) data. The report represents the first head-to-head clinical analysis of these commonly used androgen receptor inhibitors.

Among 1258 veterans treated with abiraterone and 311 treated with enzalutamide, median overall survival was 36.2 months for both drugs. Patients were followed for a mean of 28.7 months (abiraterone) and 30.8 months (enzalutamide), reported by Martin W. Schoen, MD, MPH, from Saint Louis University School of Medicine and the St. Louis VA Medical Center, in JAMA Network Open. 

Notably, there was no significant difference in outcomes among Black veterans, who often have poorer outcomes in prostate cancer, and in patients with cardiovascular disease.

“This is the first direct comparison of abiraterone and enzalutamide for mHSPC in a clinical practice setting,” Schoen told Federal Practitioner. “At the population level, there are no differences based on initial treatment choice.”

Abiraterone Is Preferred in the VA Due to Cost

According to Schoen, abiraterone and enzalutamide are the most commonly used androgen receptor inhibitors to treat mHSPC within the VA. A 2025 study by Schoen and colleagues found that 53.7% of veterans with mHSPC in 2022 received androgen receptor inhibitor therapy, up from 16.9% in 2017. 

“In the VA, the preference for most patients is abiraterone since it is the least expensive agent,” he said. A generic version has been available for several years.

Additionally, abiraterone “has been on the market for the longest, and therefore clinicians are familiar with its use,” Schoen said. However, “clinicians have little idea of the comparative efficacy between these 2 agents,” he added.

The authors suggest that the cost and toxicities of the medications should guide clinician decisions, Schoen said. “There is data that abiraterone may worsen diabetes, since it is given with prednisone and could increase the risk of cardiovascular events,” he said.

He added that 2 newer drugs, apalutamide and darolutamide, are also “viable options.” Chemotherapies and certain targeted drugs are also available, “but they are only used in a select group of patients.”

Outside Specialist: Diverse Study Population Is a Plus

Hematologist-oncologist Natalie Reizine, MD, of the University of Illinois College of Medicine, Chicago, who was not involved in the study, told Federal Practitioner that the real-world data are valuable given the limitations of clinical trial populations.

“It’s difficult to compare clinical trials because they enroll different groups of patients,” she said. And, she said, they often exclude patients with significant comorbidities. “If they have bad cardiovascular disease, for instance, or poorly controlled diabetes, they're excluded from the clinical trial. But in real life, many of our patients have other medical problems that we have to manage.”

Reizine also emphasized the significance of the study’s diverse patient population. “Black men are very underrepresented in clinical trials. Many clinical trials that lead to drug approval will have only few or no Black men at all, yet these drugs go on to be widely prescribed to all men with prostate cancer.”

Results Are ‘Reassuring’

Reizine described the overall study findings as “reassuring,” especially in light of “studies that show that abiraterone and prednisone may be associated with worse cardiovascular outcomes. This study showed that in this VA population, even for patients who had cardiovascular disease, there was not a difference in how they did.”

As for choosing between agents, she recommended considering comorbidities and potential drug-drug interactions. “One of the big reasons that you may not be able to safely prescribe enzalutamide, for instance, is if a patient is on an anticoagulant, which is incredibly common in cancer patients. Enzalutamide has more drug-drug interactions than abiraterone and prednisone.” 

Study Demographics and Findings

The study included all patients with mHSPC who initiated abiraterone or enzalutamide between July 2017 and April 2023.

Median ages were 73 (abiraterone) and 74 years (enzalutamide, P = .29). Racial distribution was similar between groups: abiraterone (68.1% White, 25.0% Black, 6.9% other/unknown) and enzalutamide (66.6% White, 27.0% Black, 6.4% other/unknown; P = .74). Ethnicity was 89.2% non-Hispanic, 4.4% Hispanic, and 6.4% unknown in the abiraterone group vs 88.4% non-Hispanic, 3.5% Hispanic, and 8.0% unknown in the enzalutamide group (P = .50).

The groups had similar rates of the most common comorbidities: diabetes (40.5% vs 46.3%, respectively, P = .07), peripheral vascular disease (40.2% vs 37.6%, respectively, P = .44), and chronic pulmonary disease (37.0% vs 40.5%, P = .29).

In an inverse probability weighting analysis with abiraterone as reference, weighted median overall survival was comparable across the entire cohort (36.2 months, P = .32), Black veterans (39.7 months, P = .90), and those with cardiovascular disease (31.5 months, P = .30).

The authors noted limitations such as the observational cohort design and data constraints. 

The study was supported by the American Society of Clinical Oncology Conquer Cancer Foundation, the Prostate Cancer Foundation, and the Blavatnik Family Foundation.

Schoen discloses relationships with the Prostate Cancer Foundation, Astellas, and US Department of Defense. Other authors disclose relationships with the American Society of Clinical Oncology, Pfizer, Exelixis, Eli Lilly, Sanofi, Merck, Seagen, Bellicum, and BMS.

Outside the submitted work. Reizine discloses relationships with the US Department of Defense, Sanofi, Exelexis, Janssen, AstraZeneca, EMD Serono, Janssen, Merck, and Tempus.

Abiraterone and enzalutamide showed identical survival outcomes when used as first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC), according to a new study using US Department of Veterans Affairs (VA) data. The report represents the first head-to-head clinical analysis of these commonly used androgen receptor inhibitors.

Among 1258 veterans treated with abiraterone and 311 treated with enzalutamide, median overall survival was 36.2 months for both drugs. Patients were followed for a mean of 28.7 months (abiraterone) and 30.8 months (enzalutamide), reported by Martin W. Schoen, MD, MPH, from Saint Louis University School of Medicine and the St. Louis VA Medical Center, in JAMA Network Open. 

Notably, there was no significant difference in outcomes among Black veterans, who often have poorer outcomes in prostate cancer, and in patients with cardiovascular disease.

“This is the first direct comparison of abiraterone and enzalutamide for mHSPC in a clinical practice setting,” Schoen told Federal Practitioner. “At the population level, there are no differences based on initial treatment choice.”

Abiraterone Is Preferred in the VA Due to Cost

According to Schoen, abiraterone and enzalutamide are the most commonly used androgen receptor inhibitors to treat mHSPC within the VA. A 2025 study by Schoen and colleagues found that 53.7% of veterans with mHSPC in 2022 received androgen receptor inhibitor therapy, up from 16.9% in 2017. 

“In the VA, the preference for most patients is abiraterone since it is the least expensive agent,” he said. A generic version has been available for several years.

Additionally, abiraterone “has been on the market for the longest, and therefore clinicians are familiar with its use,” Schoen said. However, “clinicians have little idea of the comparative efficacy between these 2 agents,” he added.

The authors suggest that the cost and toxicities of the medications should guide clinician decisions, Schoen said. “There is data that abiraterone may worsen diabetes, since it is given with prednisone and could increase the risk of cardiovascular events,” he said.

He added that 2 newer drugs, apalutamide and darolutamide, are also “viable options.” Chemotherapies and certain targeted drugs are also available, “but they are only used in a select group of patients.”

Outside Specialist: Diverse Study Population Is a Plus

Hematologist-oncologist Natalie Reizine, MD, of the University of Illinois College of Medicine, Chicago, who was not involved in the study, told Federal Practitioner that the real-world data are valuable given the limitations of clinical trial populations.

“It’s difficult to compare clinical trials because they enroll different groups of patients,” she said. And, she said, they often exclude patients with significant comorbidities. “If they have bad cardiovascular disease, for instance, or poorly controlled diabetes, they're excluded from the clinical trial. But in real life, many of our patients have other medical problems that we have to manage.”

Reizine also emphasized the significance of the study’s diverse patient population. “Black men are very underrepresented in clinical trials. Many clinical trials that lead to drug approval will have only few or no Black men at all, yet these drugs go on to be widely prescribed to all men with prostate cancer.”

Results Are ‘Reassuring’

Reizine described the overall study findings as “reassuring,” especially in light of “studies that show that abiraterone and prednisone may be associated with worse cardiovascular outcomes. This study showed that in this VA population, even for patients who had cardiovascular disease, there was not a difference in how they did.”

As for choosing between agents, she recommended considering comorbidities and potential drug-drug interactions. “One of the big reasons that you may not be able to safely prescribe enzalutamide, for instance, is if a patient is on an anticoagulant, which is incredibly common in cancer patients. Enzalutamide has more drug-drug interactions than abiraterone and prednisone.” 

Study Demographics and Findings

The study included all patients with mHSPC who initiated abiraterone or enzalutamide between July 2017 and April 2023.

Median ages were 73 (abiraterone) and 74 years (enzalutamide, P = .29). Racial distribution was similar between groups: abiraterone (68.1% White, 25.0% Black, 6.9% other/unknown) and enzalutamide (66.6% White, 27.0% Black, 6.4% other/unknown; P = .74). Ethnicity was 89.2% non-Hispanic, 4.4% Hispanic, and 6.4% unknown in the abiraterone group vs 88.4% non-Hispanic, 3.5% Hispanic, and 8.0% unknown in the enzalutamide group (P = .50).

The groups had similar rates of the most common comorbidities: diabetes (40.5% vs 46.3%, respectively, P = .07), peripheral vascular disease (40.2% vs 37.6%, respectively, P = .44), and chronic pulmonary disease (37.0% vs 40.5%, P = .29).

In an inverse probability weighting analysis with abiraterone as reference, weighted median overall survival was comparable across the entire cohort (36.2 months, P = .32), Black veterans (39.7 months, P = .90), and those with cardiovascular disease (31.5 months, P = .30).

The authors noted limitations such as the observational cohort design and data constraints. 

The study was supported by the American Society of Clinical Oncology Conquer Cancer Foundation, the Prostate Cancer Foundation, and the Blavatnik Family Foundation.

Schoen discloses relationships with the Prostate Cancer Foundation, Astellas, and US Department of Defense. Other authors disclose relationships with the American Society of Clinical Oncology, Pfizer, Exelixis, Eli Lilly, Sanofi, Merck, Seagen, Bellicum, and BMS.

Outside the submitted work. Reizine discloses relationships with the US Department of Defense, Sanofi, Exelexis, Janssen, AstraZeneca, EMD Serono, Janssen, Merck, and Tempus.

Abiraterone and enzalutamide showed identical survival outcomes when used as first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC), according to a new study using US Department of Veterans Affairs (VA) data. The report represents the first head-to-head clinical analysis of these commonly used androgen receptor inhibitors.

Among 1258 veterans treated with abiraterone and 311 treated with enzalutamide, median overall survival was 36.2 months for both drugs. Patients were followed for a mean of 28.7 months (abiraterone) and 30.8 months (enzalutamide), reported by Martin W. Schoen, MD, MPH, from Saint Louis University School of Medicine and the St. Louis VA Medical Center, in JAMA Network Open. 

Notably, there was no significant difference in outcomes among Black veterans, who often have poorer outcomes in prostate cancer, and in patients with cardiovascular disease.

“This is the first direct comparison of abiraterone and enzalutamide for mHSPC in a clinical practice setting,” Schoen told Federal Practitioner. “At the population level, there are no differences based on initial treatment choice.”

Abiraterone Is Preferred in the VA Due to Cost

According to Schoen, abiraterone and enzalutamide are the most commonly used androgen receptor inhibitors to treat mHSPC within the VA. A 2025 study by Schoen and colleagues found that 53.7% of veterans with mHSPC in 2022 received androgen receptor inhibitor therapy, up from 16.9% in 2017. 

“In the VA, the preference for most patients is abiraterone since it is the least expensive agent,” he said. A generic version has been available for several years.

Additionally, abiraterone “has been on the market for the longest, and therefore clinicians are familiar with its use,” Schoen said. However, “clinicians have little idea of the comparative efficacy between these 2 agents,” he added.

The authors suggest that the cost and toxicities of the medications should guide clinician decisions, Schoen said. “There is data that abiraterone may worsen diabetes, since it is given with prednisone and could increase the risk of cardiovascular events,” he said.

He added that 2 newer drugs, apalutamide and darolutamide, are also “viable options.” Chemotherapies and certain targeted drugs are also available, “but they are only used in a select group of patients.”

Outside Specialist: Diverse Study Population Is a Plus

Hematologist-oncologist Natalie Reizine, MD, of the University of Illinois College of Medicine, Chicago, who was not involved in the study, told Federal Practitioner that the real-world data are valuable given the limitations of clinical trial populations.

“It’s difficult to compare clinical trials because they enroll different groups of patients,” she said. And, she said, they often exclude patients with significant comorbidities. “If they have bad cardiovascular disease, for instance, or poorly controlled diabetes, they're excluded from the clinical trial. But in real life, many of our patients have other medical problems that we have to manage.”

Reizine also emphasized the significance of the study’s diverse patient population. “Black men are very underrepresented in clinical trials. Many clinical trials that lead to drug approval will have only few or no Black men at all, yet these drugs go on to be widely prescribed to all men with prostate cancer.”

Results Are ‘Reassuring’

Reizine described the overall study findings as “reassuring,” especially in light of “studies that show that abiraterone and prednisone may be associated with worse cardiovascular outcomes. This study showed that in this VA population, even for patients who had cardiovascular disease, there was not a difference in how they did.”

As for choosing between agents, she recommended considering comorbidities and potential drug-drug interactions. “One of the big reasons that you may not be able to safely prescribe enzalutamide, for instance, is if a patient is on an anticoagulant, which is incredibly common in cancer patients. Enzalutamide has more drug-drug interactions than abiraterone and prednisone.” 

Study Demographics and Findings

The study included all patients with mHSPC who initiated abiraterone or enzalutamide between July 2017 and April 2023.

Median ages were 73 (abiraterone) and 74 years (enzalutamide, P = .29). Racial distribution was similar between groups: abiraterone (68.1% White, 25.0% Black, 6.9% other/unknown) and enzalutamide (66.6% White, 27.0% Black, 6.4% other/unknown; P = .74). Ethnicity was 89.2% non-Hispanic, 4.4% Hispanic, and 6.4% unknown in the abiraterone group vs 88.4% non-Hispanic, 3.5% Hispanic, and 8.0% unknown in the enzalutamide group (P = .50).

The groups had similar rates of the most common comorbidities: diabetes (40.5% vs 46.3%, respectively, P = .07), peripheral vascular disease (40.2% vs 37.6%, respectively, P = .44), and chronic pulmonary disease (37.0% vs 40.5%, P = .29).

