Oncology

SAN DIEGO — In patients with metabolic dysfunction–associated steatotic liver disease (MASLD), hypertension, and cirrhosis, certain antihypertensive medications may lead to increased risks for hepatocellular carcinoma (HCC), according to new research.

In particular, the use of calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) was associated with a higher risk of developing HCC, compared with not using these medications.

About half of patients with MASLD have hypertension, and the use of antihypertensives in these patients is beneficial to reduce the risk for cardiovascular disease and complications related to MASLD, said lead author Ahmed Elhariri, MD, a research fellow at the University of Texas MD Anderson Cancer Center, Houston, who conducted the study as a research assistant in gastroenterology and hepatology at the Baylor College of Medicine, also in Houston.

However, previous studies have suggested a possible link between these medications and cancer development, “especially CCBs and breast and lung cancer,” said Elhariri, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

 

Analyzing Potential Risks

In a case-control study, Elhariri and colleagues analyzed antihypertensive medication use among patients with MASLD-induced HCC, as defined by histology or radiology based on the Liver Imaging Reporting & Data System, and control patients with MASLD but without HCC.

Between 2020 and 2024, the research team recruited 153 newly diagnosed HCC cases with different etiologies and 170 patients with MASLD but without HCC from Baylor College of Medicine’s outpatient clinics. For this study, they selected 47 age- and sex-matched pairs, all of whom had cirrhosis. Only those with a history of hypertension were included, however. Data on risk factors of metabolic syndrome (including diabetes) and HCC were collected, along with details about medication use such as metformin and statins.

A total of 42 patients with MASLD and HCC and 39 MASLD control individuals had a history of hypertension and were treated with antihypertensive medications. The mean age was 66.5 years for the HCC group and 63.5 years for the control group, and the mean body mass index (BMI) was 31.1 for the HCC group and 31.7 for the control group.

After adjusting for age, sex, BMI, Hispanic ethnicity, and use of other medications, patients taking CCBs had an increased HCC risk (odds ratio [OR], 2.76), compared with those not taking CCBs. Patients taking ACE inhibitors or ARBs also had an increased HCC risk (OR, 2.54), compared with those not taking ACE inhibitors or ARBs.

However, there wasn’t a statistically significant difference in HCC risk among patients taking beta-blockers (OR, 0.87).

“Patients with fatty liver in the presence of metabolic syndrome, especially in the presence of cirrhosis and antihypertensives, need to have stricter surveillance for liver cancer,” Elhariri said.

“We need to carefully review blood pressure medications in patients with MASLD and cirrhosis,” he said. CCBs, ACE inhibitors, and ARBs can be replaced with beta-blockers, “which have been shown to reduce progression of cirrhosis-related complications.”

 

Considering Clinical Implications

“Although our study showed some association between the use of some commonly used antihypertensives and the risk for HCC in this high-risk population, it is based on data collected retrospectively on a small number of selected patients with advanced liver disease,” Elhariri noted.

The associations and underlying mechanisms should be studied in larger populations and prospective trials, he said. “Until we have more data with a significantly larger sample size, it’s premature to raise the concern in the general population.”

“The cardiovascular benefits of controlling blood pressure far outweigh the risk of liver cancer in patients with metabolic syndrome,” Elhariri added.

In ongoing studies, researchers are investigating ways to improve patient outcomes and reduce the negative effects of cirrhosis-associated complications among patients with MASLD and metabolic dysfunction–associated steatohepatitis (MASH), Muhammad Ali Butt, MD, a hepatology fellow at Beth Israel Lahey Hospital & Medical Center in Burlington, Massachusetts, said in an interview.

Butt, who wasn’t involved with this study, presented separate research on statins in MASH patients with cirrhosis, which indicated statistically significant decreases in portal hypertension, thrombosis, hepatorenal syndrome, hepatic encephalopathy, and mortality.

“We know patients with MASLD- and MASH-associated cirrhosis commonly have other comorbidities, including high cardiovascular risks, diabetes, and hyperlipidemia,” he said. “All of these conditions indicate patients to be on other medications such as antihypertensives or statins. It’s important to know the role these medications play, especially given the high-risk profile of these patients.”

Elhariri and Butt reported no relevant disclosures.

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

SAN DIEGO — In patients with metabolic dysfunction–associated steatotic liver disease (MASLD), hypertension, and cirrhosis, certain antihypertensive medications may lead to increased risks for hepatocellular carcinoma (HCC), according to new research.

In particular, the use of calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) was associated with a higher risk of developing HCC, compared with not using these medications.

About half of patients with MASLD have hypertension, and the use of antihypertensives in these patients is beneficial to reduce the risk for cardiovascular disease and complications related to MASLD, said lead author Ahmed Elhariri, MD, a research fellow at the University of Texas MD Anderson Cancer Center, Houston, who conducted the study as a research assistant in gastroenterology and hepatology at the Baylor College of Medicine, also in Houston.

However, previous studies have suggested a possible link between these medications and cancer development, “especially CCBs and breast and lung cancer,” said Elhariri, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

 

Analyzing Potential Risks

In a case-control study, Elhariri and colleagues analyzed antihypertensive medication use among patients with MASLD-induced HCC, as defined by histology or radiology based on the Liver Imaging Reporting & Data System, and control patients with MASLD but without HCC.

Between 2020 and 2024, the research team recruited 153 newly diagnosed HCC cases with different etiologies and 170 patients with MASLD but without HCC from Baylor College of Medicine’s outpatient clinics. For this study, they selected 47 age- and sex-matched pairs, all of whom had cirrhosis. Only those with a history of hypertension were included, however. Data on risk factors of metabolic syndrome (including diabetes) and HCC were collected, along with details about medication use such as metformin and statins.

A total of 42 patients with MASLD and HCC and 39 MASLD control individuals had a history of hypertension and were treated with antihypertensive medications. The mean age was 66.5 years for the HCC group and 63.5 years for the control group, and the mean body mass index (BMI) was 31.1 for the HCC group and 31.7 for the control group.

After adjusting for age, sex, BMI, Hispanic ethnicity, and use of other medications, patients taking CCBs had an increased HCC risk (odds ratio [OR], 2.76), compared with those not taking CCBs. Patients taking ACE inhibitors or ARBs also had an increased HCC risk (OR, 2.54), compared with those not taking ACE inhibitors or ARBs.

However, there wasn’t a statistically significant difference in HCC risk among patients taking beta-blockers (OR, 0.87).

