Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3136
Woochan Hwang, Jong Seok Ahn, Hyun Ae Jung, Lori J. Wirth, Jong Chul Park
ImportanceHead and neck squamous cell carcinoma (HNSCC) represents a significant global health burden with limited therapeutic options for patients with recurrent or metastatic disease. Epidermal growth factor receptor (EGFR) is overexpressed in most patients with HNSCC and represents a biologically compelling target, yet current EGFR-directed therapies have demonstrated only modest clinical benefit.ObservationsThis review describes the evolving landscape of EGFR-targeted therapeutics in HNSCC, including cetuximab-based combination regimens as well as novel agents, such as bispecific antibodies, antibody-drug conjugates, immune cell engagers, and adaptive cell therapies. The biological rationale behind these approaches, and the results of early-phase trials, are presented in this review. Notably, cetuximab and other EGFR-targeted therapies have demonstrated inferior efficacy in patients with human papillomavirus (HPV)–positive disease.Conclusions and RelevanceThe emerging data of combinatorial approaches and novel EGFR-targeting therapeutic agents offer renewed optimism for patients with advanced HNSCC who have limited treatment options. Future progress will depend on novel agents leveraging a deeper understanding of tumor biology, innovative approaches to reduce on-target off-tumor toxic effects of targeting EGFR, and improving efficacy in the growing population of patients with HPV-positive HNSCC.
{"title":"Emerging EGFR-Targeted Therapy in Head and Neck Cancer","authors":"Woochan Hwang, Jong Seok Ahn, Hyun Ae Jung, Lori J. Wirth, Jong Chul Park","doi":"10.1001/jamaoncol.2025.3136","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3136","url":null,"abstract":"ImportanceHead and neck squamous cell carcinoma (HNSCC) represents a significant global health burden with limited therapeutic options for patients with recurrent or metastatic disease. Epidermal growth factor receptor (EGFR) is overexpressed in most patients with HNSCC and represents a biologically compelling target, yet current EGFR-directed therapies have demonstrated only modest clinical benefit.ObservationsThis review describes the evolving landscape of EGFR-targeted therapeutics in HNSCC, including cetuximab-based combination regimens as well as novel agents, such as bispecific antibodies, antibody-drug conjugates, immune cell engagers, and adaptive cell therapies. The biological rationale behind these approaches, and the results of early-phase trials, are presented in this review. Notably, cetuximab and other EGFR-targeted therapies have demonstrated inferior efficacy in patients with human papillomavirus (HPV)–positive disease.Conclusions and RelevanceThe emerging data of combinatorial approaches and novel EGFR-targeting therapeutic agents offer renewed optimism for patients with advanced HNSCC who have limited treatment options. Future progress will depend on novel agents leveraging a deeper understanding of tumor biology, innovative approaches to reduce on-target off-tumor toxic effects of targeting EGFR, and improving efficacy in the growing population of patients with HPV-positive HNSCC.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"94 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3549
Rina Yadav,Kathy D Miller
{"title":"Rethinking Ribociclib Dosage and Use in the Era of Patient-Centered Oncology-When Less Is More.","authors":"Rina Yadav,Kathy D Miller","doi":"10.1001/jamaoncol.2025.3549","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3549","url":null,"abstract":"","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"194 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3687
Fatima Cardoso, William Jacot, Sherko Kuemmel, Sudeep Gupta, Felipe Cruz, Rama Balaraman, Ana Ferreira, Tytti Ahola, Yana Chapko, Lyudmila Zhukova, Wendy Chiang, Zheng Li, Yan Ji, Nadia Kaakiou, Natalia Bolotova, Joseph A. Sparano