In an inverse probability weighting analysis with abiraterone as reference, weighted median overall survival was comparable across the entire cohort (36.2 months, P = .32), Black veterans (39.7 months, P = .90), and those with cardiovascular disease (31.5 months, P = .30).

The authors noted limitations such as the observational cohort design and data constraints. 

The study was supported by the American Society of Clinical Oncology Conquer Cancer Foundation, the Prostate Cancer Foundation, and the Blavatnik Family Foundation.

Schoen discloses relationships with the Prostate Cancer Foundation, Astellas, and US Department of Defense. Other authors disclose relationships with the American Society of Clinical Oncology, Pfizer, Exelixis, Eli Lilly, Sanofi, Merck, Seagen, Bellicum, and BMS.

Outside the submitted work. Reizine discloses relationships with the US Department of Defense, Sanofi, Exelexis, Janssen, AstraZeneca, EMD Serono, Janssen, Merck, and Tempus.

TOPLINE: COVID-19 infection is associated with a 25% reduction in cancer risk over 3 years among veterans who survived the initial infection. This protective effect was observed across sexes and racial groups, with stronger benefits seen in older patients and those with mild disease.

METHODOLOGY: 

• Researchers conducted a retrospective cohort study comparing Veterans who tested positive for COVID-19 between March 15, 2020, and November 30, 2020, to those who tested negative.

• Analysis included 499,396 veterans, with 88,590 (17.2%) COVID-19 positive and 427,566 (82.8%) COVID-19 negative patients, with mean (SD) ages of 57.9 (16.4) and 59.5 (15.8) years, respectively.

• Investigators utilized Cox proportional hazard regression models to determine the hazard ratio of new cancer diagnosis within a three-year follow-up period.

• Patient characteristics included age, race, ethnicity, sex, BMI, smoking status, and various comorbidities as covariates in the analysis.

TAKEAWAY:

• For patients surviving ≥ 30 days after COVID-19 testing, infection was associated with a 25% reduction in cancer hazard (hazard ratio [HR], 0.75; 95% CI, 0.73-0.77).

• The reduction in cancer risk was similar across sexes and races, with the exception of Asians, and showed greater decreases with advancing age above 45 years.

• Patients with mild COVID-19 showed the strongest reduction in cancer risk (adjusted HR, 0.72; 95% CI, 0.70-0.74), while those with moderate COVID-19 showed an 11% reduction (adjusted HR, 0.89; 95% CI, 0.83-0.93), and severe COVID-19 showed no significant reduction in cancer risk.

IN PRACTICE: "Regarding age, the incidence of cancer appeared to decrease with each decade of life in the COVID-19 group com­pared to that in the non-exposed group,” the authors noted. “This is surprising, given that cancer diagnoses typically increase with age.” 

SOURCE: The study was led by researchers at the Miami Veterans Affairs (VA) Healthcare System Geriatric Research, Education, and Clinical Center and was published online on August 25 in PLoS One.

LIMITATIONS: The findings of this retrospective and observational study should be interpreted with caution. Results may not be generalizable beyond the predominantly male, older veteran population. The 3-year follow-up period may be insufficient to fully understand long-term cancer incidence patterns. Researchers could not capture all COVID-19 reinfection cases due to testing occurring outside the Veterans Affairs system, including at-home testing. The impact of vaccination status and reinfection on cancer risk could not be fully assessed, as the initial study cohort was grouped prior to vaccine availability.

DISCLOSURES: The authors report no financial support was received for this study and declare no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: COVID-19 infection is associated with a 25% reduction in cancer risk over 3 years among veterans who survived the initial infection. This protective effect was observed across sexes and racial groups, with stronger benefits seen in older patients and those with mild disease.

METHODOLOGY: 

• Researchers conducted a retrospective cohort study comparing Veterans who tested positive for COVID-19 between March 15, 2020, and November 30, 2020, to those who tested negative.

• Analysis included 499,396 veterans, with 88,590 (17.2%) COVID-19 positive and 427,566 (82.8%) COVID-19 negative patients, with mean (SD) ages of 57.9 (16.4) and 59.5 (15.8) years, respectively.

• Investigators utilized Cox proportional hazard regression models to determine the hazard ratio of new cancer diagnosis within a three-year follow-up period.

• Patient characteristics included age, race, ethnicity, sex, BMI, smoking status, and various comorbidities as covariates in the analysis.

TAKEAWAY:

• For patients surviving ≥ 30 days after COVID-19 testing, infection was associated with a 25% reduction in cancer hazard (hazard ratio [HR], 0.75; 95% CI, 0.73-0.77).

• The reduction in cancer risk was similar across sexes and races, with the exception of Asians, and showed greater decreases with advancing age above 45 years.

• Patients with mild COVID-19 showed the strongest reduction in cancer risk (adjusted HR, 0.72; 95% CI, 0.70-0.74), while those with moderate COVID-19 showed an 11% reduction (adjusted HR, 0.89; 95% CI, 0.83-0.93), and severe COVID-19 showed no significant reduction in cancer risk.

IN PRACTICE: "Regarding age, the incidence of cancer appeared to decrease with each decade of life in the COVID-19 group com­pared to that in the non-exposed group,” the authors noted. “This is surprising, given that cancer diagnoses typically increase with age.” 

SOURCE: The study was led by researchers at the Miami Veterans Affairs (VA) Healthcare System Geriatric Research, Education, and Clinical Center and was published online on August 25 in PLoS One.

LIMITATIONS: The findings of this retrospective and observational study should be interpreted with caution. Results may not be generalizable beyond the predominantly male, older veteran population. The 3-year follow-up period may be insufficient to fully understand long-term cancer incidence patterns. Researchers could not capture all COVID-19 reinfection cases due to testing occurring outside the Veterans Affairs system, including at-home testing. The impact of vaccination status and reinfection on cancer risk could not be fully assessed, as the initial study cohort was grouped prior to vaccine availability.

DISCLOSURES: The authors report no financial support was received for this study and declare no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: COVID-19 infection is associated with a 25% reduction in cancer risk over 3 years among veterans who survived the initial infection. This protective effect was observed across sexes and racial groups, with stronger benefits seen in older patients and those with mild disease.

METHODOLOGY: 

• Researchers conducted a retrospective cohort study comparing Veterans who tested positive for COVID-19 between March 15, 2020, and November 30, 2020, to those who tested negative.

• Analysis included 499,396 veterans, with 88,590 (17.2%) COVID-19 positive and 427,566 (82.8%) COVID-19 negative patients, with mean (SD) ages of 57.9 (16.4) and 59.5 (15.8) years, respectively.

• Investigators utilized Cox proportional hazard regression models to determine the hazard ratio of new cancer diagnosis within a three-year follow-up period.

• Patient characteristics included age, race, ethnicity, sex, BMI, smoking status, and various comorbidities as covariates in the analysis.

TAKEAWAY:

• For patients surviving ≥ 30 days after COVID-19 testing, infection was associated with a 25% reduction in cancer hazard (hazard ratio [HR], 0.75; 95% CI, 0.73-0.77).

• The reduction in cancer risk was similar across sexes and races, with the exception of Asians, and showed greater decreases with advancing age above 45 years.

• Patients with mild COVID-19 showed the strongest reduction in cancer risk (adjusted HR, 0.72; 95% CI, 0.70-0.74), while those with moderate COVID-19 showed an 11% reduction (adjusted HR, 0.89; 95% CI, 0.83-0.93), and severe COVID-19 showed no significant reduction in cancer risk.

IN PRACTICE: "Regarding age, the incidence of cancer appeared to decrease with each decade of life in the COVID-19 group com­pared to that in the non-exposed group,” the authors noted. “This is surprising, given that cancer diagnoses typically increase with age.” 

SOURCE: The study was led by researchers at the Miami Veterans Affairs (VA) Healthcare System Geriatric Research, Education, and Clinical Center and was published online on August 25 in PLoS One.

LIMITATIONS: The findings of this retrospective and observational study should be interpreted with caution. Results may not be generalizable beyond the predominantly male, older veteran population. The 3-year follow-up period may be insufficient to fully understand long-term cancer incidence patterns. Researchers could not capture all COVID-19 reinfection cases due to testing occurring outside the Veterans Affairs system, including at-home testing. The impact of vaccination status and reinfection on cancer risk could not be fully assessed, as the initial study cohort was grouped prior to vaccine availability.

DISCLOSURES: The authors report no financial support was received for this study and declare no competing interests.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Male veterans with breast cancer may have a more difficult time receiving appropriate health care due to a recently revised US Department of Veterans Affairs (VA) policy that requires each individual to prove the disease’s connection to their service to qualify for coverage. 

According to a VA memo obtained by ProPublica, the change is based on a Jan. 1 presidential order titled “Defending Women from Gender Ideology Extremism and Restoring Biological Truth to the Federal Government.” VA Press Secretary Pete Kasperowicz told ProPublica that the policy was changed because the previous policy “falsely classified male breasts as reproductive organs.” 

In 2024, the VA added male breast cancer (along with urethral cancer and cancer of the paraurethral glands) to its list of presumed service-connected disabilities due to military environmental exposure, such as toxic burn pits. Male breast cancer was added to the category of “reproductive cancer of any type” after experts pointed to the similarity of male and female breast cancers.

Establishing a connection between a variety of cancers and military service has been a years-long fight only resolved recently in the form of the 2022 PACT Act. The VA lists > 20 medical conditions as “presumptive” for service connection, with some caveats, such as area of service. The act reduced the burden of proof needed: The terms “presumptive conditions” and “presumptive-exposure locations” mean veterans only have to provide their military records to show they were in an exposure location to have their care for certain conditions covered. 

Supporters of the PACT Act say the policy change could make it harder for veterans to receive timely care, a serious issue for men with breast cancer who have been “severely underrepresented” in clinical studies and many studies specifically exclude males. The American Cancer Society estimates about 2800 men have been or will be diagnosed with invasive breast cancer in 2025. Less than 1% of breast cancers in the US occur in men, but breast cancer is notably higher among veterans: 11% of 3304 veterans, according to a 2023 study. 

Breast cancer is more aggressive in men—they’re more often diagnosed at Stage IV and tend to be older—and survival rates have been lower than in women. In a 2019 study of 16,025 male and 1,800,708 female patients with breast cancer, men had 19% higher overall mortality.

Treatment for male breast cancer has lagged. A 2021 study found men were less likely than women to receive radiation therapy. However, that’s changing. Since that study, however, the American Cancer Society claims treatments and survival rates have improved. According to the Surveillance, Epidemiology, and End Results database, 5-year survival rates are 97% for localized, 86% for regional, and 31% for distant; 84% for all stages combined.

Screening and treatment have focused on women. But the VA Breast and Gynecologic Oncology System of Excellence (BGSoE) provides cancer care for all veterans diagnosed with breast malignancies. Male veterans with breast cancer do face additional challenges in addressing a cancer that is most often associated with females. “I must admit, it was awkward every time I went [to the Women’s Health Center for postmastectomy follow-ups]” William K. Lewis, described in his patient perspective on male breast cancer treatment in the VA.

Though the policy has changed, Kasperowicz told ProPublica that veterans who previously qualified for coverage can keep it: “The department grants disability benefits compensation claims for male Veterans with breast cancer on an individual basis and will continue to do so. VA encourages any male Veterans with breast cancer who feel their health may have been impacted by their military service to submit a disability compensation claim.”

Male veterans with breast cancer may have a more difficult time receiving appropriate health care due to a recently revised US Department of Veterans Affairs (VA) policy that requires each individual to prove the disease’s connection to their service to qualify for coverage. 

According to a VA memo obtained by ProPublica, the change is based on a Jan. 1 presidential order titled “Defending Women from Gender Ideology Extremism and Restoring Biological Truth to the Federal Government.” VA Press Secretary Pete Kasperowicz told ProPublica that the policy was changed because the previous policy “falsely classified male breasts as reproductive organs.” 

In 2024, the VA added male breast cancer (along with urethral cancer and cancer of the paraurethral glands) to its list of presumed service-connected disabilities due to military environmental exposure, such as toxic burn pits. Male breast cancer was added to the category of “reproductive cancer of any type” after experts pointed to the similarity of male and female breast cancers.

Establishing a connection between a variety of cancers and military service has been a years-long fight only resolved recently in the form of the 2022 PACT Act. The VA lists > 20 medical conditions as “presumptive” for service connection, with some caveats, such as area of service. The act reduced the burden of proof needed: The terms “presumptive conditions” and “presumptive-exposure locations” mean veterans only have to provide their military records to show they were in an exposure location to have their care for certain conditions covered. 

Supporters of the PACT Act say the policy change could make it harder for veterans to receive timely care, a serious issue for men with breast cancer who have been “severely underrepresented” in clinical studies and many studies specifically exclude males. The American Cancer Society estimates about 2800 men have been or will be diagnosed with invasive breast cancer in 2025. Less than 1% of breast cancers in the US occur in men, but breast cancer is notably higher among veterans: 11% of 3304 veterans, according to a 2023 study. 

Breast cancer is more aggressive in men—they’re more often diagnosed at Stage IV and tend to be older—and survival rates have been lower than in women. In a 2019 study of 16,025 male and 1,800,708 female patients with breast cancer, men had 19% higher overall mortality.

Treatment for male breast cancer has lagged. A 2021 study found men were less likely than women to receive radiation therapy. However, that’s changing. Since that study, however, the American Cancer Society claims treatments and survival rates have improved. According to the Surveillance, Epidemiology, and End Results database, 5-year survival rates are 97% for localized, 86% for regional, and 31% for distant; 84% for all stages combined.

Screening and treatment have focused on women. But the VA Breast and Gynecologic Oncology System of Excellence (BGSoE) provides cancer care for all veterans diagnosed with breast malignancies. Male veterans with breast cancer do face additional challenges in addressing a cancer that is most often associated with females. “I must admit, it was awkward every time I went [to the Women’s Health Center for postmastectomy follow-ups]” William K. Lewis, described in his patient perspective on male breast cancer treatment in the VA.

Though the policy has changed, Kasperowicz told ProPublica that veterans who previously qualified for coverage can keep it: “The department grants disability benefits compensation claims for male Veterans with breast cancer on an individual basis and will continue to do so. VA encourages any male Veterans with breast cancer who feel their health may have been impacted by their military service to submit a disability compensation claim.”

Male veterans with breast cancer may have a more difficult time receiving appropriate health care due to a recently revised US Department of Veterans Affairs (VA) policy that requires each individual to prove the disease’s connection to their service to qualify for coverage. 