“Patients with fatty liver in the presence of metabolic syndrome, especially in the presence of cirrhosis and antihypertensives, need to have stricter surveillance for liver cancer,” Elhariri said.

“We need to carefully review blood pressure medications in patients with MASLD and cirrhosis,” he said. CCBs, ACE inhibitors, and ARBs can be replaced with beta-blockers, “which have been shown to reduce progression of cirrhosis-related complications.”

 

Considering Clinical Implications

“Although our study showed some association between the use of some commonly used antihypertensives and the risk for HCC in this high-risk population, it is based on data collected retrospectively on a small number of selected patients with advanced liver disease,” Elhariri noted.

The associations and underlying mechanisms should be studied in larger populations and prospective trials, he said. “Until we have more data with a significantly larger sample size, it’s premature to raise the concern in the general population.”

“The cardiovascular benefits of controlling blood pressure far outweigh the risk of liver cancer in patients with metabolic syndrome,” Elhariri added.

In ongoing studies, researchers are investigating ways to improve patient outcomes and reduce the negative effects of cirrhosis-associated complications among patients with MASLD and metabolic dysfunction–associated steatohepatitis (MASH), Muhammad Ali Butt, MD, a hepatology fellow at Beth Israel Lahey Hospital & Medical Center in Burlington, Massachusetts, said in an interview.

Butt, who wasn’t involved with this study, presented separate research on statins in MASH patients with cirrhosis, which indicated statistically significant decreases in portal hypertension, thrombosis, hepatorenal syndrome, hepatic encephalopathy, and mortality.

“We know patients with MASLD- and MASH-associated cirrhosis commonly have other comorbidities, including high cardiovascular risks, diabetes, and hyperlipidemia,” he said. “All of these conditions indicate patients to be on other medications such as antihypertensives or statins. It’s important to know the role these medications play, especially given the high-risk profile of these patients.”

Elhariri and Butt reported no relevant disclosures.

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

SAN DIEGO — In patients with metabolic dysfunction–associated steatotic liver disease (MASLD), hypertension, and cirrhosis, certain antihypertensive medications may lead to increased risks for hepatocellular carcinoma (HCC), according to new research.

In particular, the use of calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) was associated with a higher risk of developing HCC, compared with not using these medications.

About half of patients with MASLD have hypertension, and the use of antihypertensives in these patients is beneficial to reduce the risk for cardiovascular disease and complications related to MASLD, said lead author Ahmed Elhariri, MD, a research fellow at the University of Texas MD Anderson Cancer Center, Houston, who conducted the study as a research assistant in gastroenterology and hepatology at the Baylor College of Medicine, also in Houston.

However, previous studies have suggested a possible link between these medications and cancer development, “especially CCBs and breast and lung cancer,” said Elhariri, who presented the findings at The Liver Meeting 2024: American Association for the Study of Liver Diseases (AASLD).

 

Analyzing Potential Risks

In a case-control study, Elhariri and colleagues analyzed antihypertensive medication use among patients with MASLD-induced HCC, as defined by histology or radiology based on the Liver Imaging Reporting & Data System, and control patients with MASLD but without HCC.

Between 2020 and 2024, the research team recruited 153 newly diagnosed HCC cases with different etiologies and 170 patients with MASLD but without HCC from Baylor College of Medicine’s outpatient clinics. For this study, they selected 47 age- and sex-matched pairs, all of whom had cirrhosis. Only those with a history of hypertension were included, however. Data on risk factors of metabolic syndrome (including diabetes) and HCC were collected, along with details about medication use such as metformin and statins.

A total of 42 patients with MASLD and HCC and 39 MASLD control individuals had a history of hypertension and were treated with antihypertensive medications. The mean age was 66.5 years for the HCC group and 63.5 years for the control group, and the mean body mass index (BMI) was 31.1 for the HCC group and 31.7 for the control group.

After adjusting for age, sex, BMI, Hispanic ethnicity, and use of other medications, patients taking CCBs had an increased HCC risk (odds ratio [OR], 2.76), compared with those not taking CCBs. Patients taking ACE inhibitors or ARBs also had an increased HCC risk (OR, 2.54), compared with those not taking ACE inhibitors or ARBs.

However, there wasn’t a statistically significant difference in HCC risk among patients taking beta-blockers (OR, 0.87).

“Patients with fatty liver in the presence of metabolic syndrome, especially in the presence of cirrhosis and antihypertensives, need to have stricter surveillance for liver cancer,” Elhariri said.

“We need to carefully review blood pressure medications in patients with MASLD and cirrhosis,” he said. CCBs, ACE inhibitors, and ARBs can be replaced with beta-blockers, “which have been shown to reduce progression of cirrhosis-related complications.”

 

Considering Clinical Implications

“Although our study showed some association between the use of some commonly used antihypertensives and the risk for HCC in this high-risk population, it is based on data collected retrospectively on a small number of selected patients with advanced liver disease,” Elhariri noted.

The associations and underlying mechanisms should be studied in larger populations and prospective trials, he said. “Until we have more data with a significantly larger sample size, it’s premature to raise the concern in the general population.”

“The cardiovascular benefits of controlling blood pressure far outweigh the risk of liver cancer in patients with metabolic syndrome,” Elhariri added.

In ongoing studies, researchers are investigating ways to improve patient outcomes and reduce the negative effects of cirrhosis-associated complications among patients with MASLD and metabolic dysfunction–associated steatohepatitis (MASH), Muhammad Ali Butt, MD, a hepatology fellow at Beth Israel Lahey Hospital & Medical Center in Burlington, Massachusetts, said in an interview.

Butt, who wasn’t involved with this study, presented separate research on statins in MASH patients with cirrhosis, which indicated statistically significant decreases in portal hypertension, thrombosis, hepatorenal syndrome, hepatic encephalopathy, and mortality.

“We know patients with MASLD- and MASH-associated cirrhosis commonly have other comorbidities, including high cardiovascular risks, diabetes, and hyperlipidemia,” he said. “All of these conditions indicate patients to be on other medications such as antihypertensives or statins. It’s important to know the role these medications play, especially given the high-risk profile of these patients.”

Elhariri and Butt reported no relevant disclosures.

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

TOPLINE:

Indoor tanning exposure was not associated with tumor mutational burden (TMB) in patients with cutaneous melanoma, in a retrospective cohort study. Higher TMB was linked to older age, head and neck tumors, and a history of nonmelanoma skin cancer (NMSC).

