Pub Date : 2025-10-16DOI: 10.1001/jamaoncol.2025.4079
Seema A Khan,Justin Romanoff,Constantine Gatsonis,Habib Rahbar,Ruth Carlos,Sunil Badve,Jean Wright,Ralph L Corsetti,Constance D Lehman,Derrick W Spell,Linda K Han,John R Bumberry,Ilana Gareen,Bradley S Snyder,Lynne I Wagner,Kathy D Miller,Christopher Comstock,Joseph A Sparano
ImportanceBreast ductal carcinoma in situ (DCIS) requires personalized treatment given its variable natural history. This study reports the first prospective oncologic outcomes of radiotherapy decisions as guided by 12-gene molecular assay, the DCIS score (DS).ObjectiveTo assess surgical outcomes following preoperative breast magnetic resonance imaging (MRI) in women with DCIS and estimate 5-year and 10-year ipsilateral breast event (IBE) rates in participants given DS-based postoperative radiotherapy recommendations after local excision (WLE).Design, Setting, and ParticipantsWomen with screen-detected DCIS who were eligible for WLE were enrolled to a single-arm, multicenter trial conducted at 75 institutions within the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (March 2015 to April 2016) and received a preoperative breast MRI-guided surgical treatment. Those who underwent successful WLE were advised to omit radiotherapy for low DS (<39) and receive radiotherapy for intermediate/high DS (≥39). Those achieving WLE as final treatment and successful DS assay (n = 171) were included in a prespecified analysis. Participants were followed up every 6 months for DCIS or invasive IBE, and 5-year IBE rates were analyzed from July to November 2023.InterventionDS-based postoperative radiotherapy recommendations.Main Outcomes and MeasuresFive-year IBE rates, with 95% CIs.ResultsAmong the 339 participants, the mean (SD) age was 59.1 (10.1) years. A total of 171 women (50.4%) received WLE for pure DCIS with free surgical margins and had DS data available. A total of 159 (93.0%) adhered to DS-based radiotherapy recommendations; 7 of 82 patients (8.5%) with a low DS underwent radiotherapy, and 5 of 89 patients (5.6%) with an intermediate/high DS declined radiotherapy. Over median (range) follow-up of 5 (0.5-5.0) years, 8 of 171 women experienced IBEs (4.8%; 95% CI, 2.4%-9.4%). IBE rates were similar for participants with a low DS(5.1%; 95% CI, 1.9%-12.9%) and participants with an intermediate/high DS (4.5%; 95% CI, 1.7%-11.7%). Among the 159 women who had adhered to DS-based radiotherapy recommendations, IBE rates were similar for participants with a low DS (5.5%; 95% CI, 2.1%-14.1%) and intermediate/high DS (4.8%; 95% CI, 1.8%-12.3%).Conclusions and RelevanceThe findings of this prespecified analysis of a clinical trial suggest that DS-guided radiotherapy post-WLE for DCIS shows markedly lower 5-year IBE rates (approximately 5%) for intermediate/high DS than previously reported data following WLE alone. Despite a limited sample size, these data potentially provide support for radiotherapy use in patients with intermediate/high DS, and omission when DS is low, although confirmatory studies are needed.Trial RegistrationClinicalTrials.gov Identifier: NCT02352883.