According to a VA memo obtained by ProPublica, the change is based on a Jan. 1 presidential order titled “Defending Women from Gender Ideology Extremism and Restoring Biological Truth to the Federal Government.” VA Press Secretary Pete Kasperowicz told ProPublica that the policy was changed because the previous policy “falsely classified male breasts as reproductive organs.” 

In 2024, the VA added male breast cancer (along with urethral cancer and cancer of the paraurethral glands) to its list of presumed service-connected disabilities due to military environmental exposure, such as toxic burn pits. Male breast cancer was added to the category of “reproductive cancer of any type” after experts pointed to the similarity of male and female breast cancers.

Establishing a connection between a variety of cancers and military service has been a years-long fight only resolved recently in the form of the 2022 PACT Act. The VA lists > 20 medical conditions as “presumptive” for service connection, with some caveats, such as area of service. The act reduced the burden of proof needed: The terms “presumptive conditions” and “presumptive-exposure locations” mean veterans only have to provide their military records to show they were in an exposure location to have their care for certain conditions covered. 

Supporters of the PACT Act say the policy change could make it harder for veterans to receive timely care, a serious issue for men with breast cancer who have been “severely underrepresented” in clinical studies and many studies specifically exclude males. The American Cancer Society estimates about 2800 men have been or will be diagnosed with invasive breast cancer in 2025. Less than 1% of breast cancers in the US occur in men, but breast cancer is notably higher among veterans: 11% of 3304 veterans, according to a 2023 study. 

Breast cancer is more aggressive in men—they’re more often diagnosed at Stage IV and tend to be older—and survival rates have been lower than in women. In a 2019 study of 16,025 male and 1,800,708 female patients with breast cancer, men had 19% higher overall mortality.

Treatment for male breast cancer has lagged. A 2021 study found men were less likely than women to receive radiation therapy. However, that’s changing. Since that study, however, the American Cancer Society claims treatments and survival rates have improved. According to the Surveillance, Epidemiology, and End Results database, 5-year survival rates are 97% for localized, 86% for regional, and 31% for distant; 84% for all stages combined.

Screening and treatment have focused on women. But the VA Breast and Gynecologic Oncology System of Excellence (BGSoE) provides cancer care for all veterans diagnosed with breast malignancies. Male veterans with breast cancer do face additional challenges in addressing a cancer that is most often associated with females. “I must admit, it was awkward every time I went [to the Women’s Health Center for postmastectomy follow-ups]” William K. Lewis, described in his patient perspective on male breast cancer treatment in the VA.

Though the policy has changed, Kasperowicz told ProPublica that veterans who previously qualified for coverage can keep it: “The department grants disability benefits compensation claims for male Veterans with breast cancer on an individual basis and will continue to do so. VA encourages any male Veterans with breast cancer who feel their health may have been impacted by their military service to submit a disability compensation claim.”

A global analysis challenged the notion that a rise in cancer is disproportionately affecting younger adults, finding instead that several cancer types previously seen rising in younger adults are also increasing in older adults.

More specifically, the analysis found that incidence rates for thyroid cancer, breast cancer, kidney cancer, endometrial cancer, and leukemia increased similarly in both younger and older adults in most countries over a 15-year period. Colorectal cancer (CRC) was the exception, where incidence rates increased in younger adults in most countries but only increased slightly in older adults in about half and decreased in about one quarter.

“Our findings suggest that whatever is triggering the rise in these cancers is more likely to be common across all age groups, rather than specific to cancers in the under 50s, since there were similar increases in younger and older adults,” Amy Berrington de González, DPhil, The Institute of Cancer Research, London, England, who led the study, said in a statement.

The authors of an editorial agreed, adding that the growing “concern about increasing cancer rates should recognize that this increase is not restricted to young adults but affects all generations.”

The study and editorial were published recently in Annals of Internal Medicine.

 

Data Defy Early-Onset Cancer Epidemic Narrative

A growing body of evidence suggests that cancer incidence rates are increasing among younger adults in many countries. However, studies tracking international trends have largely evaluated cancer incidence in younger adults without comparing these trends in older adults or analyses have focused the age comparison in individual countries, Berrington de González and colleagues explained.

To better understand cancer incidence trends across countries and age groups, the researchers evaluated cancer trends in 42 countries between 2003 and 2017, focusing on 13 cancer types previously reported to be climbing in adults younger than age 50 years.

The researchers found that incidence rates for six of the 13 cancer types increased among younger adults (aged 20-49 years) in more than three quarters of the countries studied.

The largest increase was in thyroid cancer (median average annual percentage change [AAPC], 3.57%), followed by kidney cancer (median AAPC, 2.21%), endometrial cancer (median AAPC, 1.66%), CRC (median AAPC, 1.45%), breast cancer (median AAPC, 0.89%), and leukemia (median AAPC, 0.78%).

But with the exception of CRC, incidence rates for these cancers increased to a similar degree in adults aged 50 years or older — with median AAPCs of 3% (vs 3.57%) for thyroid cancer, 1.65% (vs 2.21%) for kidney cancer, 1.20% (vs 1.66%) for endometrial cancer, 0.86% (vs 0.89%) for breast cancer, and 0.61% (vs 0.78%) for leukemia.

In older adults, CRC incidence rates only increased in about half the countries (median AAPC, 0.37%), and the annual percentage change was much greater in younger than older adults in nearly 70% of countries. CRC incidence rates in older individuals also decreased in nearly 25% of countries.

Why is CRC an apparent outlier?

“Bowel cancer screening not only helps detect cancer at earlier stages but also helps prevent cancer through the removal of premalignant lesions,” Berrington de González said. “This could be why bowel cancer cases seem to be rising faster in younger adults — we’re getting better at preventing them developing in older adults.”

The incidence of certain cancers also declined in younger adults. Specifically, rates of liver, oral, esophageal, and stomach cancers decreased in younger adults in more than half of countries assessed, with median AAPCs of -0.14% for liver, -0.42% for oral, -0.92% for esophageal, and -1.62% for stomach cancers.

Over half of countries also saw declining rates of stomach (median AAPC, -2.05%) and esophageal (median AAPC, -0.25%) cancers among older adults, while rates of liver and oral cancers increased in older individuals (median AAPC, 2.17% and 0.49%, respectively).

For gallbladder, pancreatic, and prostate cancers — three other cancers previously found to be increasing in younger adults — the researchers reported that incidence rates increased in younger adults in just over half of countries (median AAPCs, 3.2% for prostate cancer, 0.49% for gallbladder cancer, and 1% for pancreatic cancer). Incidence rates also often increased in older adults but to a lesser extent (median AAPCs, 0.75% for prostate cancer, -0.10% for gallbladder, and 0.96% for pancreatic cancer).

 

True Rise or Increased Scrutiny?

Why are cancer rates increasing?

“Understanding factors that contribute to the increase in incidence across the age spectrum was beyond the scope of the study,” editorialists Christopher Cann, MD, Fox Chase Cancer Center, and Efrat Dotan, MD, University of Pennsylvania Health System, both in Philadelphia, wrote.

Several studies have suggested that rising rates of obesity could help explain increasing cancer incidence, particularly in younger adults. In fact, “the cancers that we identified as increasing are all obesity-related cancers, including endometrial and kidney cancer,” Berrington de González said. However, so far, the evidence on this link remains unclear, she acknowledged.

Weighing in on the study, Gilbert Welch, MD, Brigham and Women’s Hospital, Boston, told this news organization that it’s “critically important” to distinguish between two explanations for rising cancer incidence.

There may be an increase in the true occurrence of clinically meaningful cancer, which “warrants investigation into biologic explanations, better treatment, and perhaps more testing,” Welch said.

But it may instead reflect changes in diagnostic scrutiny. “Simply put, whenever we doctors look harder for cancer, we find more,” Welch said. “And there are lots of ways to look harder: testing more people, testing people more frequently, using tests with increasing ability to detect small irregularities, and using lower diagnostic thresholds for labeling these as cancer.”

If increased incidence is the result of greater diagnostic scrutiny, searching for biologic causes is bound to be unproductive and more testing will only aggravate the problem, he explained.

Welch pointed out that the fastest rising cancer in both younger and older adults was thyroid cancer (AAPC, ≥ 3%), which is “exquisitely sensitive” to diagnostic scrutiny.

Take what happened in South Korea. Around 2000, the government of South Korea started a national screening program for breast, colon, and stomach cancers. Doctors and hospitals often added on ultrasound scans for thyroid cancer for a small additional fee.

“A decade later the rate of thyroid cancer diagnosis had increased 15-fold, turning what was once a rare cancer into the most common cancer in Korea,” Welch said. “But the death rate from thyroid cancer did not change. This was not an epidemic of disease; this was an epidemic of diagnosis.”

Welch also noted that the study authors and editorialists put the finding in perspective by explaining that, despite the rising rates of certain cancers in younger adults, cancer remains rare in these adults.

Welch highlighted that, for younger adults in the US, cancer death rates in young adults have cut in half over the last 30 years. “Cancer accounts for only 10% of deaths in young people in the US — and that number is falling,” Welch said.

The study was funded by the Institute of Cancer Research and the National Institutes of Health Intramural Research Program. Disclosures for authors and editorial writers are available with the original articles. Welch reported receiving royalties from three books including “Should I be tested for cancer?”

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

A global analysis challenged the notion that a rise in cancer is disproportionately affecting younger adults, finding instead that several cancer types previously seen rising in younger adults are also increasing in older adults.

More specifically, the analysis found that incidence rates for thyroid cancer, breast cancer, kidney cancer, endometrial cancer, and leukemia increased similarly in both younger and older adults in most countries over a 15-year period. Colorectal cancer (CRC) was the exception, where incidence rates increased in younger adults in most countries but only increased slightly in older adults in about half and decreased in about one quarter.

“Our findings suggest that whatever is triggering the rise in these cancers is more likely to be common across all age groups, rather than specific to cancers in the under 50s, since there were similar increases in younger and older adults,” Amy Berrington de González, DPhil, The Institute of Cancer Research, London, England, who led the study, said in a statement.

The authors of an editorial agreed, adding that the growing “concern about increasing cancer rates should recognize that this increase is not restricted to young adults but affects all generations.”

The study and editorial were published recently in Annals of Internal Medicine.

 

Data Defy Early-Onset Cancer Epidemic Narrative

A growing body of evidence suggests that cancer incidence rates are increasing among younger adults in many countries. However, studies tracking international trends have largely evaluated cancer incidence in younger adults without comparing these trends in older adults or analyses have focused the age comparison in individual countries, Berrington de González and colleagues explained.

To better understand cancer incidence trends across countries and age groups, the researchers evaluated cancer trends in 42 countries between 2003 and 2017, focusing on 13 cancer types previously reported to be climbing in adults younger than age 50 years.

The researchers found that incidence rates for six of the 13 cancer types increased among younger adults (aged 20-49 years) in more than three quarters of the countries studied.

The largest increase was in thyroid cancer (median average annual percentage change [AAPC], 3.57%), followed by kidney cancer (median AAPC, 2.21%), endometrial cancer (median AAPC, 1.66%), CRC (median AAPC, 1.45%), breast cancer (median AAPC, 0.89%), and leukemia (median AAPC, 0.78%).

But with the exception of CRC, incidence rates for these cancers increased to a similar degree in adults aged 50 years or older — with median AAPCs of 3% (vs 3.57%) for thyroid cancer, 1.65% (vs 2.21%) for kidney cancer, 1.20% (vs 1.66%) for endometrial cancer, 0.86% (vs 0.89%) for breast cancer, and 0.61% (vs 0.78%) for leukemia.

In older adults, CRC incidence rates only increased in about half the countries (median AAPC, 0.37%), and the annual percentage change was much greater in younger than older adults in nearly 70% of countries. CRC incidence rates in older individuals also decreased in nearly 25% of countries.

Why is CRC an apparent outlier?

“Bowel cancer screening not only helps detect cancer at earlier stages but also helps prevent cancer through the removal of premalignant lesions,” Berrington de González said. “This could be why bowel cancer cases seem to be rising faster in younger adults — we’re getting better at preventing them developing in older adults.”

The incidence of certain cancers also declined in younger adults. Specifically, rates of liver, oral, esophageal, and stomach cancers decreased in younger adults in more than half of countries assessed, with median AAPCs of -0.14% for liver, -0.42% for oral, -0.92% for esophageal, and -1.62% for stomach cancers.

Over half of countries also saw declining rates of stomach (median AAPC, -2.05%) and esophageal (median AAPC, -0.25%) cancers among older adults, while rates of liver and oral cancers increased in older individuals (median AAPC, 2.17% and 0.49%, respectively).

For gallbladder, pancreatic, and prostate cancers — three other cancers previously found to be increasing in younger adults — the researchers reported that incidence rates increased in younger adults in just over half of countries (median AAPCs, 3.2% for prostate cancer, 0.49% for gallbladder cancer, and 1% for pancreatic cancer). Incidence rates also often increased in older adults but to a lesser extent (median AAPCs, 0.75% for prostate cancer, -0.10% for gallbladder, and 0.96% for pancreatic cancer).

 

True Rise or Increased Scrutiny?

Why are cancer rates increasing?

“Understanding factors that contribute to the increase in incidence across the age spectrum was beyond the scope of the study,” editorialists Christopher Cann, MD, Fox Chase Cancer Center, and Efrat Dotan, MD, University of Pennsylvania Health System, both in Philadelphia, wrote.

Several studies have suggested that rising rates of obesity could help explain increasing cancer incidence, particularly in younger adults. In fact, “the cancers that we identified as increasing are all obesity-related cancers, including endometrial and kidney cancer,” Berrington de González said. However, so far, the evidence on this link remains unclear, she acknowledged.

Weighing in on the study, Gilbert Welch, MD, Brigham and Women’s Hospital, Boston, told this news organization that it’s “critically important” to distinguish between two explanations for rising cancer incidence.

There may be an increase in the true occurrence of clinically meaningful cancer, which “warrants investigation into biologic explanations, better treatment, and perhaps more testing,” Welch said.

But it may instead reflect changes in diagnostic scrutiny. “Simply put, whenever we doctors look harder for cancer, we find more,” Welch said. “And there are lots of ways to look harder: testing more people, testing people more frequently, using tests with increasing ability to detect small irregularities, and using lower diagnostic thresholds for labeling these as cancer.”