METHODOLOGY:

• Researchers conducted a retrospective cohort study at a tertiary care cancer center between 2013 and 2022.
• A total of 617 patients (median age at diagnosis, 61 years; 62.9% men) with melanoma who had next-generation sequencing data and indoor tanning bed exposure history available were included.
• Analysis involved multivariable modeling to evaluate the association between tanning bed use and TMB.
• Patients’ demographics, pathologic staging, TMB, and dermatologic history, including Fitzpatrick skin type, history of exposure to ultraviolet (UV) light, indoor tanning, NMSC, atypical nevi, and blistering sunburns, were considered for the analysis.

TAKEAWAY:

• About 22% of participants had an indoor tanning history. Indoor tanning exposure showed no association with TMB after adjustment for all possible predictors.
• A significant association was found between TMB and age at diagnosis, primary melanoma site, and history of NMSC (P < .001 for all).
• Patients with a history of atypical nevi demonstrated a significantly lower TMB than those without (log2 TMB, 3.89 vs 4.15; P = .01).
• Tumors of the head and neck exhibited a significantly higher TMB than those occurring in other primary sites, while skin-localized melanomas at diagnosis showed a significantly higher TMB than node-positive or metastatic stage III or IV tumors (log2 TMB, 3.88 vs 3.48; P = .005).

IN PRACTICE:

“Despite the known association between indoor tanning and melanoma risk,” the study did not find an association between indoor tanning and melanoma TMB, which “suggests that cumulative lifetime sun exposure may be a greater primary driver of TMB than intermittent radiation during indoor tanning,” the authors of the study wrote.

SOURCE:

The study was led by Grace B. Hanrahan, BA, of the Center for Melanoma Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, and was published online on December 11 in JAMA Dermatology.

LIMITATIONS:

The study was conducted at a tertiary referral center, potentially representing a higher-risk subset with more advanced disease than the broader population. Additionally, the retrospective collection of UV exposure history, including indoor tanning and blistering sunburns, may have introduced recall bias.

DISCLOSURES:

The authors did not disclose any funding information. No conflicts of interest were reported.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Indoor tanning exposure was not associated with tumor mutational burden (TMB) in patients with cutaneous melanoma, in a retrospective cohort study. Higher TMB was linked to older age, head and neck tumors, and a history of nonmelanoma skin cancer (NMSC).

METHODOLOGY:

• Researchers conducted a retrospective cohort study at a tertiary care cancer center between 2013 and 2022.
• A total of 617 patients (median age at diagnosis, 61 years; 62.9% men) with melanoma who had next-generation sequencing data and indoor tanning bed exposure history available were included.
• Analysis involved multivariable modeling to evaluate the association between tanning bed use and TMB.
• Patients’ demographics, pathologic staging, TMB, and dermatologic history, including Fitzpatrick skin type, history of exposure to ultraviolet (UV) light, indoor tanning, NMSC, atypical nevi, and blistering sunburns, were considered for the analysis.

TAKEAWAY:

• About 22% of participants had an indoor tanning history. Indoor tanning exposure showed no association with TMB after adjustment for all possible predictors.
• A significant association was found between TMB and age at diagnosis, primary melanoma site, and history of NMSC (P < .001 for all).
• Patients with a history of atypical nevi demonstrated a significantly lower TMB than those without (log2 TMB, 3.89 vs 4.15; P = .01).
• Tumors of the head and neck exhibited a significantly higher TMB than those occurring in other primary sites, while skin-localized melanomas at diagnosis showed a significantly higher TMB than node-positive or metastatic stage III or IV tumors (log2 TMB, 3.88 vs 3.48; P = .005).

IN PRACTICE:

“Despite the known association between indoor tanning and melanoma risk,” the study did not find an association between indoor tanning and melanoma TMB, which “suggests that cumulative lifetime sun exposure may be a greater primary driver of TMB than intermittent radiation during indoor tanning,” the authors of the study wrote.

SOURCE:

The study was led by Grace B. Hanrahan, BA, of the Center for Melanoma Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, and was published online on December 11 in JAMA Dermatology.

LIMITATIONS:

The study was conducted at a tertiary referral center, potentially representing a higher-risk subset with more advanced disease than the broader population. Additionally, the retrospective collection of UV exposure history, including indoor tanning and blistering sunburns, may have introduced recall bias.

DISCLOSURES:

The authors did not disclose any funding information. No conflicts of interest were reported.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Indoor tanning exposure was not associated with tumor mutational burden (TMB) in patients with cutaneous melanoma, in a retrospective cohort study. Higher TMB was linked to older age, head and neck tumors, and a history of nonmelanoma skin cancer (NMSC).

METHODOLOGY:

• Researchers conducted a retrospective cohort study at a tertiary care cancer center between 2013 and 2022.
• A total of 617 patients (median age at diagnosis, 61 years; 62.9% men) with melanoma who had next-generation sequencing data and indoor tanning bed exposure history available were included.
• Analysis involved multivariable modeling to evaluate the association between tanning bed use and TMB.
• Patients’ demographics, pathologic staging, TMB, and dermatologic history, including Fitzpatrick skin type, history of exposure to ultraviolet (UV) light, indoor tanning, NMSC, atypical nevi, and blistering sunburns, were considered for the analysis.

TAKEAWAY:

• About 22% of participants had an indoor tanning history. Indoor tanning exposure showed no association with TMB after adjustment for all possible predictors.
• A significant association was found between TMB and age at diagnosis, primary melanoma site, and history of NMSC (P < .001 for all).
• Patients with a history of atypical nevi demonstrated a significantly lower TMB than those without (log2 TMB, 3.89 vs 4.15; P = .01).
• Tumors of the head and neck exhibited a significantly higher TMB than those occurring in other primary sites, while skin-localized melanomas at diagnosis showed a significantly higher TMB than node-positive or metastatic stage III or IV tumors (log2 TMB, 3.88 vs 3.48; P = .005).

IN PRACTICE:

“Despite the known association between indoor tanning and melanoma risk,” the study did not find an association between indoor tanning and melanoma TMB, which “suggests that cumulative lifetime sun exposure may be a greater primary driver of TMB than intermittent radiation during indoor tanning,” the authors of the study wrote.

SOURCE:

The study was led by Grace B. Hanrahan, BA, of the Center for Melanoma Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, and was published online on December 11 in JAMA Dermatology.

LIMITATIONS:

The study was conducted at a tertiary referral center, potentially representing a higher-risk subset with more advanced disease than the broader population. Additionally, the retrospective collection of UV exposure history, including indoor tanning and blistering sunburns, may have introduced recall bias.