ImportanceRibociclib, 600 mg showed substantial survival benefits in patients with hormone receptor–positive (HR+)/ERRB2–negative (ERBB2−; formerly HER2) advanced breast cancer (ABC) in the phase 3 MONALEESA trials but was associated with dose-dependent adverse events (AEs) that were manageable with dose reductions.ObjectiveTo investigate whether a 400-mg ribociclib starting dose could reduce the incidence of AEs while maintaining efficacy in ABC.Design, Setting, and ParticipantsThe AMALEE phase 2, multicenter, randomized, open-label, interventional noninferiority study was conducted between June 18, 2019, and December 8, 2020, and included pre- and postmenopausal women with newly diagnosed HR+/ERBB2− ABC. The study was conducted across 107 sites in 23 countries (across Europe and Australia, Latin America, North America, and Asia). The data were analyzed at the final data cutoff (August 30, 2024).InterventionsRandomization 1:1 to ribociclib, 400 mg + a nonsteroidal aromatase inhibitor or ribociclib, 600 mg + a nonsteroidal aromatase inhibitor (premenopausal patients also received goserelin).Main Outcomes and MeasuresOverall response rate (ORR; primary end point); ΔFridericia-corrected QT interval (QTcF) from baseline to cycle 1 day 15, 2 hours postdose (ΔQTcF; secondary end point); duration of response (DOR); time to response (TTR); progression-free survival (PFS); pharmacokinetics; and safety. Final analysis results are reported.ResultsBaseline characteristics and prior anticancer therapy were balanced among the 376 patients (median [range] age, 58.0 [27-96] years). Median (range) follow-up from randomization was 53.5 (36.0-64.0) months (final data cutoff: August 30, 2024). The absolute ORR difference between ribociclib, 400 mg and ribociclib, 600 mg was −7.2% (ORR ratio, 0.87; 90% CI, 0.74-1.03). With ribociclib, 400 mg vs ribociclib, 600 mg, median PFS (26.9 vs 25.1 months) and DOR (26.5 vs 28.8 months) were similar; TTR was longer (13.1 vs 9.0 months). The maximal plasma concentration after dose and the 24-hour area under the curve (measured at the primary data cutoff) were 28.0% and 42.7% lower, respectively, with ribociclib, 400 mg than ribociclib, 600 mg. Ribociclib, 400 mg had a shorter ΔQTcF (12.5 vs 19.7 milliseconds at cycle 1 day 15, 2 hours postdose), lower grade 3 or4 neutropenia rate (41.0% vs 58.5%), and fewer patients who required dose reduction due to AEs (29 patients [15.4%] vs 69 patients [36.9%]). Liver-related AEs, kidney toxic effects, interstitial lung disease or pneumonitis, and AE-prompted discontinuation rates were similar between arms.Conclusions and RelevanceThe AMALEE randomized clinical trial did not demonstrate ORR noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg, with comparable DOR and PFS between doses. Ribociclib
{"title":"600- vs 400-mg First-Line Ribociclib in Hormone Receptor–Positive/ERBB2-Negative Advanced Breast Cancer","authors":"Fatima Cardoso, William Jacot, Sherko Kuemmel, Sudeep Gupta, Felipe Cruz, Rama Balaraman, Ana Ferreira, Tytti Ahola, Yana Chapko, Lyudmila Zhukova, Wendy Chiang, Zheng Li, Yan Ji, Nadia Kaakiou, Natalia Bolotova, Joseph A. Sparano","doi":"10.1001/jamaoncol.2025.3687","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3687","url":null,"abstract":"ImportanceRibociclib, 600 mg showed substantial survival benefits in patients with hormone receptor–positive (HR<jats:sup>+</jats:sup>)/<jats:italic>ERRB2</jats:italic>–negative (<jats:italic>ERBB2</jats:italic><jats:sup>−</jats:sup>; formerly <jats:italic>HER2</jats:italic>) advanced breast cancer (ABC) in the phase 3 MONALEESA trials but was associated with dose-dependent adverse events (AEs) that were manageable with dose reductions.ObjectiveTo investigate whether a 400-mg ribociclib starting dose could reduce the incidence of AEs while maintaining efficacy in ABC.Design, Setting, and ParticipantsThe AMALEE phase 2, multicenter, randomized, open-label, interventional noninferiority study was conducted between June 18, 2019, and December 8, 2020, and included pre- and postmenopausal women with newly diagnosed HR<jats:sup>+</jats:sup>/<jats:italic>ERBB2</jats:italic><jats:sup>−</jats:sup> ABC. The study was conducted across 107 sites in 23 countries (across Europe and Australia, Latin America, North America, and Asia). The data were analyzed at the final data cutoff (August 30, 2024).InterventionsRandomization 1:1 to ribociclib, 400 mg + a nonsteroidal aromatase inhibitor or ribociclib, 600 mg + a nonsteroidal aromatase