If increased incidence is the result of greater diagnostic scrutiny, searching for biologic causes is bound to be unproductive and more testing will only aggravate the problem, he explained.

Welch pointed out that the fastest rising cancer in both younger and older adults was thyroid cancer (AAPC, ≥ 3%), which is “exquisitely sensitive” to diagnostic scrutiny.

Take what happened in South Korea. Around 2000, the government of South Korea started a national screening program for breast, colon, and stomach cancers. Doctors and hospitals often added on ultrasound scans for thyroid cancer for a small additional fee.

“A decade later the rate of thyroid cancer diagnosis had increased 15-fold, turning what was once a rare cancer into the most common cancer in Korea,” Welch said. “But the death rate from thyroid cancer did not change. This was not an epidemic of disease; this was an epidemic of diagnosis.”

Welch also noted that the study authors and editorialists put the finding in perspective by explaining that, despite the rising rates of certain cancers in younger adults, cancer remains rare in these adults.

Welch highlighted that, for younger adults in the US, cancer death rates in young adults have cut in half over the last 30 years. “Cancer accounts for only 10% of deaths in young people in the US — and that number is falling,” Welch said.

The study was funded by the Institute of Cancer Research and the National Institutes of Health Intramural Research Program. Disclosures for authors and editorial writers are available with the original articles. Welch reported receiving royalties from three books including “Should I be tested for cancer?”

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

A global analysis challenged the notion that a rise in cancer is disproportionately affecting younger adults, finding instead that several cancer types previously seen rising in younger adults are also increasing in older adults.

More specifically, the analysis found that incidence rates for thyroid cancer, breast cancer, kidney cancer, endometrial cancer, and leukemia increased similarly in both younger and older adults in most countries over a 15-year period. Colorectal cancer (CRC) was the exception, where incidence rates increased in younger adults in most countries but only increased slightly in older adults in about half and decreased in about one quarter.

“Our findings suggest that whatever is triggering the rise in these cancers is more likely to be common across all age groups, rather than specific to cancers in the under 50s, since there were similar increases in younger and older adults,” Amy Berrington de González, DPhil, The Institute of Cancer Research, London, England, who led the study, said in a statement.

The authors of an editorial agreed, adding that the growing “concern about increasing cancer rates should recognize that this increase is not restricted to young adults but affects all generations.”

The study and editorial were published recently in Annals of Internal Medicine.

 

Data Defy Early-Onset Cancer Epidemic Narrative

A growing body of evidence suggests that cancer incidence rates are increasing among younger adults in many countries. However, studies tracking international trends have largely evaluated cancer incidence in younger adults without comparing these trends in older adults or analyses have focused the age comparison in individual countries, Berrington de González and colleagues explained.

To better understand cancer incidence trends across countries and age groups, the researchers evaluated cancer trends in 42 countries between 2003 and 2017, focusing on 13 cancer types previously reported to be climbing in adults younger than age 50 years.

The researchers found that incidence rates for six of the 13 cancer types increased among younger adults (aged 20-49 years) in more than three quarters of the countries studied.

The largest increase was in thyroid cancer (median average annual percentage change [AAPC], 3.57%), followed by kidney cancer (median AAPC, 2.21%), endometrial cancer (median AAPC, 1.66%), CRC (median AAPC, 1.45%), breast cancer (median AAPC, 0.89%), and leukemia (median AAPC, 0.78%).

But with the exception of CRC, incidence rates for these cancers increased to a similar degree in adults aged 50 years or older — with median AAPCs of 3% (vs 3.57%) for thyroid cancer, 1.65% (vs 2.21%) for kidney cancer, 1.20% (vs 1.66%) for endometrial cancer, 0.86% (vs 0.89%) for breast cancer, and 0.61% (vs 0.78%) for leukemia.

In older adults, CRC incidence rates only increased in about half the countries (median AAPC, 0.37%), and the annual percentage change was much greater in younger than older adults in nearly 70% of countries. CRC incidence rates in older individuals also decreased in nearly 25% of countries.

Why is CRC an apparent outlier?

“Bowel cancer screening not only helps detect cancer at earlier stages but also helps prevent cancer through the removal of premalignant lesions,” Berrington de González said. “This could be why bowel cancer cases seem to be rising faster in younger adults — we’re getting better at preventing them developing in older adults.”

The incidence of certain cancers also declined in younger adults. Specifically, rates of liver, oral, esophageal, and stomach cancers decreased in younger adults in more than half of countries assessed, with median AAPCs of -0.14% for liver, -0.42% for oral, -0.92% for esophageal, and -1.62% for stomach cancers.

Over half of countries also saw declining rates of stomach (median AAPC, -2.05%) and esophageal (median AAPC, -0.25%) cancers among older adults, while rates of liver and oral cancers increased in older individuals (median AAPC, 2.17% and 0.49%, respectively).

For gallbladder, pancreatic, and prostate cancers — three other cancers previously found to be increasing in younger adults — the researchers reported that incidence rates increased in younger adults in just over half of countries (median AAPCs, 3.2% for prostate cancer, 0.49% for gallbladder cancer, and 1% for pancreatic cancer). Incidence rates also often increased in older adults but to a lesser extent (median AAPCs, 0.75% for prostate cancer, -0.10% for gallbladder, and 0.96% for pancreatic cancer).

 

True Rise or Increased Scrutiny?

Why are cancer rates increasing?

“Understanding factors that contribute to the increase in incidence across the age spectrum was beyond the scope of the study,” editorialists Christopher Cann, MD, Fox Chase Cancer Center, and Efrat Dotan, MD, University of Pennsylvania Health System, both in Philadelphia, wrote.

Several studies have suggested that rising rates of obesity could help explain increasing cancer incidence, particularly in younger adults. In fact, “the cancers that we identified as increasing are all obesity-related cancers, including endometrial and kidney cancer,” Berrington de González said. However, so far, the evidence on this link remains unclear, she acknowledged.

Weighing in on the study, Gilbert Welch, MD, Brigham and Women’s Hospital, Boston, told this news organization that it’s “critically important” to distinguish between two explanations for rising cancer incidence.

There may be an increase in the true occurrence of clinically meaningful cancer, which “warrants investigation into biologic explanations, better treatment, and perhaps more testing,” Welch said.

But it may instead reflect changes in diagnostic scrutiny. “Simply put, whenever we doctors look harder for cancer, we find more,” Welch said. “And there are lots of ways to look harder: testing more people, testing people more frequently, using tests with increasing ability to detect small irregularities, and using lower diagnostic thresholds for labeling these as cancer.”

If increased incidence is the result of greater diagnostic scrutiny, searching for biologic causes is bound to be unproductive and more testing will only aggravate the problem, he explained.

Welch pointed out that the fastest rising cancer in both younger and older adults was thyroid cancer (AAPC, ≥ 3%), which is “exquisitely sensitive” to diagnostic scrutiny.

Take what happened in South Korea. Around 2000, the government of South Korea started a national screening program for breast, colon, and stomach cancers. Doctors and hospitals often added on ultrasound scans for thyroid cancer for a small additional fee.

“A decade later the rate of thyroid cancer diagnosis had increased 15-fold, turning what was once a rare cancer into the most common cancer in Korea,” Welch said. “But the death rate from thyroid cancer did not change. This was not an epidemic of disease; this was an epidemic of diagnosis.”

Welch also noted that the study authors and editorialists put the finding in perspective by explaining that, despite the rising rates of certain cancers in younger adults, cancer remains rare in these adults.

Welch highlighted that, for younger adults in the US, cancer death rates in young adults have cut in half over the last 30 years. “Cancer accounts for only 10% of deaths in young people in the US — and that number is falling,” Welch said.

The study was funded by the Institute of Cancer Research and the National Institutes of Health Intramural Research Program. Disclosures for authors and editorial writers are available with the original articles. Welch reported receiving royalties from three books including “Should I be tested for cancer?”

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

TOPLINE: Large Language Models (LLMs) achieve more than 95% accuracy in extracting colorectal cancer and dysplasia diagnoses from Veterans Health Administration (VHA) pathology reports, including patients with Million Veteran Program (MVP) genomic data. The validated approach using publicly available LLMs demonstrates excellent performance across both Inflammatory Bowel Disease (IBD) and non-IBD populations.

METHODOLOGY: 

Researchers analyzed 116,373 pathology reports generated in the VHA between 1999 and 2024, utilizing search term filtering followed by simple yes/no question prompts for identifying colorectal dysplasia, high-grade dysplasia and/or colorectal adenocarcinoma, and invasive colorectal cancer.

• Results were compared to blinded manual chart review of 200 to 300 pathology reports for each patient cohort and diagnostic task, totaling 3,816 reviewed reports, to validate the LLM approach.

• Validation was performed independently in IBD and non-IBD populations using Gemma-2 and Llama-3 LLMs without any task-specific training or fine-tuning.

• Performance metrics included F1 scores, positive predictive value, negative predictive value, sensitivity, specificity, and Matthew's correlation coefficient to evaluate accuracy across different tasks.

TAKEAWAY:

• In patients with IBD in the MVP, the LLM achieved (F1-score, 96.9%; 95% confidence interval [CI], 94.0%-99.6%) for identifying dysplasia, (F1-score, 93.7%; 95% CI, 88.2%-98.4%) for identifying high-grade dysplasia/colorectal cancer, and (F1-score, 98%; 95% CI, 96.3%-99.4%) for identifying colorectal cancer.

• In non-IBD MVP patients, the LLM demonstrated (F1-score, 99.2%; 95% CI, 98.2%-100%) for identifying colorectal dysplasia, (F1-score, 96.5%; 95% CI, 93.0%-99.2%) for high-grade dysplasia/colorectal cancer, and (F1-score, 95%; 95% CI, 92.8%-97.2%) for identifying colorectal cancer.

• Agreement between reviewers was excellent across tasks, with (Cohen's kappa, 89%-97%) for main tasks, and (Cohen's kappa, 78.1%-93.1%) for indefinite for dysplasia in IBD cohort.

• The LLM approach maintained high accuracy when applied to full pathology reports, with (F1-score, 97.1%; 95% CI, 93.5%-100%) for dysplasia detection in IBD patients.

IN PRACTICE: “We have shown that LLMs are powerful, potentially generalizable tools for accurately extracting important information from clinical semistructured and unstructured text and which require little human-led development.” the authors of the study wrote

SOURCE: The study was based on data from the Million Veteran Program and supported by the Office of Research and Development, Veterans Health Administration, and the US Department of Veterans Affairs Biomedical Laboratory. It was published online in BMJ Open Gastroenterology.

LIMITATIONS:  According to the authors, this research may be specific to the VHA system and the LLM models used. The authors did not test larger models. The authors acknowledge that without long-term access to graphics processing units, they could not feasibly test larger models, which may overcome some of the shortcomings seen in smaller models. Additionally, the researchers could not rule out overlap between Million Veteran Program and Corporate Data Warehouse reports, though they state that results in either cohort alone are sufficient validation compared with previously published work.

DISCLOSURES: The study was supported by Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, AGA Research Foundation, National Institutes of Health grants, and the National Library of Medicine Training Grant. Kit Curtius reported receiving an investigator-led research grant from Phathom Pharmaceuticals. Shailja C Shah disclosed being a paid consultant for RedHill Biopharma and Phathom Pharmaceuticals, and an unpaid scientific advisory board member for Ilico Genetics, Inc.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Large Language Models (LLMs) achieve more than 95% accuracy in extracting colorectal cancer and dysplasia diagnoses from Veterans Health Administration (VHA) pathology reports, including patients with Million Veteran Program (MVP) genomic data. The validated approach using publicly available LLMs demonstrates excellent performance across both Inflammatory Bowel Disease (IBD) and non-IBD populations.

METHODOLOGY: 

Researchers analyzed 116,373 pathology reports generated in the VHA between 1999 and 2024, utilizing search term filtering followed by simple yes/no question prompts for identifying colorectal dysplasia, high-grade dysplasia and/or colorectal adenocarcinoma, and invasive colorectal cancer.

• Results were compared to blinded manual chart review of 200 to 300 pathology reports for each patient cohort and diagnostic task, totaling 3,816 reviewed reports, to validate the LLM approach.

• Validation was performed independently in IBD and non-IBD populations using Gemma-2 and Llama-3 LLMs without any task-specific training or fine-tuning.

• Performance metrics included F1 scores, positive predictive value, negative predictive value, sensitivity, specificity, and Matthew's correlation coefficient to evaluate accuracy across different tasks.

TAKEAWAY:

• In patients with IBD in the MVP, the LLM achieved (F1-score, 96.9%; 95% confidence interval [CI], 94.0%-99.6%) for identifying dysplasia, (F1-score, 93.7%; 95% CI, 88.2%-98.4%) for identifying high-grade dysplasia/colorectal cancer, and (F1-score, 98%; 95% CI, 96.3%-99.4%) for identifying colorectal cancer.

• In non-IBD MVP patients, the LLM demonstrated (F1-score, 99.2%; 95% CI, 98.2%-100%) for identifying colorectal dysplasia, (F1-score, 96.5%; 95% CI, 93.0%-99.2%) for high-grade dysplasia/colorectal cancer, and (F1-score, 95%; 95% CI, 92.8%-97.2%) for identifying colorectal cancer.

• Agreement between reviewers was excellent across tasks, with (Cohen's kappa, 89%-97%) for main tasks, and (Cohen's kappa, 78.1%-93.1%) for indefinite for dysplasia in IBD cohort.

• The LLM approach maintained high accuracy when applied to full pathology reports, with (F1-score, 97.1%; 95% CI, 93.5%-100%) for dysplasia detection in IBD patients.

IN PRACTICE: “We have shown that LLMs are powerful, potentially generalizable tools for accurately extracting important information from clinical semistructured and unstructured text and which require little human-led development.” the authors of the study wrote

SOURCE: The study was based on data from the Million Veteran Program and supported by the Office of Research and Development, Veterans Health Administration, and the US Department of Veterans Affairs Biomedical Laboratory. It was published online in BMJ Open Gastroenterology.

LIMITATIONS:  According to the authors, this research may be specific to the VHA system and the LLM models used. The authors did not test larger models. The authors acknowledge that without long-term access to graphics processing units, they could not feasibly test larger models, which may overcome some of the shortcomings seen in smaller models. Additionally, the researchers could not rule out overlap between Million Veteran Program and Corporate Data Warehouse reports, though they state that results in either cohort alone are sufficient validation compared with previously published work.