DISCLOSURES:

The authors did not disclose any funding information. No conflicts of interest were reported.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Patients with BRCA mutations and a history of early-onset breast cancer benefited from risk-reducing surgeries, according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.

Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.

“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”

“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing. 

Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.

The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery. 

Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.

During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported. 

The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not. 

During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).

For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.

“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.

Overall survival results were similar in patients who underwent one or both surgeries.

Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”

In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.

The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.

In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?” 

This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said. 

“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.

The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.

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

Patients with BRCA mutations and a history of early-onset breast cancer benefited from risk-reducing surgeries, according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.

Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.

“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”

“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing. 

Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.

The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery. 

Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.

During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported. 

The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not. 

During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).

For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.

“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.

Overall survival results were similar in patients who underwent one or both surgeries.

Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”

In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.

The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.

In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?” 

This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said. 

“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.

The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.

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

Patients with BRCA mutations and a history of early-onset breast cancer benefited from risk-reducing surgeries, according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.

Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.

“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”

“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing. 

Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.

The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery. 

Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.

During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported. 

The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not. 

During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).

For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.

“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.

Overall survival results were similar in patients who underwent one or both surgeries.

Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”

In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.

The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.

In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?” 

This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said. 

“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.

The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.

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

TOPLINE:

The use of active surveillance or watchful waiting increased by more than twofold overall between 2010 and 2020 among patients with intermediate-risk prostate cancer.

METHODOLOGY:

• Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
• To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
• Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
• Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.

TAKEAWAY:

• Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
• Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
• Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
• Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.

IN PRACTICE:

“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”

SOURCE:

This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.

LIMITATIONS:

This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.

DISCLOSURES:

This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.

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:

The use of active surveillance or watchful waiting increased by more than twofold overall between 2010 and 2020 among patients with intermediate-risk prostate cancer.

METHODOLOGY:

• Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
• To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
• Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
• Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.

TAKEAWAY:

• Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
• Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
• Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
• Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.

IN PRACTICE:

“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”

SOURCE:

This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.

LIMITATIONS:

This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.

DISCLOSURES:

This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.

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:

The use of active surveillance or watchful waiting increased by more than twofold overall between 2010 and 2020 among patients with intermediate-risk prostate cancer.

METHODOLOGY:

• Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
• To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
• Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
• Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.

TAKEAWAY:

• Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
• Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
• Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
• Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.

IN PRACTICE:

“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”

SOURCE:

This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.

LIMITATIONS:

This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.

DISCLOSURES:

This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.

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:

The risk for melanoma-related death was higher in individuals with tumors with a Breslow thickness of 0.8-1.0 mm than in individuals with tumors smaller than 0.8 mm, in an Australian study that used registry data.

METHODOLOGY:

• The study analyzed 144,447 individuals (median age, 56 years, 54% men) diagnosed with thin (T1) primary invasive melanomas (Breslow thickness, ≤ 1.0 mm) between 1982 and 2014 from all eight Australian state and territory population-based cancer registries.
• The researchers evaluated the associations between Breslow thickness (< 0.8 mm vs 0.8-1.0 mm) and incidences of melanoma-related and nonmelanoma-related deaths.
• The primary endpoint was time to death attributable to a melanoma-related cause, with death by a nonmelanoma-related cause as a competing event.

TAKEAWAY:

• The 20-year cumulative incidence of melanoma-related deaths was 6.3% for the whole cohort. The incidence was higher for tumors with a thickness of 0.8-1.0 mm (11%) than for those with a thickness < 0.8 mm (5.6%).
• The overall 20-year melanoma-specific survival rate was 95.9%, with rates of 94.2% for tumors < 0.8 mm and 87.8% for tumors measuring 0.8-1.0 mm in thickness. Each 0.1-mm increase in Breslow thickness was associated with worse prognosis.
• A multivariable analysis revealed that a tumor thickness of 0.8-1.0 mm was associated with both a greater absolute risk for melanoma-related deaths (subdistribution hazard ratio, 2.92) and a higher rate of melanoma-related deaths (hazard ratio, 2.98) than a tumor thickness < 0.8 mm.
• The 20-year incidence of death from nonmelanoma-related causes was 23.4%, but the risk for death from these causes showed no significant association with Breslow thickness categories.

IN PRACTICE:

“The findings of this large-scale population–based analysis suggest the separation of risk for patients with melanomas with a Breslow thickness above and below 0.8 mm,” the authors wrote, adding: “These results suggest that a change of the T1 threshold from 1.0 mm to 0.8 mm should be considered when the AJCC [American Joint Committee on Cancer] staging system is next reviewed.”

SOURCE:

The study was led by Serigne N. Lo, PhD, Melanoma Institute Australia, the University of Sydney. It was published online on December 11, 2024, in JAMA Dermatology.

LIMITATIONS:

The study was registry-based and did not capture details such as tumor characteristics and treatment modalities. Inaccuracies in reporting the cause of death may have led to an underestimation of melanoma-specific mortality risks across all thickness groups and an overestimation of nonmelanoma mortality risks.

DISCLOSURES:

The study received funding support from Melanoma Institute Australia and two grants from the Australian National Health and Medical Research Council (NHMRC). Several authors reported receiving grants or personal fees from or having ties with various sources, including NHMRC.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The risk for melanoma-related death was higher in individuals with tumors with a Breslow thickness of 0.8-1.0 mm than in individuals with tumors smaller than 0.8 mm, in an Australian study that used registry data.

METHODOLOGY:

• The study analyzed 144,447 individuals (median age, 56 years, 54% men) diagnosed with thin (T1) primary invasive melanomas (Breslow thickness, ≤ 1.0 mm) between 1982 and 2014 from all eight Australian state and territory population-based cancer registries.
• The researchers evaluated the associations between Breslow thickness (< 0.8 mm vs 0.8-1.0 mm) and incidences of melanoma-related and nonmelanoma-related deaths.
• The primary endpoint was time to death attributable to a melanoma-related cause, with death by a nonmelanoma-related cause as a competing event.

TAKEAWAY:

• The 20-year cumulative incidence of melanoma-related deaths was 6.3% for the whole cohort. The incidence was higher for tumors with a thickness of 0.8-1.0 mm (11%) than for those with a thickness < 0.8 mm (5.6%).
• The overall 20-year melanoma-specific survival rate was 95.9%, with rates of 94.2% for tumors < 0.8 mm and 87.8% for tumors measuring 0.8-1.0 mm in thickness. Each 0.1-mm increase in Breslow thickness was associated with worse prognosis.
• A multivariable analysis revealed that a tumor thickness of 0.8-1.0 mm was associated with both a greater absolute risk for melanoma-related deaths (subdistribution hazard ratio, 2.92) and a higher rate of melanoma-related deaths (hazard ratio, 2.98) than a tumor thickness < 0.8 mm.
• The 20-year incidence of death from nonmelanoma-related causes was 23.4%, but the risk for death from these causes showed no significant association with Breslow thickness categories.