inhibitor (premenopausal patients also received goserelin).Main Outcomes and MeasuresOverall response rate (ORR; primary end point); ΔFridericia-corrected QT interval (QTcF) from baseline to cycle 1 day 15, 2 hours postdose (ΔQTcF; secondary end point); duration of response (DOR); time to response (TTR); progression-free survival (PFS); pharmacokinetics; and safety. Final analysis results are reported.ResultsBaseline characteristics and prior anticancer therapy were balanced among the 376 patients (median [range] age, 58.0 [27-96] years). Median (range) follow-up from randomization was 53.5 (36.0-64.0) months (final data cutoff: August 30, 2024). The absolute ORR difference between ribociclib, 400 mg and ribociclib, 600 mg was −7.2% (ORR ratio, 0.87; 90% CI, 0.74-1.03). With ribociclib, 400 mg vs ribociclib, 600 mg, median PFS (26.9 vs 25.1 months) and DOR (26.5 vs 28.8 months) were similar; TTR was longer (13.1 vs 9.0 months). The maximal plasma concentration after dose and the 24-hour area under the curve (measured at the primary data cutoff) were 28.0% and 42.7% lower, respectively, with ribociclib, 400 mg than ribociclib, 600 mg. Ribociclib, 400 mg had a shorter ΔQTcF (12.5 vs 19.7 milliseconds at cycle 1 day 15, 2 hours postdose), lower grade 3 or4 neutropenia rate (41.0% vs 58.5%), and fewer patients who required dose reduction due to AEs (29 patients [15.4%] vs 69 patients [36.9%]). Liver-related AEs, kidney toxic effects, interstitial lung disease or pneumonitis, and AE-prompted discontinuation rates were similar between arms.Conclusions and RelevanceThe AMALEE randomized clinical trial did not demonstrate ORR noninferiority of ribociclib, 400 mg vs ribociclib, 600 mg, with comparable DOR and PFS between doses. Ribociclib","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"64 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3700
Peter A Fasching,Daniil Stroyakovskiy,Denise A Yardley,Chiun-Sheng Huang,John Crown,Aditya Bardia,Stephen Chia,Seock-Ah Im,Miguel Martin,Binghe Xu,Sherene Loi,Carlos Barrios,Michael Untch,Rebecca Moroose,Frances Visco,Gabriel N Hortobagyi,Dennis J Slamon,Rodrigo Fresco,Juan Pablo Zarate,Zheng Li,Sorcha Waters,Sara A Hurvitz
ImportanceRibociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.ObjectiveTo evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.Design, Setting, and ParticipantsThis exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.InterventionsPatients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).Main Outcomes and MeasuresThe primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.ResultsAmong 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.Conclusions and RelevanceThis exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.Trial RegistrationClinicalTrials.gov Identifier: NCT03701334.
{"title":"Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial.","authors":"Peter A Fasching,Daniil Stroyakovskiy,Denise A Yardley,Chiun-Sheng Huang,John Crown,Aditya Bardia,Stephen Chia,Seock-Ah Im,Miguel Martin,Binghe Xu,Sherene Loi,Carlos Barrios,Michael Untch,Rebecca Moroose,Frances Visco,Gabriel N Hortobagyi,Dennis J Slamon,Rodrigo Fresco,Juan Pablo Zarate,Zheng Li,Sorcha Waters,Sara A Hurvitz","doi":"10.1001/jamaoncol.2025.3700","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3700","url":null,"abstract":"ImportanceRibociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.ObjectiveTo evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.Design, Setting, and ParticipantsThis exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.InterventionsPatients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).Main Outcomes and MeasuresThe primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.ResultsAmong 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.Conclusions and RelevanceThis exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.Trial RegistrationClinicalTrials.gov Identifier: NCT03701334.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"13 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3320
Mara B. Antonoff, Leah Phillips, Eric K. Singhi
This JAMA Oncology Patient Page describes causes, types, and symptoms of lung cancer in people younger than 50 years and how it can be treated.