DISCLOSURES: The study was supported by Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, AGA Research Foundation, National Institutes of Health grants, and the National Library of Medicine Training Grant. Kit Curtius reported receiving an investigator-led research grant from Phathom Pharmaceuticals. Shailja C Shah disclosed being a paid consultant for RedHill Biopharma and Phathom Pharmaceuticals, and an unpaid scientific advisory board member for Ilico Genetics, Inc.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Large Language Models (LLMs) achieve more than 95% accuracy in extracting colorectal cancer and dysplasia diagnoses from Veterans Health Administration (VHA) pathology reports, including patients with Million Veteran Program (MVP) genomic data. The validated approach using publicly available LLMs demonstrates excellent performance across both Inflammatory Bowel Disease (IBD) and non-IBD populations.

METHODOLOGY: 

Researchers analyzed 116,373 pathology reports generated in the VHA between 1999 and 2024, utilizing search term filtering followed by simple yes/no question prompts for identifying colorectal dysplasia, high-grade dysplasia and/or colorectal adenocarcinoma, and invasive colorectal cancer.

• Results were compared to blinded manual chart review of 200 to 300 pathology reports for each patient cohort and diagnostic task, totaling 3,816 reviewed reports, to validate the LLM approach.

• Validation was performed independently in IBD and non-IBD populations using Gemma-2 and Llama-3 LLMs without any task-specific training or fine-tuning.

• Performance metrics included F1 scores, positive predictive value, negative predictive value, sensitivity, specificity, and Matthew's correlation coefficient to evaluate accuracy across different tasks.

TAKEAWAY:

• In patients with IBD in the MVP, the LLM achieved (F1-score, 96.9%; 95% confidence interval [CI], 94.0%-99.6%) for identifying dysplasia, (F1-score, 93.7%; 95% CI, 88.2%-98.4%) for identifying high-grade dysplasia/colorectal cancer, and (F1-score, 98%; 95% CI, 96.3%-99.4%) for identifying colorectal cancer.

• In non-IBD MVP patients, the LLM demonstrated (F1-score, 99.2%; 95% CI, 98.2%-100%) for identifying colorectal dysplasia, (F1-score, 96.5%; 95% CI, 93.0%-99.2%) for high-grade dysplasia/colorectal cancer, and (F1-score, 95%; 95% CI, 92.8%-97.2%) for identifying colorectal cancer.

• Agreement between reviewers was excellent across tasks, with (Cohen's kappa, 89%-97%) for main tasks, and (Cohen's kappa, 78.1%-93.1%) for indefinite for dysplasia in IBD cohort.

• The LLM approach maintained high accuracy when applied to full pathology reports, with (F1-score, 97.1%; 95% CI, 93.5%-100%) for dysplasia detection in IBD patients.

IN PRACTICE: “We have shown that LLMs are powerful, potentially generalizable tools for accurately extracting important information from clinical semistructured and unstructured text and which require little human-led development.” the authors of the study wrote

SOURCE: The study was based on data from the Million Veteran Program and supported by the Office of Research and Development, Veterans Health Administration, and the US Department of Veterans Affairs Biomedical Laboratory. It was published online in BMJ Open Gastroenterology.

LIMITATIONS:  According to the authors, this research may be specific to the VHA system and the LLM models used. The authors did not test larger models. The authors acknowledge that without long-term access to graphics processing units, they could not feasibly test larger models, which may overcome some of the shortcomings seen in smaller models. Additionally, the researchers could not rule out overlap between Million Veteran Program and Corporate Data Warehouse reports, though they state that results in either cohort alone are sufficient validation compared with previously published work.

DISCLOSURES: The study was supported by Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, AGA Research Foundation, National Institutes of Health grants, and the National Library of Medicine Training Grant. Kit Curtius reported receiving an investigator-led research grant from Phathom Pharmaceuticals. Shailja C Shah disclosed being a paid consultant for RedHill Biopharma and Phathom Pharmaceuticals, and an unpaid scientific advisory board member for Ilico Genetics, Inc.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

PHOENIX ‑ A US Department of Veterans Affairs (VA) hospital in Tennessee has performed the first “bloodless” autologous stem cell transplant within the Veterans Health Administration, treating a 61-year-old Jehovah’s Witness patient with multiple myeloma who traveled from California for the procedure.

The case, presented at the annual meeting of the Association of VA Hematology/Oncology, stated that “we should not withhold any therapies for patients who are Jehovah’s Witnesses out of fear of them bleeding out or having complications from anemia,” said Bhagirathbhai Dholaria, MBBS, an associate professor of medicine at Vanderbilt University Medical Center who worked with the VA Tennessee Valley Healthcare System in Nashville.

While Jehovah’s Witnesses accept medical treatment, their faith forbids blood transfusions, including of preoperative autologous blood, due to its interpretation of the Bible. The faith allows individuals to decide whether to accept stem cells collected from their blood or someone else’s “provided that blood components are not intentionally collected, stored, and reinfused along with the stem cells.”

There are an estimated 1.2 million Jehovah’s Witnesses in the US. 

Traditional Stem Cell Transplants Require Blood Support

In conventional autologous stem cell transplants for multiple myeloma, high-dose chemotherapy temporarily wipes out the patient’s bone marrow for about 2 to 3 weeks, Dholaria explained. During this period, patients typically receive 2 units of packed red blood cells and platelet transfusions to prevent severe complications from anemia and low platelet counts.

“Because of this reason, Jehovah’s Witnesses have been traditionally denied these therapies,” Dholaria said.

However, bloodless autologous transplants have been performed for about 2 decades, and Vanderbilt University has been offering the procedures for about 3 years, according to Dholaria.

For the first bloodless procedure in the VA, the patient–who had an aggressive, newly diagnosed IgG kappa multiple myeloma–was evaluated.

“He had been treated by local doctors in California. Otherwise, he was actually in really good shape. Physically, he didn’t have any major issues,” Dholaria said. “So, he met the criteria for our bloodless protocol, and we decided to offer him the procedure.”

The team consulted ethics and legal departments and noted the patient’s blood product preferences in his electronic health record. The patient then underwent a preoptimization protocol that included erythropoiesis-stimulating agents, intravenous iron, and vitamin B12 supplementation to boost blood counts before the transplant, according to the case presentation. 

Special Protocol Required in ‘Bloodless’ Procedures

After stem cell collection and chemotherapy, patients undergoing bloodless procedures receive aggressive growth factor support to minimize the duration and severity of cytopenia, Dholaria said. As part of the protocol, the care team uses pediatric tubes for blood draws to minimize blood loss and monitors patients closely on cardiac monitors, he added. In addition, blood draws are only performed every 3 days. 

“We watch for any cardiac decompensation because these patients have severe anemia for a brief period of time. We make sure they don’t [have a] heart attack or arrhythmias,” Dholaria said. “Or if the platelets are too low, and they start oozing blood from the nose, gums, or gut, that needs to be dealt with accordingly.”

For bleeding complications, the team uses clotting factors and intravenous and oral medications to support remaining platelet function rather than platelet transfusions.

The patient in this case tolerated the transplant “exceptionally well with minimal complications,” according to the case presentation. He achieved full engraftment on day 14 after transplant and was discharged from inpatient care with continued monitoring through day 30.

“The patient was very compliant,” said Salyka Sengsayadeth, MD, medical director of the VA Tennessee Valley Healthcare System Stem Cell Transplant and Cellular Therapy Program and associate professor of medicine at Vanderbilt. 

“He tolerated everything that we needed to do,” she said. “He called us when he needed to call us and did everything that we asked and recommended for him.”

The patient’s roughly 30-day hospital stay matched that of typical transplant patients, Sengsayadeth noted. His myeloma responded to treatment, and he returned to California, Dholaria said.

‘Bloodless’ Procedures Not for All Stem Cell Transplants 

The case highlights the availability of stem cell transplants in the VA–they are only performed in Seattle and Nashville–and opportunities for patients who wish to avoid blood transfusions. Sengsayadeth said the bloodless protocol is available for patients without religious objections who simply prefer to avoid blood products.

Dholaria cautioned that bloodless protocol applies specifically to autologous transplants, where patients receive their own stem cells. The team does not plan to offer bloodless allogeneic transplants, which use donor stem cells for conditions like leukemia, due to higher risks. In addition, most Jehovah’s Witnesses decline allogeneic transplants because they do not accept stem cells from another person, Dholaria said.

Beyond multiple myeloma, the Tennessee Valley Healthcare System offers bloodless autologous transplants for various blood cancers, including non-Hodgkin lymphomas such as large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, as well as lymphomas affecting the brain, Dholaria said.

Clinicians “should start thinking about this early on, as soon as the cancer diagnosis is made, to make the referral and get the patient on our radar,” Dholaria said.

Sengsayadeth said physicians within the VA typically know how to refer appropriate patients to her team. “They just send us an email or give us a call or a message to say ‘I have this patient. Do you think they’re someone I should send to you?’ We usually answer right back, and then we can proceed with the full evaluation if we think that’s a reasonable thing to do.”

‘Treated Like Family’

The patient, a Marine Corps veteran named Keith Cody, spoke about the procedure in a video interview. Cody said he was reluctant at first to undergo the procedure because he didn’t understand what it would accomplish. 

“As I was doing the massive chemo every week, and then suffering with the side effects, I decided to ask again about this procedure and how it improves my quality of life,” he said. 

At the time of the taping of the video, Cody was getting ready to go home to California. “They’ve told me that I’ll still need more time to get my energy back, but I do feel much better already,” he said.

He also praised the staff. “Everybody that we came across, I enjoyed the interactions. It’s actually sad to leave people behind that you really felt treated you like family.”

Dholaria discloses relationships with Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, Adicet, BMS, Molecular Templates, Atara, MJH, Arvinas, Janssen, ADC, Gilead, GSK, Caribou, F. Hoffmann-La Roche AG, Autolus, and Pierre Fabre.

Sengsayadeth has no disclosures. 

PHOENIX ‑ A US Department of Veterans Affairs (VA) hospital in Tennessee has performed the first “bloodless” autologous stem cell transplant within the Veterans Health Administration, treating a 61-year-old Jehovah’s Witness patient with multiple myeloma who traveled from California for the procedure.

The case, presented at the annual meeting of the Association of VA Hematology/Oncology, stated that “we should not withhold any therapies for patients who are Jehovah’s Witnesses out of fear of them bleeding out or having complications from anemia,” said Bhagirathbhai Dholaria, MBBS, an associate professor of medicine at Vanderbilt University Medical Center who worked with the VA Tennessee Valley Healthcare System in Nashville.

While Jehovah’s Witnesses accept medical treatment, their faith forbids blood transfusions, including of preoperative autologous blood, due to its interpretation of the Bible. The faith allows individuals to decide whether to accept stem cells collected from their blood or someone else’s “provided that blood components are not intentionally collected, stored, and reinfused along with the stem cells.”

There are an estimated 1.2 million Jehovah’s Witnesses in the US. 

Traditional Stem Cell Transplants Require Blood Support

In conventional autologous stem cell transplants for multiple myeloma, high-dose chemotherapy temporarily wipes out the patient’s bone marrow for about 2 to 3 weeks, Dholaria explained. During this period, patients typically receive 2 units of packed red blood cells and platelet transfusions to prevent severe complications from anemia and low platelet counts.

“Because of this reason, Jehovah’s Witnesses have been traditionally denied these therapies,” Dholaria said.

However, bloodless autologous transplants have been performed for about 2 decades, and Vanderbilt University has been offering the procedures for about 3 years, according to Dholaria.

For the first bloodless procedure in the VA, the patient–who had an aggressive, newly diagnosed IgG kappa multiple myeloma–was evaluated.

“He had been treated by local doctors in California. Otherwise, he was actually in really good shape. Physically, he didn’t have any major issues,” Dholaria said. “So, he met the criteria for our bloodless protocol, and we decided to offer him the procedure.”

The team consulted ethics and legal departments and noted the patient’s blood product preferences in his electronic health record. The patient then underwent a preoptimization protocol that included erythropoiesis-stimulating agents, intravenous iron, and vitamin B12 supplementation to boost blood counts before the transplant, according to the case presentation. 

Special Protocol Required in ‘Bloodless’ Procedures

After stem cell collection and chemotherapy, patients undergoing bloodless procedures receive aggressive growth factor support to minimize the duration and severity of cytopenia, Dholaria said. As part of the protocol, the care team uses pediatric tubes for blood draws to minimize blood loss and monitors patients closely on cardiac monitors, he added. In addition, blood draws are only performed every 3 days. 

“We watch for any cardiac decompensation because these patients have severe anemia for a brief period of time. We make sure they don’t [have a] heart attack or arrhythmias,” Dholaria said. “Or if the platelets are too low, and they start oozing blood from the nose, gums, or gut, that needs to be dealt with accordingly.”

For bleeding complications, the team uses clotting factors and intravenous and oral medications to support remaining platelet function rather than platelet transfusions.

The patient in this case tolerated the transplant “exceptionally well with minimal complications,” according to the case presentation. He achieved full engraftment on day 14 after transplant and was discharged from inpatient care with continued monitoring through day 30.

“The patient was very compliant,” said Salyka Sengsayadeth, MD, medical director of the VA Tennessee Valley Healthcare System Stem Cell Transplant and Cellular Therapy Program and associate professor of medicine at Vanderbilt. 

“He tolerated everything that we needed to do,” she said. “He called us when he needed to call us and did everything that we asked and recommended for him.”

The patient’s roughly 30-day hospital stay matched that of typical transplant patients, Sengsayadeth noted. His myeloma responded to treatment, and he returned to California, Dholaria said.

‘Bloodless’ Procedures Not for All Stem Cell Transplants 

The case highlights the availability of stem cell transplants in the VA–they are only performed in Seattle and Nashville–and opportunities for patients who wish to avoid blood transfusions. Sengsayadeth said the bloodless protocol is available for patients without religious objections who simply prefer to avoid blood products.

Dholaria cautioned that bloodless protocol applies specifically to autologous transplants, where patients receive their own stem cells. The team does not plan to offer bloodless allogeneic transplants, which use donor stem cells for conditions like leukemia, due to higher risks. In addition, most Jehovah’s Witnesses decline allogeneic transplants because they do not accept stem cells from another person, Dholaria said.

Beyond multiple myeloma, the Tennessee Valley Healthcare System offers bloodless autologous transplants for various blood cancers, including non-Hodgkin lymphomas such as large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, as well as lymphomas affecting the brain, Dholaria said.