IN PRACTICE:

“The findings of this large-scale population–based analysis suggest the separation of risk for patients with melanomas with a Breslow thickness above and below 0.8 mm,” the authors wrote, adding: “These results suggest that a change of the T1 threshold from 1.0 mm to 0.8 mm should be considered when the AJCC [American Joint Committee on Cancer] staging system is next reviewed.”

SOURCE:

The study was led by Serigne N. Lo, PhD, Melanoma Institute Australia, the University of Sydney. It was published online on December 11, 2024, in JAMA Dermatology.

LIMITATIONS:

The study was registry-based and did not capture details such as tumor characteristics and treatment modalities. Inaccuracies in reporting the cause of death may have led to an underestimation of melanoma-specific mortality risks across all thickness groups and an overestimation of nonmelanoma mortality risks.

DISCLOSURES:

The study received funding support from Melanoma Institute Australia and two grants from the Australian National Health and Medical Research Council (NHMRC). Several authors reported receiving grants or personal fees from or having ties with various sources, including NHMRC.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The risk for melanoma-related death was higher in individuals with tumors with a Breslow thickness of 0.8-1.0 mm than in individuals with tumors smaller than 0.8 mm, in an Australian study that used registry data.

METHODOLOGY:

• The study analyzed 144,447 individuals (median age, 56 years, 54% men) diagnosed with thin (T1) primary invasive melanomas (Breslow thickness, ≤ 1.0 mm) between 1982 and 2014 from all eight Australian state and territory population-based cancer registries.
• The researchers evaluated the associations between Breslow thickness (< 0.8 mm vs 0.8-1.0 mm) and incidences of melanoma-related and nonmelanoma-related deaths.
• The primary endpoint was time to death attributable to a melanoma-related cause, with death by a nonmelanoma-related cause as a competing event.

TAKEAWAY:

• The 20-year cumulative incidence of melanoma-related deaths was 6.3% for the whole cohort. The incidence was higher for tumors with a thickness of 0.8-1.0 mm (11%) than for those with a thickness < 0.8 mm (5.6%).
• The overall 20-year melanoma-specific survival rate was 95.9%, with rates of 94.2% for tumors < 0.8 mm and 87.8% for tumors measuring 0.8-1.0 mm in thickness. Each 0.1-mm increase in Breslow thickness was associated with worse prognosis.
• A multivariable analysis revealed that a tumor thickness of 0.8-1.0 mm was associated with both a greater absolute risk for melanoma-related deaths (subdistribution hazard ratio, 2.92) and a higher rate of melanoma-related deaths (hazard ratio, 2.98) than a tumor thickness < 0.8 mm.
• The 20-year incidence of death from nonmelanoma-related causes was 23.4%, but the risk for death from these causes showed no significant association with Breslow thickness categories.

IN PRACTICE:

“The findings of this large-scale population–based analysis suggest the separation of risk for patients with melanomas with a Breslow thickness above and below 0.8 mm,” the authors wrote, adding: “These results suggest that a change of the T1 threshold from 1.0 mm to 0.8 mm should be considered when the AJCC [American Joint Committee on Cancer] staging system is next reviewed.”

SOURCE:

The study was led by Serigne N. Lo, PhD, Melanoma Institute Australia, the University of Sydney. It was published online on December 11, 2024, in JAMA Dermatology.

LIMITATIONS:

The study was registry-based and did not capture details such as tumor characteristics and treatment modalities. Inaccuracies in reporting the cause of death may have led to an underestimation of melanoma-specific mortality risks across all thickness groups and an overestimation of nonmelanoma mortality risks.

DISCLOSURES:

The study received funding support from Melanoma Institute Australia and two grants from the Australian National Health and Medical Research Council (NHMRC). Several authors reported receiving grants or personal fees from or having ties with various sources, including NHMRC.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

The US Preventive Services Task Force (USPSTF) has posted a draft updated statement on cervical cancer screening. The statement is open for public comment until January 13, 2025, on the task force’s website. 

Nearly all cases of cervical cancer are caused by human papilloma virus (HPV) and most occur in women who have not been regularly screened or appropriately treated, the task force stressed.
 

New Screening Option

In 2024, there will be an estimated 13,820 new cases of cervical cancer and 4360 deaths.

“Evidence shows that screening saves lives, and all women aged 21-65 need to be screened,” task force member Esa Davis, MD, MPH, FAAFP, a professor of family and community medicine and associate vice president for community health at the University of Maryland, Baltimore, said in an interview. A new feature in the 2024 draft statement endorsing self-collection of cervical samples for HPV testing may facilitate broader screening. 

“We hope the new effective option of self-collecting will expand screening and allow even more women to get screened regularly,” Davis said. “Some may feel more comfortable collecting samples themselves, and the collection can be office-based or home-based, but it’s very important that it be done under the direction of a clinician.” 

In agreement is Diego Aviles, MD, an assistant professor and a gynecologic oncologist with UTHealth Houston. “Self-collection will absolutely expand screening. I think it’s an incredible advancement in medicine that patients are able to collect in the comfort of their own homes with no need to come into the office for an uncomfortable pelvic exam,” he said in an interview. “This empowers the patient and gives her a choice.”

As to concern about potential error, he added that while this is a concern on paper, “a lot of studies have shown that self-collection is just as effective doctor collection.” 

Largely consistent with the task force’s 2018 screening recommendations, the updated suggestions also align with those of other organizations such as the American College of Obstetricians and Gynecologists (ACOG), Davis said.

Christopher M. Zahn, MD, ACOG’s chief of clinical practice and health equity and quality, stressed the importance of cervical cancer screening and said his organization will be reviewing the USPSTF recommendations. He urges ACOG members to consider them and offer their comments on the public-input platform.

Drawing on the latest evidence, the task force is also highlighting for the first time that stand-alone HPV screening gives women aged 30-65 years the best balance of benefits and harms when it comes to finding and preventing cervical cancer, while continuing to reinforce that Pap testing and co-testing are also effective screening options for these women. 