{"title":"Radiotherapy With a 12-Gene Expression Assay for Ductal Carcinoma In Situ: A Randomized Clinical Trial.","authors":"Seema A Khan,Justin Romanoff,Constantine Gatsonis,Habib Rahbar,Ruth Carlos,Sunil Badve,Jean Wright,Ralph L Corsetti,Constance D Lehman,Derrick W Spell,Linda K Han,John R Bumberry,Ilana Gareen,Bradley S Snyder,Lynne I Wagner,Kathy D Miller,Christopher Comstock,Joseph A Sparano","doi":"10.1001/jamaoncol.2025.4079","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.4079","url":null,"abstract":"ImportanceBreast ductal carcinoma in situ (DCIS) requires personalized treatment given its variable natural history. This study reports the first prospective oncologic outcomes of radiotherapy decisions as guided by 12-gene molecular assay, the DCIS score (DS).ObjectiveTo assess surgical outcomes following preoperative breast magnetic resonance imaging (MRI) in women with DCIS and estimate 5-year and 10-year ipsilateral breast event (IBE) rates in participants given DS-based postoperative radiotherapy recommendations after local excision (WLE).Design, Setting, and ParticipantsWomen with screen-detected DCIS who were eligible for WLE were enrolled to a single-arm, multicenter trial conducted at 75 institutions within the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (March 2015 to April 2016) and received a preoperative breast MRI-guided surgical treatment. Those who underwent successful WLE were advised to omit radiotherapy for low DS (<39) and receive radiotherapy for intermediate/high DS (≥39). Those achieving WLE as final treatment and successful DS assay (n = 171) were included in a prespecified analysis. Participants were followed up every 6 months for DCIS or invasive IBE, and 5-year IBE rates were analyzed from July to November 2023.InterventionDS-based postoperative radiotherapy recommendations.Main Outcomes and MeasuresFive-year IBE rates, with 95% CIs.ResultsAmong the 339 participants, the mean (SD) age was 59.1 (10.1) years. A total of 171 women (50.4%) received WLE for pure DCIS with free surgical margins and had DS data available. A total of 159 (93.0%) adhered to DS-based radiotherapy recommendations; 7 of 82 patients (8.5%) with a low DS underwent radiotherapy, and 5 of 89 patients (5.6%) with an intermediate/high DS declined radiotherapy. Over median (range) follow-up of 5 (0.5-5.0) years, 8 of 171 women experienced IBEs (4.8%; 95% CI, 2.4%-9.4%). IBE rates were similar for participants with a low DS(5.1%; 95% CI, 1.9%-12.9%) and participants with an intermediate/high DS (4.5%; 95% CI, 1.7%-11.7%). Among the 159 women who had adhered to DS-based radiotherapy recommendations, IBE rates were similar for participants with a low DS (5.5%; 95% CI, 2.1%-14.1%) and intermediate/high DS (4.8%; 95% CI, 1.8%-12.3%).Conclusions and RelevanceThe findings of this prespecified analysis of a clinical trial suggest that DS-guided radiotherapy post-WLE for DCIS shows markedly lower 5-year IBE rates (approximately 5%) for intermediate/high DS than previously reported data following WLE alone. Despite a limited sample size, these data potentially provide support for radiotherapy use in patients with intermediate/high DS, and omission when DS is low, although confirmatory studies are needed.Trial RegistrationClinicalTrials.gov Identifier: NCT02352883.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"11 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296089","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 : 2025-10-16DOI: 10.1001/jamaoncol.2025.3608
César Serrano,Sebastian Bauer,Jean-Yves Blay,Paolo G Casali,Carlo M Cicala,Angelo P Dei Tos,Antonia Digklia,Hans Gelderblom,Antoine Italiano,Robin L Jones,Bernd Kasper,Anastasios Kyriazoglou,Francois Le Loarer,Javier Martín-Broto,Andrea Napolitano,Piotr Rutkowski,Silvia Stacchiotti,William Tap,David Thomas,Khin Thway,Claudia Valverde,Winette T A van der Graaf,Eva Wardelmann,Judith V M G Bovée
ImportanceSarcomas comprise a heterogeneous group of malignant neoplasms that include genomically simple (driven by recurrent genetic alterations) and genomically complex (characterized by extensive genomic rearrangements) subtypes. Regardless, sarcomas exhibit a remarkably low mutational burden. In this context, there is a growing demand for the use of next-generation sequencing (NGS)-based technologies to aid in the clinical management of patients with sarcoma. However, a broad, clinically impactful implementation faces inherent challenges associated with their rarity, heterogeneity, and limited molecular understanding.ObservationsFrom a diagnostic standpoint, there is a lack of prospective studies comparing up-front, indiscriminate use of NGS fusion panels in all new cases suggestive of sarcoma diagnosis in comparison with a use only indicated by a sarcoma-expert pathologist during the assessment. Therefore, although a significant proportion of sarcomas harbor specific molecular alterations, not all cases require NGS for a definitive diagnosis given that most sarcoma subtypes display classic histologic features. From a therapeutic perspective, current evidence does not support routine clinical use of NGS in all patients with sarcoma due to the small number of actionable alterations and the limited evidence for clinical benefit achieved with NGS-matched treatments. Although certain entities and molecular backgrounds demonstrate potential advantages, the consensus group emphasizes that indication of targeted agents for treatment is largely based on the specific subtype, and therefore, an accurate diagnosis is indispensable.Conclusions and RelevanceEvidence supporting the routine, nonselective use of NGS in patients with sarcoma is currently limited. Given the complexity, the decision to perform an NGS panel, as well as the interpretation and use of its results for diagnostic or therapeutic purposes, should take place only in sarcoma-expert institutions, including a multidisciplinary review. The results of multigene panels performed in nonexpert sarcoma centers cannot replace the pathology review or the recommendation of NGS-guided therapies without prior evaluation by sarcoma experts.