Clinicians “should start thinking about this early on, as soon as the cancer diagnosis is made, to make the referral and get the patient on our radar,” Dholaria said.

Sengsayadeth said physicians within the VA typically know how to refer appropriate patients to her team. “They just send us an email or give us a call or a message to say ‘I have this patient. Do you think they’re someone I should send to you?’ We usually answer right back, and then we can proceed with the full evaluation if we think that’s a reasonable thing to do.”

‘Treated Like Family’

The patient, a Marine Corps veteran named Keith Cody, spoke about the procedure in a video interview. Cody said he was reluctant at first to undergo the procedure because he didn’t understand what it would accomplish. 

“As I was doing the massive chemo every week, and then suffering with the side effects, I decided to ask again about this procedure and how it improves my quality of life,” he said. 

At the time of the taping of the video, Cody was getting ready to go home to California. “They’ve told me that I’ll still need more time to get my energy back, but I do feel much better already,” he said.

He also praised the staff. “Everybody that we came across, I enjoyed the interactions. It’s actually sad to leave people behind that you really felt treated you like family.”

Dholaria discloses relationships with Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, Adicet, BMS, Molecular Templates, Atara, MJH, Arvinas, Janssen, ADC, Gilead, GSK, Caribou, F. Hoffmann-La Roche AG, Autolus, and Pierre Fabre.

Sengsayadeth has no disclosures. 

PHOENIX ‑ A US Department of Veterans Affairs (VA) hospital in Tennessee has performed the first “bloodless” autologous stem cell transplant within the Veterans Health Administration, treating a 61-year-old Jehovah’s Witness patient with multiple myeloma who traveled from California for the procedure.

The case, presented at the annual meeting of the Association of VA Hematology/Oncology, stated that “we should not withhold any therapies for patients who are Jehovah’s Witnesses out of fear of them bleeding out or having complications from anemia,” said Bhagirathbhai Dholaria, MBBS, an associate professor of medicine at Vanderbilt University Medical Center who worked with the VA Tennessee Valley Healthcare System in Nashville.

While Jehovah’s Witnesses accept medical treatment, their faith forbids blood transfusions, including of preoperative autologous blood, due to its interpretation of the Bible. The faith allows individuals to decide whether to accept stem cells collected from their blood or someone else’s “provided that blood components are not intentionally collected, stored, and reinfused along with the stem cells.”

There are an estimated 1.2 million Jehovah’s Witnesses in the US. 

Traditional Stem Cell Transplants Require Blood Support

In conventional autologous stem cell transplants for multiple myeloma, high-dose chemotherapy temporarily wipes out the patient’s bone marrow for about 2 to 3 weeks, Dholaria explained. During this period, patients typically receive 2 units of packed red blood cells and platelet transfusions to prevent severe complications from anemia and low platelet counts.

“Because of this reason, Jehovah’s Witnesses have been traditionally denied these therapies,” Dholaria said.

However, bloodless autologous transplants have been performed for about 2 decades, and Vanderbilt University has been offering the procedures for about 3 years, according to Dholaria.

For the first bloodless procedure in the VA, the patient–who had an aggressive, newly diagnosed IgG kappa multiple myeloma–was evaluated.

“He had been treated by local doctors in California. Otherwise, he was actually in really good shape. Physically, he didn’t have any major issues,” Dholaria said. “So, he met the criteria for our bloodless protocol, and we decided to offer him the procedure.”

The team consulted ethics and legal departments and noted the patient’s blood product preferences in his electronic health record. The patient then underwent a preoptimization protocol that included erythropoiesis-stimulating agents, intravenous iron, and vitamin B12 supplementation to boost blood counts before the transplant, according to the case presentation. 

Special Protocol Required in ‘Bloodless’ Procedures

After stem cell collection and chemotherapy, patients undergoing bloodless procedures receive aggressive growth factor support to minimize the duration and severity of cytopenia, Dholaria said. As part of the protocol, the care team uses pediatric tubes for blood draws to minimize blood loss and monitors patients closely on cardiac monitors, he added. In addition, blood draws are only performed every 3 days. 

“We watch for any cardiac decompensation because these patients have severe anemia for a brief period of time. We make sure they don’t [have a] heart attack or arrhythmias,” Dholaria said. “Or if the platelets are too low, and they start oozing blood from the nose, gums, or gut, that needs to be dealt with accordingly.”

For bleeding complications, the team uses clotting factors and intravenous and oral medications to support remaining platelet function rather than platelet transfusions.

The patient in this case tolerated the transplant “exceptionally well with minimal complications,” according to the case presentation. He achieved full engraftment on day 14 after transplant and was discharged from inpatient care with continued monitoring through day 30.

“The patient was very compliant,” said Salyka Sengsayadeth, MD, medical director of the VA Tennessee Valley Healthcare System Stem Cell Transplant and Cellular Therapy Program and associate professor of medicine at Vanderbilt. 

“He tolerated everything that we needed to do,” she said. “He called us when he needed to call us and did everything that we asked and recommended for him.”

The patient’s roughly 30-day hospital stay matched that of typical transplant patients, Sengsayadeth noted. His myeloma responded to treatment, and he returned to California, Dholaria said.

‘Bloodless’ Procedures Not for All Stem Cell Transplants 

The case highlights the availability of stem cell transplants in the VA–they are only performed in Seattle and Nashville–and opportunities for patients who wish to avoid blood transfusions. Sengsayadeth said the bloodless protocol is available for patients without religious objections who simply prefer to avoid blood products.

Dholaria cautioned that bloodless protocol applies specifically to autologous transplants, where patients receive their own stem cells. The team does not plan to offer bloodless allogeneic transplants, which use donor stem cells for conditions like leukemia, due to higher risks. In addition, most Jehovah’s Witnesses decline allogeneic transplants because they do not accept stem cells from another person, Dholaria said.

Beyond multiple myeloma, the Tennessee Valley Healthcare System offers bloodless autologous transplants for various blood cancers, including non-Hodgkin lymphomas such as large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, as well as lymphomas affecting the brain, Dholaria said.

Clinicians “should start thinking about this early on, as soon as the cancer diagnosis is made, to make the referral and get the patient on our radar,” Dholaria said.

Sengsayadeth said physicians within the VA typically know how to refer appropriate patients to her team. “They just send us an email or give us a call or a message to say ‘I have this patient. Do you think they’re someone I should send to you?’ We usually answer right back, and then we can proceed with the full evaluation if we think that’s a reasonable thing to do.”

‘Treated Like Family’

The patient, a Marine Corps veteran named Keith Cody, spoke about the procedure in a video interview. Cody said he was reluctant at first to undergo the procedure because he didn’t understand what it would accomplish. 

“As I was doing the massive chemo every week, and then suffering with the side effects, I decided to ask again about this procedure and how it improves my quality of life,” he said. 

At the time of the taping of the video, Cody was getting ready to go home to California. “They’ve told me that I’ll still need more time to get my energy back, but I do feel much better already,” he said.

He also praised the staff. “Everybody that we came across, I enjoyed the interactions. It’s actually sad to leave people behind that you really felt treated you like family.”

Dholaria discloses relationships with Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, Adicet, BMS, Molecular Templates, Atara, MJH, Arvinas, Janssen, ADC, Gilead, GSK, Caribou, F. Hoffmann-La Roche AG, Autolus, and Pierre Fabre.

Sengsayadeth has no disclosures. 

PHOENIX — Patients with head and neck cancer face high rates of malnutrition during treatment, and oral supplements are often recommended. But they are not the entire answer, a dietician told colleagues at the Association of Veterans Affairs (VA) Hematology/Oncology annual meeting.

“Patients should consume the most liberal diet possible throughout treatment,” said advanced practice oncology dietician Brittany Leneweaver, RD, CSO, CES, at the VA Washington DC Healthcare System. “This means not solely relying on oral nutrition supplements like Ensure if possible.”

While Leneweaver said many patients will need supplements, she stressed these products “are meant to supplement the diet and not be the sole source of nutrition, ideally.” Encouraging the intake of whole foods “is really key to make the transition back to solid foods after they’re done with treatment. This makes it so much easier when they’re already swallowing those thicker textures, rather than just liquid the entire time.”

Malnutrition: Common and Damaging

As Leneweaver noted, malnutrition is common in patients with head and neck cancer, and can lead to “increased treatment toxicity, increased risk of infection, decreased survival, increased surgical complication, delayed healing, decreased physical function, and decreased quality of life.”

Malnutrition data in patients with head and neck cancer in the US is sparse. However, a 2024 study found malnutrition in 20% of patients undergoing head and neck cancer surgery and linked the condition to increased length of stay (β, 5.20 additional days), higher costs (β, $15,722) higher odds of potentially preventable complications (adjusted odds ratio [aOR], 2.04), and lower odds of discharge to home (aOR, 0.34).

Leneweaver said her role involves addressing “nutrition impact symptoms” that reduce veteran food intake such as difficulty swallowing, taste disorders, dry mouth, and inflammation of the mucus membranes.

“I can’t tell you how much time I spend just talking to the patient about their medication regimens, making sure they have antiemetics on board, letting the radiation oncologist know, ‘Hey, it’s probably time for medicine,’” she said. “We’re constantly looking at side effects and addressing to alert the team as quickly as possible so that we can prevent further weight loss.”

Better Diets Lead to Better Outcomes

Leneweaver noted that “many times, patients will continue to rely on oral supplements as their primary source of nutrition over the long term. They may be missing out on several health benefits as a result.”

Research shows that high-quality diets matter in this patient group, she said. They’re associated with “decreased symptoms during treatment, reduced head and neck cancer risk, and reduced risk of those chronic nutrition impact symptoms,” Leneweaver said.

Diets before and after cancer diagnosis can make a difference. A 2019 study examined patient diets prior to diagnosis of head and neck cancer. It found that patients with better diet quality were less likely to experience overall nutrition impact symptoms (OR 0.45). However, “studies have found that the majority of our patients with head and neck cancer have an inadequate diet prior to diagnosis,” Leneweaver said. 

As for postdiagnosis nutrition, a 2022 study linked healthier diets in patients with head and neck cancer to 93% lower 3-year risk of all-cause mortality and 85% lower risk of cancer-specific mortality. 

What’s in a High-Quality Diet?

Regarding specific food recommendations, Leneweaver prefers the American Institute for Cancer Research (AICR) nutrition guidelines over the US Department of Agriculture’s Dietary Guidelines for Americans. The AICR “more clearly recommends plant-based diet with at least two-thirds of each meal coming from a variety of plant sources” and recommends avoiding alcohol entirely and limiting red meat, she said. 

Leneweaver said she recognizes that dietary change can be gradual.

“It’s not going to happen overnight,” she said. “We know that lifestyle change takes a lot of work.”

Basic interventions can be effective, she said: “This can be just as simple as recommending a plant-based diet to your patient or recommending they eat the rainbow. And I don’t mean Skittles, I mean actual plants. If you just mention these couple of things to the patients, this can really go a long way, especially if they’re hearing that consistent messaging.”

Team-Based Follow-Up Is Key

Leneweaver emphasized the importance of following up over time even if patients do not initially accept referrals to nutritional services. Dieticians ideally see patients before or during initial treatment and then weekly during radiation therapy. Posttreatment follow-up continues “until they’re nutritionally stable. This can be anywhere from weekly to monthly.”

Leneweaver emphasized collaborating with other team members. For example, she works with a speech pathologist at joint visits, either weekly or monthly, “so that they can get off of that feeding tube or get back to a solid consistency diet, typically before that 3-month PET scan.”

It is also important to understand barriers to healthy eating in the veteran population, including transportation challenges and poor access to healthy food, Leneweaver said.

“Make sure you’re utilizing your social worker, your psychologist, other resources, and food pantries, if you have them.” 

Even when the most ideal choices are not available, she said, “if they only have access to canned vegetables, I’d much rather them eat that than have nothing.”

No disclosures for Leneweaver were provided. 

PHOENIX — Patients with head and neck cancer face high rates of malnutrition during treatment, and oral supplements are often recommended. But they are not the entire answer, a dietician told colleagues at the Association of Veterans Affairs (VA) Hematology/Oncology annual meeting.

“Patients should consume the most liberal diet possible throughout treatment,” said advanced practice oncology dietician Brittany Leneweaver, RD, CSO, CES, at the VA Washington DC Healthcare System. “This means not solely relying on oral nutrition supplements like Ensure if possible.”

While Leneweaver said many patients will need supplements, she stressed these products “are meant to supplement the diet and not be the sole source of nutrition, ideally.” Encouraging the intake of whole foods “is really key to make the transition back to solid foods after they’re done with treatment. This makes it so much easier when they’re already swallowing those thicker textures, rather than just liquid the entire time.”

Malnutrition: Common and Damaging

As Leneweaver noted, malnutrition is common in patients with head and neck cancer, and can lead to “increased treatment toxicity, increased risk of infection, decreased survival, increased surgical complication, delayed healing, decreased physical function, and decreased quality of life.”

Malnutrition data in patients with head and neck cancer in the US is sparse. However, a 2024 study found malnutrition in 20% of patients undergoing head and neck cancer surgery and linked the condition to increased length of stay (β, 5.20 additional days), higher costs (β, $15,722) higher odds of potentially preventable complications (adjusted odds ratio [aOR], 2.04), and lower odds of discharge to home (aOR, 0.34).

Leneweaver said her role involves addressing “nutrition impact symptoms” that reduce veteran food intake such as difficulty swallowing, taste disorders, dry mouth, and inflammation of the mucus membranes.

“I can’t tell you how much time I spend just talking to the patient about their medication regimens, making sure they have antiemetics on board, letting the radiation oncologist know, ‘Hey, it’s probably time for medicine,’” she said. “We’re constantly looking at side effects and addressing to alert the team as quickly as possible so that we can prevent further weight loss.”

Better Diets Lead to Better Outcomes

Leneweaver noted that “many times, patients will continue to rely on oral supplements as their primary source of nutrition over the long term. They may be missing out on several health benefits as a result.”

Research shows that high-quality diets matter in this patient group, she said. They’re associated with “decreased symptoms during treatment, reduced head and neck cancer risk, and reduced risk of those chronic nutrition impact symptoms,” Leneweaver said.

Diets before and after cancer diagnosis can make a difference. A 2019 study examined patient diets prior to diagnosis of head and neck cancer. It found that patients with better diet quality were less likely to experience overall nutrition impact symptoms (OR 0.45). However, “studies have found that the majority of our patients with head and neck cancer have an inadequate diet prior to diagnosis,” Leneweaver said. 