The current draft statement applies to cisgender women and those assigned female sex at birth, including transgender men and nonbinary individuals. The recommendations do not apply to women at increased risk of cervical cancer such as those with HIV infection, a compromised immune system, or a history of treatment for precancerous lesions or cervical cancer. 

Based on a review of evidence on the benefits and harms of screening, the USPSTF’s independent panel of national experts proposed the following:
 

Recommendations for Screening (Based on Grade A Evidence):

• Ages 21-65 years: All women should get screened regularly for this preventable disease.
• Ages 21-29 years: All women in this age group should undergo a Pap test every 3 years but do not need HPV testing. “In this age group most HPV infections will go away on their own because young women have strong immune systems. Older women are likely to have HPV that lasts longer and so they need testing for the virus,” Davis said.
• Ages 30-65 years: As noted, HPV screening gives women in this age category the best balance of benefits and harms in terms of preventing and finding cervical cancer. Pap testing or co-testing (Pap tests and HPV tests) are also effective screening options for this population. Ideally, these women should have an HPV test every 5 years or, alternatively, a Pap test every 3 years, or a combined HPV and Pap test every 5 years (co-testing).

Recommendations Against Screening (No Benefit or Benefit Outweighed by Harms — Grade D evidence):

• Women aged less than 21 years: Screening is not necessary.
• Other women not needing screening: Nor is screening necessary for those of any age who have had a total hysterectomy with removal of the cervix and those aged > 65 years who have had regular screenings with normal results. That means normal results from their last three Pap tests or their last two HPV tests, completed in the past 10 years, with at least one of the tests done in the past 5 years.
• Women aged 65 or more: These women should continue screening only if they have not been screened regularly or have had abnormal results in the past decade such as a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer.

Davis noted that none of the current recommendations are likely to be controversial or to spark pushback. “But,” said Aviles, “any time I see recent change in medicine, there’s always a little bit of pushback and it may take some time for everyone to be comfortable with the self-collection option. The recommendations still give doctors the grace to use the screening test they feel comfortable with, but I think eventually everyone will get on board with self-collection.”

As for the future, he added, “Over the next few years we’ll have to look at women who are on immune-weakening medications like Skyrizi [risankizumab] for skin conditions like psoriasis. These are commonly used in young people and can increase the risk of cervical cancer. I haven’t seen a lot of conversation about this, but patients should be aware of this risk and recommendations for this group should be different than for the general population.”

The USPSTF also noted a need to assess the magnitude of the incremental benefit and harms of screening and the interval of multiple rounds of HPV-primary screening in HPV-vaccinated cohorts in US populations.

Davis, Aviles, and Zahn and had no relevant competing interests to disclose.
 

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

The US Preventive Services Task Force (USPSTF) has posted a draft updated statement on cervical cancer screening. The statement is open for public comment until January 13, 2025, on the task force’s website. 

Nearly all cases of cervical cancer are caused by human papilloma virus (HPV) and most occur in women who have not been regularly screened or appropriately treated, the task force stressed.
 

New Screening Option

In 2024, there will be an estimated 13,820 new cases of cervical cancer and 4360 deaths.

“Evidence shows that screening saves lives, and all women aged 21-65 need to be screened,” task force member Esa Davis, MD, MPH, FAAFP, a professor of family and community medicine and associate vice president for community health at the University of Maryland, Baltimore, said in an interview. A new feature in the 2024 draft statement endorsing self-collection of cervical samples for HPV testing may facilitate broader screening. 

“We hope the new effective option of self-collecting will expand screening and allow even more women to get screened regularly,” Davis said. “Some may feel more comfortable collecting samples themselves, and the collection can be office-based or home-based, but it’s very important that it be done under the direction of a clinician.” 

In agreement is Diego Aviles, MD, an assistant professor and a gynecologic oncologist with UTHealth Houston. “Self-collection will absolutely expand screening. I think it’s an incredible advancement in medicine that patients are able to collect in the comfort of their own homes with no need to come into the office for an uncomfortable pelvic exam,” he said in an interview. “This empowers the patient and gives her a choice.”

As to concern about potential error, he added that while this is a concern on paper, “a lot of studies have shown that self-collection is just as effective doctor collection.” 

Largely consistent with the task force’s 2018 screening recommendations, the updated suggestions also align with those of other organizations such as the American College of Obstetricians and Gynecologists (ACOG), Davis said.

Christopher M. Zahn, MD, ACOG’s chief of clinical practice and health equity and quality, stressed the importance of cervical cancer screening and said his organization will be reviewing the USPSTF recommendations. He urges ACOG members to consider them and offer their comments on the public-input platform.

Drawing on the latest evidence, the task force is also highlighting for the first time that stand-alone HPV screening gives women aged 30-65 years the best balance of benefits and harms when it comes to finding and preventing cervical cancer, while continuing to reinforce that Pap testing and co-testing are also effective screening options for these women. 

The current draft statement applies to cisgender women and those assigned female sex at birth, including transgender men and nonbinary individuals. The recommendations do not apply to women at increased risk of cervical cancer such as those with HIV infection, a compromised immune system, or a history of treatment for precancerous lesions or cervical cancer. 

Based on a review of evidence on the benefits and harms of screening, the USPSTF’s independent panel of national experts proposed the following:
 

Recommendations for Screening (Based on Grade A Evidence):

• Ages 21-65 years: All women should get screened regularly for this preventable disease.
• Ages 21-29 years: All women in this age group should undergo a Pap test every 3 years but do not need HPV testing. “In this age group most HPV infections will go away on their own because young women have strong immune systems. Older women are likely to have HPV that lasts longer and so they need testing for the virus,” Davis said.
• Ages 30-65 years: As noted, HPV screening gives women in this age category the best balance of benefits and harms in terms of preventing and finding cervical cancer. Pap testing or co-testing (Pap tests and HPV tests) are also effective screening options for this population. Ideally, these women should have an HPV test every 5 years or, alternatively, a Pap test every 3 years, or a combined HPV and Pap test every 5 years (co-testing).

Recommendations Against Screening (No Benefit or Benefit Outweighed by Harms — Grade D evidence):

• Women aged less than 21 years: Screening is not necessary.
• Other women not needing screening: Nor is screening necessary for those of any age who have had a total hysterectomy with removal of the cervix and those aged > 65 years who have had regular screenings with normal results. That means normal results from their last three Pap tests or their last two HPV tests, completed in the past 10 years, with at least one of the tests done in the past 5 years.
• Women aged 65 or more: These women should continue screening only if they have not been screened regularly or have had abnormal results in the past decade such as a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer.