这个JAMA肿瘤学患者页面描述了50岁以下人群肺癌的原因、类型和症状，以及如何治疗。
{"title":"Understanding Lung Cancer in Younger People","authors":"Mara B. Antonoff, Leah Phillips, Eric K. Singhi","doi":"10.1001/jamaoncol.2025.3320","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3320","url":null,"abstract":"This <jats:italic>JAMA Oncology</jats:italic> Patient Page describes causes, types, and symptoms of lung cancer in people younger than 50 years and how it can be treated.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"16 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-25DOI: 10.1001/jamaoncol.2025.3593
Le Thi Phuong Thao,Tri-Long Nguyen,Jasmine Singh,Sean G Byars,Alexander G Bick,Leslie Ford,Peter Gibbs,John J McNeil,Anne M Murray,Suzanne G Orchard,James Phung,Asad Umar,Erica M Wood,Robyn L Woods,Paul Lacaze,Andrew T Chan,David J Curtis,Zoe K McQuilten,Rory Wolfe
ImportanceThe role of low-dose aspirin (LDA) in cancer prevention among older adults is unclear. Identifying individuals likely to experience benefit or harm is crucial for guiding personalized prevention strategies.ObjectiveTo identify subgroups of the older population who may benefit most from LDA for cancer prevention by developing and validating an effect score model, including individual characteristics such as clonal hematopoiesis of indeterminate potential (CHIP) and other factors, to predict the individualized treatment effects (ITEs) of LDA in cancer incidence.Design, Setting, and ParticipantsThis comparative effectiveness study is a nonprespecified secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial conducted between 2010 and 2014. Australian community-dwelling ASPREE participants (aged ≥70 years) provided biospecimen samples for CHIP testing. CHIP was measured in 18 genes using a targeted sequencing assay. Analyses were conducted between May 2023 and July 2025.ExposuresLDA (100 mg per day) or placebo.Main Outcomes and MeasuresThe primary outcome was overall cancer incidence at 5 years. Twelve candidate models for predicting ITEs were assessed; the final model was selected to maximize cancer risk reduction and internally validated using bootstrapping. Participants were grouped into treatment-favorable (ITE >0) and treatment-unfavorable (ITE <0) subgroups based on the final predictive model.ResultsA total of 9350 participants were included in the analysis (median age, 73.7 [IQR, 71.6-77.1] years; 5021 females [53.7%]) to LDA (4667 [49.9%]) or placebo (4683 [50.1%]). The median follow-up was 4.5 (IQR, 3.3-5.5) years. Factors associated with LDA benefit included older age, nonsmoking status, CHIP with a variant allele frequency of 10% or greater, family history of cancer, and lower body mass index. CHIP was the strongest predictor of benefit. Personalized treatment based on the model improved 5-year absolute cancer risk reduction by a median of 2.3% (IQR, 0.7%-3.7%) compared with a treat-all approach (LDA to all participants). LDA was associated with lower cancer risk (hazard ratio [HR], 0.85 [95% CI, 0.72-1.00]) in the treatment-favorable subgroup and higher cancer risk (HR, 1.14 [95% CI, 0.95-1.38]) in the treatment-unfavorable subgroup (P = .02 for heterogeneity).Conclusions and RelevanceThe findings of this study suggest significant heterogeneity in the effectiveness of LDA for cancer prevention among older adults, with CHIP identified as a key predictive factor. Further study is needed to fully understand the implications of these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT01038583.