As for postdiagnosis nutrition, a 2022 study linked healthier diets in patients with head and neck cancer to 93% lower 3-year risk of all-cause mortality and 85% lower risk of cancer-specific mortality. 

What’s in a High-Quality Diet?

Regarding specific food recommendations, Leneweaver prefers the American Institute for Cancer Research (AICR) nutrition guidelines over the US Department of Agriculture’s Dietary Guidelines for Americans. The AICR “more clearly recommends plant-based diet with at least two-thirds of each meal coming from a variety of plant sources” and recommends avoiding alcohol entirely and limiting red meat, she said. 

Leneweaver said she recognizes that dietary change can be gradual.

“It’s not going to happen overnight,” she said. “We know that lifestyle change takes a lot of work.”

Basic interventions can be effective, she said: “This can be just as simple as recommending a plant-based diet to your patient or recommending they eat the rainbow. And I don’t mean Skittles, I mean actual plants. If you just mention these couple of things to the patients, this can really go a long way, especially if they’re hearing that consistent messaging.”

Team-Based Follow-Up Is Key

Leneweaver emphasized the importance of following up over time even if patients do not initially accept referrals to nutritional services. Dieticians ideally see patients before or during initial treatment and then weekly during radiation therapy. Posttreatment follow-up continues “until they’re nutritionally stable. This can be anywhere from weekly to monthly.”

Leneweaver emphasized collaborating with other team members. For example, she works with a speech pathologist at joint visits, either weekly or monthly, “so that they can get off of that feeding tube or get back to a solid consistency diet, typically before that 3-month PET scan.”

It is also important to understand barriers to healthy eating in the veteran population, including transportation challenges and poor access to healthy food, Leneweaver said.

“Make sure you’re utilizing your social worker, your psychologist, other resources, and food pantries, if you have them.” 

Even when the most ideal choices are not available, she said, “if they only have access to canned vegetables, I’d much rather them eat that than have nothing.”

No disclosures for Leneweaver were provided. 

PHOENIX — Patients with head and neck cancer face high rates of malnutrition during treatment, and oral supplements are often recommended. But they are not the entire answer, a dietician told colleagues at the Association of Veterans Affairs (VA) Hematology/Oncology annual meeting.

“Patients should consume the most liberal diet possible throughout treatment,” said advanced practice oncology dietician Brittany Leneweaver, RD, CSO, CES, at the VA Washington DC Healthcare System. “This means not solely relying on oral nutrition supplements like Ensure if possible.”

While Leneweaver said many patients will need supplements, she stressed these products “are meant to supplement the diet and not be the sole source of nutrition, ideally.” Encouraging the intake of whole foods “is really key to make the transition back to solid foods after they’re done with treatment. This makes it so much easier when they’re already swallowing those thicker textures, rather than just liquid the entire time.”

Malnutrition: Common and Damaging

As Leneweaver noted, malnutrition is common in patients with head and neck cancer, and can lead to “increased treatment toxicity, increased risk of infection, decreased survival, increased surgical complication, delayed healing, decreased physical function, and decreased quality of life.”

Malnutrition data in patients with head and neck cancer in the US is sparse. However, a 2024 study found malnutrition in 20% of patients undergoing head and neck cancer surgery and linked the condition to increased length of stay (β, 5.20 additional days), higher costs (β, $15,722) higher odds of potentially preventable complications (adjusted odds ratio [aOR], 2.04), and lower odds of discharge to home (aOR, 0.34).

Leneweaver said her role involves addressing “nutrition impact symptoms” that reduce veteran food intake such as difficulty swallowing, taste disorders, dry mouth, and inflammation of the mucus membranes.

“I can’t tell you how much time I spend just talking to the patient about their medication regimens, making sure they have antiemetics on board, letting the radiation oncologist know, ‘Hey, it’s probably time for medicine,’” she said. “We’re constantly looking at side effects and addressing to alert the team as quickly as possible so that we can prevent further weight loss.”

Better Diets Lead to Better Outcomes

Leneweaver noted that “many times, patients will continue to rely on oral supplements as their primary source of nutrition over the long term. They may be missing out on several health benefits as a result.”

Research shows that high-quality diets matter in this patient group, she said. They’re associated with “decreased symptoms during treatment, reduced head and neck cancer risk, and reduced risk of those chronic nutrition impact symptoms,” Leneweaver said.

Diets before and after cancer diagnosis can make a difference. A 2019 study examined patient diets prior to diagnosis of head and neck cancer. It found that patients with better diet quality were less likely to experience overall nutrition impact symptoms (OR 0.45). However, “studies have found that the majority of our patients with head and neck cancer have an inadequate diet prior to diagnosis,” Leneweaver said. 

As for postdiagnosis nutrition, a 2022 study linked healthier diets in patients with head and neck cancer to 93% lower 3-year risk of all-cause mortality and 85% lower risk of cancer-specific mortality. 

What’s in a High-Quality Diet?

Regarding specific food recommendations, Leneweaver prefers the American Institute for Cancer Research (AICR) nutrition guidelines over the US Department of Agriculture’s Dietary Guidelines for Americans. The AICR “more clearly recommends plant-based diet with at least two-thirds of each meal coming from a variety of plant sources” and recommends avoiding alcohol entirely and limiting red meat, she said. 

Leneweaver said she recognizes that dietary change can be gradual.

“It’s not going to happen overnight,” she said. “We know that lifestyle change takes a lot of work.”

Basic interventions can be effective, she said: “This can be just as simple as recommending a plant-based diet to your patient or recommending they eat the rainbow. And I don’t mean Skittles, I mean actual plants. If you just mention these couple of things to the patients, this can really go a long way, especially if they’re hearing that consistent messaging.”

Team-Based Follow-Up Is Key

Leneweaver emphasized the importance of following up over time even if patients do not initially accept referrals to nutritional services. Dieticians ideally see patients before or during initial treatment and then weekly during radiation therapy. Posttreatment follow-up continues “until they’re nutritionally stable. This can be anywhere from weekly to monthly.”

Leneweaver emphasized collaborating with other team members. For example, she works with a speech pathologist at joint visits, either weekly or monthly, “so that they can get off of that feeding tube or get back to a solid consistency diet, typically before that 3-month PET scan.”

It is also important to understand barriers to healthy eating in the veteran population, including transportation challenges and poor access to healthy food, Leneweaver said.

“Make sure you’re utilizing your social worker, your psychologist, other resources, and food pantries, if you have them.” 

Even when the most ideal choices are not available, she said, “if they only have access to canned vegetables, I’d much rather them eat that than have nothing.”

No disclosures for Leneweaver were provided. 

TOPLINE:

A comprehensive review of 92 studies found that 15% to 20% of lung cancers occurred among nonsmokers and were associated with environmental and germline risk factors. These cancers frequently harbored actionable genomic drivers, and targeted EGFR and ALK therapies produced significant diseasefree survival (DFS) and overall survival benefits.

METHODOLOGY:

• Lung cancer continues to be the leading cause of cancer death worldwide, causing about 1.8 million deaths in 2022, with smoking remaining the predominant risk factor. However, the incidence of lung cancer among nonsmokers (those who have smoked less than 100 cigarettes in their lifetime) is rising, varies by sex and geography, and is linked to environmental exposures and family history. The misperception that lung cancer is almost invariably caused by smoking may delay assessment and diagnosis.
• Researchers conducted a review of 92 studies on lung cancer in nonsmokers: 6 meta-analyses or systematic reviews, 16 randomized clinical trials, eight prospective cohort studies, seven retrospective cohort studies, three cross-sectional studies, four observational or case-control studies, 13 genomic studies, and 35 other studies.
• Overall, lung cancer among nonsmokers accounted for 15% to 20% of all lung cancer cases. Most lung cancers in nonsmokers were adenocarcinomas (60% to 80%), with a median age at diagnosis of 67 years in this group compared with 70 years in people with a history of smoking.
• Data analysis from three US hospital networks showed that the proportion of lung cancer among nonsmokers increased from 8.0% to 14.9% between 1990 and 2013. A pooled analysis of seven Finnish cohorts reported an absolute increase in lung cancer among nonsmokers from 6.9 per 100,000 person-years in 1972 to 12.9 per 100,000 person-years in 2015.
• The age-adjusted incidence rate of lung cancer in the US between 2000 and 2013 was 17.5 per 100,000 individuals among Asian female nonsmokers compared with 10.1 per 100,000 among non-Hispanic White female nonsmokers.

TAKEAWAY:

• Environmental and occupational risk factors were secondhand smoke, residential radon, outdoor and household air pollution (PM_2.5), asbestos and silica exposure, and prior thoracic radiotherapy. Having a first-degree relative with lung cancer increased the risk of developing lung cancer, and genome-wide association studies identified susceptibility loci associated with lung cancer risk in nonsmokers.
• Family history and inherited susceptibility increased lung cancer risk in never smokers (odds ratio [OR] for lung cancer in those with a first–degree relative, 1.51), and clonal hematopoiesis was also associated with higher risk (OR, 1.43). Importantly, tumors in nonsmokers were frequently driven by actionable somatic alterations (EGFR mutations, 40% to 60% in nonsmokers compared with 10% in smokers) and enrichment of ALK/ROS1/RET/ERBB2/NTRK/NRG1 fusions; 78% to 92% of adenocarcinomas in nonsmokers harbored actionable drivers (compared with 49.5% in ever smokers), and nonsmokers had a substantially lower tumor mutational burden (10–fold lower).
• Similar to individuals with a history of smoking, nonsmokers with lung cancer presented with cough, pain, dyspnea, or weight loss or had disease detected incidentally. Surgical resection remained the preferred treatment for anatomically resectable lung cancer (stages I-III) in medically eligible patients, with follow-up CT screening recommended every 6 months for 2 to 3 years and then annually.
• Targeted adjuvant therapy substantially improved outcomes for resected EGFR–mutant or ALK–rearranged non-small cell lung cancer (NSCLC). Four-year DFS was increased to 70% with osimertinib compared with 29% with placebo (hazard ratio [HR], 0.23) and 5–year overall survival was increased to 85% compared with 73% (HR, 0.49). Two–year DFS was 93.8% with alectinib compared with 63% with placebo (HR, 0.24). In unresectable EGFR-mutated stage III NSCLC, median progression-free survival was 39.1 months with adjuvant osimertinib compared with 5.6 months with placebo. For resected ALKpositive disease, 2–year DFS was 93.8% with adjuvant alectinib compared with 63.0% with chemotherapy (HR, 0.24).
• However, singleagent single agent programmed cell death protein 1 inhibitors or programmed death-ligand 1 inhibitors demonstrated limited efficacy in EGFR or ALK–driven tumors, and benefit was attenuated in never smokers. Regarding screening and early detection, the US Preventive Services Task Force did not recommend lowdose CT screening for nonsmokers, whereas Taiwan implemented a biennial screening program for selected nonsmoking high–risk groups.

IN PRACTICE:

“Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations, such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with TKIs compared with chemotherapy,” the authors of the study wrote.

SOURCE:

The study, led by Cian Murphy, PhD, Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, England, was published online in JAMA.

LIMITATIONS:

Becausesmoking history was often not included in many databases, cancer registries, and trials, the incidence and prevalence of lung cancer in nonsmokers could not be accurately determined. Additionally, accurate quantification of environmental exposures, such as air pollution, presented significant challenges. The quality of the evidence was not formally evaluated, and some relevant articles may have been missed in the literature review.

DISCLOSURES:

The study received support from multiple organizations, including the Rosetrees Trust, Ruth Strauss Foundation, Cancer Research UK, and the National Health and Medical Research Council. Several authors reported receiving grants or personal fees from and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

A comprehensive review of 92 studies found that 15% to 20% of lung cancers occurred among nonsmokers and were associated with environmental and germline risk factors. These cancers frequently harbored actionable genomic drivers, and targeted EGFR and ALK therapies produced significant diseasefree survival (DFS) and overall survival benefits.

METHODOLOGY:

• Lung cancer continues to be the leading cause of cancer death worldwide, causing about 1.8 million deaths in 2022, with smoking remaining the predominant risk factor. However, the incidence of lung cancer among nonsmokers (those who have smoked less than 100 cigarettes in their lifetime) is rising, varies by sex and geography, and is linked to environmental exposures and family history. The misperception that lung cancer is almost invariably caused by smoking may delay assessment and diagnosis.
• Researchers conducted a review of 92 studies on lung cancer in nonsmokers: 6 meta-analyses or systematic reviews, 16 randomized clinical trials, eight prospective cohort studies, seven retrospective cohort studies, three cross-sectional studies, four observational or case-control studies, 13 genomic studies, and 35 other studies.
• Overall, lung cancer among nonsmokers accounted for 15% to 20% of all lung cancer cases. Most lung cancers in nonsmokers were adenocarcinomas (60% to 80%), with a median age at diagnosis of 67 years in this group compared with 70 years in people with a history of smoking.
• Data analysis from three US hospital networks showed that the proportion of lung cancer among nonsmokers increased from 8.0% to 14.9% between 1990 and 2013. A pooled analysis of seven Finnish cohorts reported an absolute increase in lung cancer among nonsmokers from 6.9 per 100,000 person-years in 1972 to 12.9 per 100,000 person-years in 2015.
• The age-adjusted incidence rate of lung cancer in the US between 2000 and 2013 was 17.5 per 100,000 individuals among Asian female nonsmokers compared with 10.1 per 100,000 among non-Hispanic White female nonsmokers.