Davis noted that none of the current recommendations are likely to be controversial or to spark pushback. “But,” said Aviles, “any time I see recent change in medicine, there’s always a little bit of pushback and it may take some time for everyone to be comfortable with the self-collection option. The recommendations still give doctors the grace to use the screening test they feel comfortable with, but I think eventually everyone will get on board with self-collection.”

As for the future, he added, “Over the next few years we’ll have to look at women who are on immune-weakening medications like Skyrizi [risankizumab] for skin conditions like psoriasis. These are commonly used in young people and can increase the risk of cervical cancer. I haven’t seen a lot of conversation about this, but patients should be aware of this risk and recommendations for this group should be different than for the general population.”

The USPSTF also noted a need to assess the magnitude of the incremental benefit and harms of screening and the interval of multiple rounds of HPV-primary screening in HPV-vaccinated cohorts in US populations.

Davis, Aviles, and Zahn and had no relevant competing interests to disclose.
 

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

The US Preventive Services Task Force (USPSTF) has posted a draft updated statement on cervical cancer screening. The statement is open for public comment until January 13, 2025, on the task force’s website. 

Nearly all cases of cervical cancer are caused by human papilloma virus (HPV) and most occur in women who have not been regularly screened or appropriately treated, the task force stressed.
 

New Screening Option

In 2024, there will be an estimated 13,820 new cases of cervical cancer and 4360 deaths.

“Evidence shows that screening saves lives, and all women aged 21-65 need to be screened,” task force member Esa Davis, MD, MPH, FAAFP, a professor of family and community medicine and associate vice president for community health at the University of Maryland, Baltimore, said in an interview. A new feature in the 2024 draft statement endorsing self-collection of cervical samples for HPV testing may facilitate broader screening. 

“We hope the new effective option of self-collecting will expand screening and allow even more women to get screened regularly,” Davis said. “Some may feel more comfortable collecting samples themselves, and the collection can be office-based or home-based, but it’s very important that it be done under the direction of a clinician.” 

In agreement is Diego Aviles, MD, an assistant professor and a gynecologic oncologist with UTHealth Houston. “Self-collection will absolutely expand screening. I think it’s an incredible advancement in medicine that patients are able to collect in the comfort of their own homes with no need to come into the office for an uncomfortable pelvic exam,” he said in an interview. “This empowers the patient and gives her a choice.”

As to concern about potential error, he added that while this is a concern on paper, “a lot of studies have shown that self-collection is just as effective doctor collection.” 

Largely consistent with the task force’s 2018 screening recommendations, the updated suggestions also align with those of other organizations such as the American College of Obstetricians and Gynecologists (ACOG), Davis said.

Christopher M. Zahn, MD, ACOG’s chief of clinical practice and health equity and quality, stressed the importance of cervical cancer screening and said his organization will be reviewing the USPSTF recommendations. He urges ACOG members to consider them and offer their comments on the public-input platform.

Drawing on the latest evidence, the task force is also highlighting for the first time that stand-alone HPV screening gives women aged 30-65 years the best balance of benefits and harms when it comes to finding and preventing cervical cancer, while continuing to reinforce that Pap testing and co-testing are also effective screening options for these women. 

The current draft statement applies to cisgender women and those assigned female sex at birth, including transgender men and nonbinary individuals. The recommendations do not apply to women at increased risk of cervical cancer such as those with HIV infection, a compromised immune system, or a history of treatment for precancerous lesions or cervical cancer. 

Based on a review of evidence on the benefits and harms of screening, the USPSTF’s independent panel of national experts proposed the following:
 

Recommendations for Screening (Based on Grade A Evidence):

• Ages 21-65 years: All women should get screened regularly for this preventable disease.
• Ages 21-29 years: All women in this age group should undergo a Pap test every 3 years but do not need HPV testing. “In this age group most HPV infections will go away on their own because young women have strong immune systems. Older women are likely to have HPV that lasts longer and so they need testing for the virus,” Davis said.
• Ages 30-65 years: As noted, HPV screening gives women in this age category the best balance of benefits and harms in terms of preventing and finding cervical cancer. Pap testing or co-testing (Pap tests and HPV tests) are also effective screening options for this population. Ideally, these women should have an HPV test every 5 years or, alternatively, a Pap test every 3 years, or a combined HPV and Pap test every 5 years (co-testing).

Recommendations Against Screening (No Benefit or Benefit Outweighed by Harms — Grade D evidence):

• Women aged less than 21 years: Screening is not necessary.
• Other women not needing screening: Nor is screening necessary for those of any age who have had a total hysterectomy with removal of the cervix and those aged > 65 years who have had regular screenings with normal results. That means normal results from their last three Pap tests or their last two HPV tests, completed in the past 10 years, with at least one of the tests done in the past 5 years.
• Women aged 65 or more: These women should continue screening only if they have not been screened regularly or have had abnormal results in the past decade such as a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer.

Davis noted that none of the current recommendations are likely to be controversial or to spark pushback. “But,” said Aviles, “any time I see recent change in medicine, there’s always a little bit of pushback and it may take some time for everyone to be comfortable with the self-collection option. The recommendations still give doctors the grace to use the screening test they feel comfortable with, but I think eventually everyone will get on board with self-collection.”

As for the future, he added, “Over the next few years we’ll have to look at women who are on immune-weakening medications like Skyrizi [risankizumab] for skin conditions like psoriasis. These are commonly used in young people and can increase the risk of cervical cancer. I haven’t seen a lot of conversation about this, but patients should be aware of this risk and recommendations for this group should be different than for the general population.”

The USPSTF also noted a need to assess the magnitude of the incremental benefit and harms of screening and the interval of multiple rounds of HPV-primary screening in HPV-vaccinated cohorts in US populations.

Davis, Aviles, and Zahn and had no relevant competing interests to disclose.
 

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

This transcript has been edited for clarity. 

I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.

This is an issue that we must address, I think, epidemiologically. We know that early-onset colorectal cancer is defined as a disease arising in those under the age of 50. There’s been a very sharp increase globally over the past 20-30 years, and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.

The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease. 

There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.

The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.

Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.

They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age. 

All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later. 

This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it. 

Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.

More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology. 

I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.

This is an issue that we must address, I think, epidemiologically. We know that early-onset colorectal cancer is defined as a disease arising in those under the age of 50. There’s been a very sharp increase globally over the past 20-30 years, and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.

The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease. 

There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.

The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.

Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.

They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age. 

All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later. 

This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it. 

Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.

More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology. 

I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche. 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity. 