{"title":"Low-Dose Aspirin for Individualized Cancer Prevention in Older Adults: A Secondary Analysis of the ASPREE Randomized Clinical Trial.","authors":"Le Thi Phuong Thao,Tri-Long Nguyen,Jasmine Singh,Sean G Byars,Alexander G Bick,Leslie Ford,Peter Gibbs,John J McNeil,Anne M Murray,Suzanne G Orchard,James Phung,Asad Umar,Erica M Wood,Robyn L Woods,Paul Lacaze,Andrew T Chan,David J Curtis,Zoe K McQuilten,Rory Wolfe","doi":"10.1001/jamaoncol.2025.3593","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3593","url":null,"abstract":"ImportanceThe role of low-dose aspirin (LDA) in cancer prevention among older adults is unclear. Identifying individuals likely to experience benefit or harm is crucial for guiding personalized prevention strategies.ObjectiveTo identify subgroups of the older population who may benefit most from LDA for cancer prevention by developing and validating an effect score model, including individual characteristics such as clonal hematopoiesis of indeterminate potential (CHIP) and other factors, to predict the individualized treatment effects (ITEs) of LDA in cancer incidence.Design, Setting, and ParticipantsThis comparative effectiveness study is a nonprespecified secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial conducted between 2010 and 2014. Australian community-dwelling ASPREE participants (aged ≥70 years) provided biospecimen samples for CHIP testing. CHIP was measured in 18 genes using a targeted sequencing assay. Analyses were conducted between May 2023 and July 2025.ExposuresLDA (100 mg per day) or placebo.Main Outcomes and MeasuresThe primary outcome was overall cancer incidence at 5 years. Twelve candidate models for predicting ITEs were assessed; the final model was selected to maximize cancer risk reduction and internally validated using bootstrapping. Participants were grouped into treatment-favorable (ITE >0) and treatment-unfavorable (ITE <0) subgroups based on the final predictive model.ResultsA total of 9350 participants were included in the analysis (median age, 73.7 [IQR, 71.6-77.1] years; 5021 females [53.7%]) to LDA (4667 [49.9%]) or placebo (4683 [50.1%]). The median follow-up was 4.5 (IQR, 3.3-5.5) years. Factors associated with LDA benefit included older age, nonsmoking status, CHIP with a variant allele frequency of 10% or greater, family history of cancer, and lower body mass index. CHIP was the strongest predictor of benefit. Personalized treatment based on the model improved 5-year absolute cancer risk reduction by a median of 2.3% (IQR, 0.7%-3.7%) compared with a treat-all approach (LDA to all participants). LDA was associated with lower cancer risk (hazard ratio [HR], 0.85 [95% CI, 0.72-1.00]) in the treatment-favorable subgroup and higher cancer risk (HR, 1.14 [95% CI, 0.95-1.38]) in the treatment-unfavorable subgroup (P = .02 for heterogeneity).Conclusions and RelevanceThe findings of this study suggest significant heterogeneity in the effectiveness of LDA for cancer prevention among older adults, with CHIP identified as a key predictive factor. Further study is needed to fully understand the implications of these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT01038583.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"24 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1001/jamaoncol.2025.3377
Yixuan Meng,Feng Wu,Soyoung Kwak,Chan Wang,Mykhaylo Usyk,Neal D Freedman,Wen-Yi Huang,Caroline Y Um,Tamas A Gonda,Paul E Oberstein,Huilin Li,Richard B Hayes,Jiyoung Ahn
ImportanceThe oral microbiota may be involved in the development of pancreatic cancer, yet current evidence is largely limited to bacterial 16S amplicon sequencing and small retrospective case-control studies.ObjectiveTo test whether the oral bacterial and fungal microbiome is associated with the subsequent development of pancreatic cancer.Design, Setting, and ParticipantsThis cohort study used data from 2 epidemiological cohorts: the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among cohort participants who provided oral samples, those who prospectively developed pancreatic cancer were identified during follow-up. Control participants who remained free of cancer were selected by 1:1 frequency matching on cohort, 5-year age band, sex, race and ethnicity, and time since oral sample collection. Data were collected from August 2023 to September 2024, and data were analyzed from August 2023 to January 2025.ExposuresThe oral bacterial and fungal microbiome were characterized via whole-genome shotgun sequencing and internal transcribed spacer (ITS) sequencing, respectively. The association of periodontal pathogens of the red complex (Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia) and orange complex (Fusobacterium nucleatum, F periodonticum, Prevotella intermedia, P nigrescens, Parvimonas micra, Eubacterium nodatum, Campylobacter shower, and C gracilis) with