TAKEAWAY:

• Environmental and occupational risk factors were secondhand smoke, residential radon, outdoor and household air pollution (PM_2.5), asbestos and silica exposure, and prior thoracic radiotherapy. Having a first-degree relative with lung cancer increased the risk of developing lung cancer, and genome-wide association studies identified susceptibility loci associated with lung cancer risk in nonsmokers.
• Family history and inherited susceptibility increased lung cancer risk in never smokers (odds ratio [OR] for lung cancer in those with a first–degree relative, 1.51), and clonal hematopoiesis was also associated with higher risk (OR, 1.43). Importantly, tumors in nonsmokers were frequently driven by actionable somatic alterations (EGFR mutations, 40% to 60% in nonsmokers compared with 10% in smokers) and enrichment of ALK/ROS1/RET/ERBB2/NTRK/NRG1 fusions; 78% to 92% of adenocarcinomas in nonsmokers harbored actionable drivers (compared with 49.5% in ever smokers), and nonsmokers had a substantially lower tumor mutational burden (10–fold lower).
• Similar to individuals with a history of smoking, nonsmokers with lung cancer presented with cough, pain, dyspnea, or weight loss or had disease detected incidentally. Surgical resection remained the preferred treatment for anatomically resectable lung cancer (stages I-III) in medically eligible patients, with follow-up CT screening recommended every 6 months for 2 to 3 years and then annually.
• Targeted adjuvant therapy substantially improved outcomes for resected EGFR–mutant or ALK–rearranged non-small cell lung cancer (NSCLC). Four-year DFS was increased to 70% with osimertinib compared with 29% with placebo (hazard ratio [HR], 0.23) and 5–year overall survival was increased to 85% compared with 73% (HR, 0.49). Two–year DFS was 93.8% with alectinib compared with 63% with placebo (HR, 0.24). In unresectable EGFR-mutated stage III NSCLC, median progression-free survival was 39.1 months with adjuvant osimertinib compared with 5.6 months with placebo. For resected ALKpositive disease, 2–year DFS was 93.8% with adjuvant alectinib compared with 63.0% with chemotherapy (HR, 0.24).
• However, singleagent single agent programmed cell death protein 1 inhibitors or programmed death-ligand 1 inhibitors demonstrated limited efficacy in EGFR or ALK–driven tumors, and benefit was attenuated in never smokers. Regarding screening and early detection, the US Preventive Services Task Force did not recommend lowdose CT screening for nonsmokers, whereas Taiwan implemented a biennial screening program for selected nonsmoking high–risk groups.

IN PRACTICE:

“Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations, such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with TKIs compared with chemotherapy,” the authors of the study wrote.

SOURCE:

The study, led by Cian Murphy, PhD, Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, England, was published online in JAMA.

LIMITATIONS:

Becausesmoking history was often not included in many databases, cancer registries, and trials, the incidence and prevalence of lung cancer in nonsmokers could not be accurately determined. Additionally, accurate quantification of environmental exposures, such as air pollution, presented significant challenges. The quality of the evidence was not formally evaluated, and some relevant articles may have been missed in the literature review.

DISCLOSURES:

The study received support from multiple organizations, including the Rosetrees Trust, Ruth Strauss Foundation, Cancer Research UK, and the National Health and Medical Research Council. Several authors reported receiving grants or personal fees from and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

A comprehensive review of 92 studies found that 15% to 20% of lung cancers occurred among nonsmokers and were associated with environmental and germline risk factors. These cancers frequently harbored actionable genomic drivers, and targeted EGFR and ALK therapies produced significant diseasefree survival (DFS) and overall survival benefits.

METHODOLOGY:

• Lung cancer continues to be the leading cause of cancer death worldwide, causing about 1.8 million deaths in 2022, with smoking remaining the predominant risk factor. However, the incidence of lung cancer among nonsmokers (those who have smoked less than 100 cigarettes in their lifetime) is rising, varies by sex and geography, and is linked to environmental exposures and family history. The misperception that lung cancer is almost invariably caused by smoking may delay assessment and diagnosis.
• Researchers conducted a review of 92 studies on lung cancer in nonsmokers: 6 meta-analyses or systematic reviews, 16 randomized clinical trials, eight prospective cohort studies, seven retrospective cohort studies, three cross-sectional studies, four observational or case-control studies, 13 genomic studies, and 35 other studies.
• Overall, lung cancer among nonsmokers accounted for 15% to 20% of all lung cancer cases. Most lung cancers in nonsmokers were adenocarcinomas (60% to 80%), with a median age at diagnosis of 67 years in this group compared with 70 years in people with a history of smoking.
• Data analysis from three US hospital networks showed that the proportion of lung cancer among nonsmokers increased from 8.0% to 14.9% between 1990 and 2013. A pooled analysis of seven Finnish cohorts reported an absolute increase in lung cancer among nonsmokers from 6.9 per 100,000 person-years in 1972 to 12.9 per 100,000 person-years in 2015.
• The age-adjusted incidence rate of lung cancer in the US between 2000 and 2013 was 17.5 per 100,000 individuals among Asian female nonsmokers compared with 10.1 per 100,000 among non-Hispanic White female nonsmokers.

TAKEAWAY:

• Environmental and occupational risk factors were secondhand smoke, residential radon, outdoor and household air pollution (PM_2.5), asbestos and silica exposure, and prior thoracic radiotherapy. Having a first-degree relative with lung cancer increased the risk of developing lung cancer, and genome-wide association studies identified susceptibility loci associated with lung cancer risk in nonsmokers.
• Family history and inherited susceptibility increased lung cancer risk in never smokers (odds ratio [OR] for lung cancer in those with a first–degree relative, 1.51), and clonal hematopoiesis was also associated with higher risk (OR, 1.43). Importantly, tumors in nonsmokers were frequently driven by actionable somatic alterations (EGFR mutations, 40% to 60% in nonsmokers compared with 10% in smokers) and enrichment of ALK/ROS1/RET/ERBB2/NTRK/NRG1 fusions; 78% to 92% of adenocarcinomas in nonsmokers harbored actionable drivers (compared with 49.5% in ever smokers), and nonsmokers had a substantially lower tumor mutational burden (10–fold lower).
• Similar to individuals with a history of smoking, nonsmokers with lung cancer presented with cough, pain, dyspnea, or weight loss or had disease detected incidentally. Surgical resection remained the preferred treatment for anatomically resectable lung cancer (stages I-III) in medically eligible patients, with follow-up CT screening recommended every 6 months for 2 to 3 years and then annually.
• Targeted adjuvant therapy substantially improved outcomes for resected EGFR–mutant or ALK–rearranged non-small cell lung cancer (NSCLC). Four-year DFS was increased to 70% with osimertinib compared with 29% with placebo (hazard ratio [HR], 0.23) and 5–year overall survival was increased to 85% compared with 73% (HR, 0.49). Two–year DFS was 93.8% with alectinib compared with 63% with placebo (HR, 0.24). In unresectable EGFR-mutated stage III NSCLC, median progression-free survival was 39.1 months with adjuvant osimertinib compared with 5.6 months with placebo. For resected ALKpositive disease, 2–year DFS was 93.8% with adjuvant alectinib compared with 63.0% with chemotherapy (HR, 0.24).
• However, singleagent single agent programmed cell death protein 1 inhibitors or programmed death-ligand 1 inhibitors demonstrated limited efficacy in EGFR or ALK–driven tumors, and benefit was attenuated in never smokers. Regarding screening and early detection, the US Preventive Services Task Force did not recommend lowdose CT screening for nonsmokers, whereas Taiwan implemented a biennial screening program for selected nonsmoking high–risk groups.

IN PRACTICE:

“Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations, such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with TKIs compared with chemotherapy,” the authors of the study wrote.

SOURCE:

The study, led by Cian Murphy, PhD, Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London, England, was published online in JAMA.

LIMITATIONS:

Becausesmoking history was often not included in many databases, cancer registries, and trials, the incidence and prevalence of lung cancer in nonsmokers could not be accurately determined. Additionally, accurate quantification of environmental exposures, such as air pollution, presented significant challenges. The quality of the evidence was not formally evaluated, and some relevant articles may have been missed in the literature review.

DISCLOSURES:

The study received support from multiple organizations, including the Rosetrees Trust, Ruth Strauss Foundation, Cancer Research UK, and the National Health and Medical Research Council. Several authors reported receiving grants or personal fees from and having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.

The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.

Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.

Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.

Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”

He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”

Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.

Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”

Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.

Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.

Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.

Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.

 

Methods and Results

For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.

The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.

In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.

The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.

Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.

However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.

Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).

“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”

It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.

Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.

However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.

Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.

 

Adverse Events

In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.

There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.

The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.

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

BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.

The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.

Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.

Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.

Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”

He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”

Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.

Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”

Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.

Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.

Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.

Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.

 

Methods and Results

For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.

The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.

In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.

The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.

Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.

However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.

Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).

“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”

It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.

Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.

However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.

Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.

 

Adverse Events

In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.

There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.

The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.

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

BERLIN — Re-treatment with an antiepidermal growth factor receptor (EGFR) agent is effective in patients with chemorefractory metastatic colorectal cancer (mCRC) with RAS and BRAF wild-type tumors confirmed on circulating tumor DNA (ctDNA), although the sequencing of therapy does not seem to matter, suggest overall survival results from the crossover trial PARERE.

The findings nevertheless indicate that anti-EGFR rechallenge with panitumumab may prolong progression-free survival (PFS) over the multiple kinase inhibitor regorafenib. This suggests that “the most pragmatic choice” would be to give the anti-EGFR before regorafenib, said study presenter Marco Maria Germani, MD, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

The caveat, however, is in patients who have an anti-EGFR interval since previously receiving the drugs of < 6 months. Those patients appeared to do better if they had regorafenib first and then anti-EGFR rechallenge.

Overall, Germani said that “since [trifluridine/tipiracil] plus bevacizumab is today the third-line standard of care” in this patient population, “anti-EGFR re-treatment might be considered after progression” on that combination.

Germani presented the research on October 18 at the European Society for Medical Oncology (ESMO) Annual Meeting 2025, which was simultaneously published in the Annals of Oncology.

Michel P. Ducreux, MD, PhD, head of the Digestive Cancer Committee at Gustave Roussy, Villejuif, France, and invited discussant for the results, said, despite the study being negative, it is “very important to continue to perform this kind of trial to evaluate the [ideal] sequence in the treatment of our patients.”

He continued that the secondary endpoints in the trial of PFS and objective response and disease control rates were “fairly in favor of the use of rechallenge before regorafenib, and in my opinion, this is really quite convincing.”

Ducreux, who was not involved in PARERE trail, also pointed to the sex difference seen in the study, which suggested that women responded much better to having anti-EGFR retreatment before regorafenib than did men.

Similar findings have been reported in a number of other trials, and previous work has suggested that there are sex differences in the pharmacokinetics of several anticancer drugs. However, while this is “very important,” he said that “we never consider it, because we are not able to really explain [it].”

Overall, he concluded that, on the basis of these results, he would agree with the notion that it is better to propose a rechallenge with anti-EGFR treatment as the fourth-line therapy in this patient population, before administering regorafenib.

Ducreux explained that, after a partial response, tumors acquire resistance to EGFR inhibitors through alterations and mutations that occur during treatment, via nongenetic mechanisms, and through treatment-induced selection for preexisting mutations.

Previous work has shown that mutations, such as in the RAS gene, are detectable early during EGFR inhibitor therapy, but that they then decay exponentially once the drugs are stopped, with the potential that tumors regain their sensitivity to them.

Germani said that this means that ctDNA-guided retreatment with anti-EGFR therapies is a “promising approach” in pretreated patients with RAS and BRAF wild-type mCRC, and that the sequencing of the drugs may be important. Indeed, the REVERCE trial showed that giving regorafenib followed by the anti-EGFR drug cetuzximab was associated with longer overall survival than the other way around in anti-EGFR medication-naive patients.

 

Methods and Results

For PARERE, the researchers enrolled patients aged at least 18 years with RAS and BRAF wild-type mCRC who were previously treated with a first-line anti-EGFR-containing regimen and had at least a partial response or stable disease for at least 6 months.

The patients were also required to have had at least one intervening anti-EGFR-free line of therapy, and to have previously received treatment with fluoropyrimidine, oxaliplatin, irinotecan, and anti-angiogenics. At least 4 months were required to have passed between the end of anti-EGFR administration and screening for the study.

In all, 428 patients were screened between December 2020 and December 2024, with 213 patients with RAS and BRAF wild-type mCRC, as detected on ctDNA, enrolled. They were randomized to panitumumab or regorafenib until first progression, followed by regorafenib, if they started on panitumumab, or panitumumab, if they started on regorafenib, until second progression.

The median age of the patients was 61 years among those who started on panitumumab and 64 years among those initially given regorafenib in the trial, and 63% and 57%, respectively, were male. The median number of prior lines of therapy was two in both groups, and 65% and 69%, respectively, had received pantitumumab as their first-line anti-EGFR.

Initial findings from the study presented at the 2025 ASCO Annual Meeting indicated that, after a median follow-up of 23.5 months, there was no significant difference in the median first PFS between the two treatment arms.

However, patients who started with panitumumab had a significant improvement in both the objective response and disease control rates (P < .001), as well as a signal for a potentially longer median second PFS, than those who started with regorafenib, particularly on the per-protocol analysis.

Presenting the overall survival results, Germani said that there was no significant difference between the groups on the intention-to-treat analysis, at a stratified hazard ratio of 1.13 (P = .440), or on the per-protocol analysis, at a hazard ratio of 1.07 (P = .730).

“We then ran a subgroup analysis,” he continued, “and we found out that an anti-EGFR-free interval before liquid biopsy shorter than 6 months was associated with less benefit from a panitumumab [first] sequence, which is biologically sound.”

It was also observed that women did significantly better when having panitumumab first, whereas men did not, for which “we do not have a clear biological explanation,” Germani added.

Confining the analysis to so-called “hyperselected” patients, who not only were RAS and BRAF wild type but also had no pathogenic mutations associated with anti-EGFR resistance, did not reveal any significant overall survival differences between the treatment groups.

However, Ducreux took issue with the way in which hyperselection, which is turning up more and more regularly in trials, is defined, as the choice of which mutations to include varies widely. He suggested that a consensus group be assembled to resolve this issue.

Looking more broadly, the researchers were able to show that, in this updated analysis, anti-EGFR re-treatment was superior to regorafenib regardless of the treatment sequence in terms of PFS, at 4.2 months vs 2.4 months (P = .103) when given first in the trial, and 3.9 months vs 2.7 months (P = .019) when given second in the trial, as well as in terms of objective response and disease control rates.

 

Adverse Events

In terms of safety, the results showed that, as expected, acneiform rash, fatigue, and hypomagnesemia were the most common adverse events associated with panitumumb, while those with regorafenib were fatigue, hand-foot skin reactions, and hypertension.

There were no notable differences in the number of patients receiving a post-study treatment nor in the post-study therapeutic choices, between the study arms.

The study was sponsored by GONO Foundation and partially supported by Amgen and Bayer. Germani declared having relationships with MSD and Amgen. Ducreux declared having relationships with Amgen, Bayer, BeiGene, Incyte, Jazz, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche, Servier, Keocyt, AbbVie, Abcely, Arcus, Bayer, BMS, Boehringer, GlaxoSmithKline, Sanofi, Scandion, and Zymeworks.

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