I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.

This is an issue that we must address, I think, epidemiologically. We know that early-onset colorectal cancer is defined as a disease arising in those under the age of 50. There’s been a very sharp increase globally over the past 20-30 years, and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.

The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease. 

There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.

The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.

Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.

They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age. 

All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later. 

This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it. 

Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.

More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology. 

I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?

Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche. 

A version of this article appeared on Medscape.com.

TOPLINE:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

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:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

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:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lipid-lowering drugs, were associated with a 22% lower risk for nonmelanoma skin cancer (NMSC) in patients with atherosclerotic cardiovascular disease (ASCVD), an effect that was particularly significant among men, those older than 65 years, and those with immunosuppression.

METHODOLOGY:

• To evaluate the risk for NMSC — basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) — in patients with ASCVD on PCSK9 inhibitors, researchers analyzed data from the US Collaborative Network in the TriNetX database of adults aged ≥ 40 years with ASCVD who received statin therapy between 2016 and 2022.
• A total of 73,636 patients were included, divided equally between those receiving a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) plus statin therapy and the control group (those on statin therapy only).
• The analysis used propensity score matching for head-to-head comparisons, with hazard ratios (HRs) estimated using Cox proportional hazard models.
• Stratified analyses examined outcomes by age, sex, Fitzpatrick skin type, and immune status. (Immunosuppressed patients were those treated with immunosuppressants for more than 90 days in the year before the index date — the date when exposed patients were first prescribed a PCSK9 inhibitor, which was also index date for matched patients in the statin-only group.)

TAKEAWAY:

• Patients with ASCVD in the PCSK9 group showed significantly lower risks for NMSC (HR, 0.78; 95% CI, 0.71-0.87), BCC (HR, 0.78; 95% CI, 0.69-0.89), and SCC (HR, 0.79; 95% CI, 0.67-0.93) than control individuals on a statin only (P < .001 for all three).
• Both evolocumab and alirocumab demonstrated similar protective effects against the development of NMSC.
• The reduced risk for NMSC was particularly notable among patients aged 65-79 years (HR, 0.75; 95% CI, 0.66-0.86) and those aged ≥ 80 years (HR, 0.74; 95% CI, 0.60-0.91).
• Men showed a more pronounced reduction in the risk for NMSC (HR, 0.73; 95% CI, 0.64-0.83) than women (HR, 0.93; 95% CI, 0.78-1.11). The effect on lowering NMSC risk was also evident among immunosuppressed patients in the PCSK9 group (HR, 0.68; 95% CI, 0.60-0.75).

IN PRACTICE:

“The findings suggest the promising pleiotropic effect of PCSK9 inhibitors on the chemoprevention of NMSC,” the study authors wrote. Referring to previous studies that “provided mechanistic clues to our findings,” they added that “further studies are required to investigate the underlying mechanisms and establish causality.”

SOURCE:

The study was led by Cheng-Yuan Li, Taipei Veterans General Hospital, Taipei, Taiwan, and was published online in The British Journal of Dermatology.

LIMITATIONS:

Electronic health records lack information on sun protection habits, family history of skin cancer, diet, body mass index, and air pollution exposure, risk factors for NMSC. The study also lacked detailed information on enrollees’ lipid profiles and was focused mostly on patients in the United States, limiting the generalizability of the findings to other regions.

DISCLOSURES:

The study was supported by grants from Taipei Veterans General Hospital and the Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

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.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Merkel cell polyomavirus (MCPyV) and ambient ultraviolet radiation (UVR) exposure account for most Merkel cell carcinoma (MCC) cases in the United States.

METHODOLOGY:

• Researchers evaluated 38,020 MCC cases (38% women; 93% non-Hispanic White, 4% Hispanic, 1% non-Hispanic Black) diagnosed in the United States from 2001 to 2019 to estimate the contribution of potentially modifiable risk factors to the burden of MCC.
• Population-based cancer registries and linkages with HIV and transplant registries were utilized to identify MCC cases in patients with HIV, solid organ transplant recipients, and patients with chronic lymphocytic leukemia (CLL).
• Data on cloud-adjusted daily ambient UVR irradiance were merged with cancer registry information on the county of residence at diagnosis to assess UVR exposure. Studies reporting the prevalence of MCPyV in MCC specimens collected in the United States were combined via a meta-analysis.
• The study assessed population attributable fractions of MCC cases that were attributable to major immunosuppressive conditions (HIV, solid organ transplant, and chronic CLL), ambient UVR exposure, and MCPyV.

TAKEAWAY:

• The incidence of MCC was higher in people with HIV (standardized incidence ratio [SIR], 2.78), organ transplant recipients (SIR, 13.1), and patients with CLL (SIR, 5.75) than in the general US population. However, only 2.5% of MCC cases were attributable to these immunosuppressive conditions.
• Non-Hispanic White individuals showed elevated MCC incidence at both lower and higher ambient UVR exposure levels, with incidence rate ratios of 4.05 and 4.91, respectively, for MCC on the head and neck.
• A meta-analysis of 19 case series revealed that 63.8% of MCC cases were attributable to MCPyV, with a similar prevalence observed between immunocompromised and immunocompetent patients.
• Overall, 65.1% of MCC cases were attributable to ambient UVR exposure, with higher attribution for cases diagnosed on the head and neck than those diagnosed on other sites (72.1% vs 60.2%).

IN PRACTICE:

“The results of this study suggest that most MCC cases in the US are attributable to MCPyV and/or ambient UVR [UV radiation] exposure, with a smaller fraction attributable to three major immunosuppressive conditions,” the authors wrote. “Future studies should investigate UVR mutational signature, TMB [tumor mutational burden], and MCPyV prevalence according to race and ethnicity and patient immune status to help clarify the overlap between MCC risk factors.”

SOURCE:

The study was led by Jacob T. Tribble, BA, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland. It was published online on November 27, 2024, in JAMA Dermatology.

LIMITATIONS:

Incidences of MCC may have been inflated because of increased medical surveillance in immunosuppressed populations. The analysis assumed that only cases among non-Hispanic White individuals were associated with UVR. Additionally, the meta-analysis of MCPyV prevalence primarily included studies from large academic institutions, which may not be representative of the entire US population.

DISCLOSURES:

This study was supported in part by the Intramural Research Program of the NCI and the National Institutes of Health Medical Research Scholars Program. Additional funding was provided through a public-private partnership with contributions from the American Association for Dental Research and the Colgate-Palmolive Company to the Foundation for the National Institutes of Health. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.