pancreatic cancer was tested via logistic regression. The association of the microbiome-wide bacterial and fungal taxa with pancreatic cancer was assessed by Analysis of Compositions of Microbiomes With Bias Correction 2 (ANCOM-BC2). Microbial risk scores (MRS) for pancreatic cancer were calculated from the risk-associated bacterial and fungal species.Main Outcomes and MeasuresPancreatic cancer incidence.ResultsOf 122 000 cohort participants who provided samples, 445 developed pancreatic cancer over a median (IQR) follow-up of 8.8 (4.9-13.4) years and were matched with 445 controls. Of these 890 participants, 474 (53.3%) were male, and the mean (SD) age was 67.2 (7.5) years. Three oral bacterial periodontal pathogens-P gingivalis, E nodatum, and P micra-were associated with increased risk of pancreatic cancer. A bacteriome-wide scan revealed 8 oral bacteria associated with decreased and 13 oral bacteria associated with increased risk of pancreatic cancer (false discovery rate-adjusted Q statistic less than .05). Of the fungi, genus Candida was associated with increased risk of pancreatic cancer. The MRS, based on 27 oral species, was associated with an increase in pancreatic cancer risk (multivariate odds ratio per 1-SD increase in MRS, 3.44; 95% CI, 2.63-4.51).Conclusions and RelevanceIn this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development. Oral microbiota hold promise as biomarkers to identify individuals at high risk of panc
{"title":"Oral Bacterial and Fungal Microbiome and Subsequent Risk for Pancreatic Cancer.","authors":"Yixuan Meng,Feng Wu,Soyoung Kwak,Chan Wang,Mykhaylo Usyk,Neal D Freedman,Wen-Yi Huang,Caroline Y Um,Tamas A Gonda,Paul E Oberstein,Huilin Li,Richard B Hayes,Jiyoung Ahn","doi":"10.1001/jamaoncol.2025.3377","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3377","url":null,"abstract":"ImportanceThe oral microbiota may be involved in the development of pancreatic cancer, yet current evidence is largely limited to bacterial 16S amplicon sequencing and small retrospective case-control studies.ObjectiveTo test whether the oral bacterial and fungal microbiome is associated with the subsequent development of pancreatic cancer.Design, Setting, and ParticipantsThis cohort study used data from 2 epidemiological cohorts: the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among cohort participants who provided oral samples, those who prospectively developed pancreatic cancer were identified during follow-up. Control participants who remained free of cancer were selected by 1:1 frequency matching on cohort, 5-year age band, sex, race and ethnicity, and time since oral sample collection. Data were collected from August 2023 to September 2024, and data were analyzed from August 2023 to January 2025.ExposuresThe oral bacterial and fungal microbiome were characterized via whole-genome shotgun sequencing and internal transcribed spacer (ITS) sequencing, respectively. The association of periodontal pathogens of the red complex (Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia) and orange complex (Fusobacterium nucleatum, F periodonticum, Prevotella intermedia, P nigrescens, Parvimonas micra, Eubacterium nodatum, Campylobacter shower, and C gracilis) with pancreatic cancer was tested via logistic regression. The association of the microbiome-wide bacterial and fungal taxa with pancreatic cancer was assessed by Analysis of Compositions of Microbiomes With Bias Correction 2 (ANCOM-BC2). Microbial risk scores (MRS) for pancreatic cancer were calculated from the risk-associated bacterial and fungal species.Main Outcomes and MeasuresPancreatic cancer incidence.ResultsOf 122 000 cohort participants who provided samples, 445 developed pancreatic cancer over a median (IQR) follow-up of 8.8 (4.9-13.4) years and were matched with 445 controls. Of these 890 participants, 474 (53.3%) were male, and the mean (SD) age was 67.2 (7.5) years. Three oral bacterial periodontal pathogens-P gingivalis, E nodatum, and P micra-were associated with increased risk of pancreatic cancer. A bacteriome-wide scan revealed 8 oral bacteria associated with decreased and 13 oral bacteria associated with increased risk of pancreatic cancer (false discovery rate-adjusted Q statistic less than .05). Of the fungi, genus Candida was associated with increased risk of pancreatic cancer. The MRS, based on 27 oral species, was associated with an increase in pancreatic cancer risk (multivariate odds ratio per 1-SD increase in MRS, 3.44; 95% CI, 2.63-4.51).Conclusions and RelevanceIn this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development. Oral microbiota hold promise as biomarkers to identify individuals at high risk of panc","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"36 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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