{"title":"Guidelines for Next-Generation Sequencing in Sarcoma Diagnosis and Treatment: A Consensus Review.","authors":"César Serrano,Sebastian Bauer,Jean-Yves Blay,Paolo G Casali,Carlo M Cicala,Angelo P Dei Tos,Antonia Digklia,Hans Gelderblom,Antoine Italiano,Robin L Jones,Bernd Kasper,Anastasios Kyriazoglou,Francois Le Loarer,Javier Martín-Broto,Andrea Napolitano,Piotr Rutkowski,Silvia Stacchiotti,William Tap,David Thomas,Khin Thway,Claudia Valverde,Winette T A van der Graaf,Eva Wardelmann,Judith V M G Bovée","doi":"10.1001/jamaoncol.2025.3608","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3608","url":null,"abstract":"ImportanceSarcomas comprise a heterogeneous group of malignant neoplasms that include genomically simple (driven by recurrent genetic alterations) and genomically complex (characterized by extensive genomic rearrangements) subtypes. Regardless, sarcomas exhibit a remarkably low mutational burden. In this context, there is a growing demand for the use of next-generation sequencing (NGS)-based technologies to aid in the clinical management of patients with sarcoma. However, a broad, clinically impactful implementation faces inherent challenges associated with their rarity, heterogeneity, and limited molecular understanding.ObservationsFrom a diagnostic standpoint, there is a lack of prospective studies comparing up-front, indiscriminate use of NGS fusion panels in all new cases suggestive of sarcoma diagnosis in comparison with a use only indicated by a sarcoma-expert pathologist during the assessment. Therefore, although a significant proportion of sarcomas harbor specific molecular alterations, not all cases require NGS for a definitive diagnosis given that most sarcoma subtypes display classic histologic features. From a therapeutic perspective, current evidence does not support routine clinical use of NGS in all patients with sarcoma due to the small number of actionable alterations and the limited evidence for clinical benefit achieved with NGS-matched treatments. Although certain entities and molecular backgrounds demonstrate potential advantages, the consensus group emphasizes that indication of targeted agents for treatment is largely based on the specific subtype, and therefore, an accurate diagnosis is indispensable.Conclusions and RelevanceEvidence supporting the routine, nonselective use of NGS in patients with sarcoma is currently limited. Given the complexity, the decision to perform an NGS panel, as well as the interpretation and use of its results for diagnostic or therapeutic purposes, should take place only in sarcoma-expert institutions, including a multidisciplinary review. The results of multigene panels performed in nonexpert sarcoma centers cannot replace the pathology review or the recommendation of NGS-guided therapies without prior evaluation by sarcoma experts.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"2 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296111","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 : 2025-10-16DOI: 10.1001/jamaoncol.2025.4125
Nikita Sushentsev,Anne Y Warren,Richard Colling,Clare Verrill,Ekaterina Pazukhina,Oleg Blyuss,Tyler M Seibert,Tristan Barrett,Ian G Mills,Richard J Bryant,Jenny L Donovan,David E Neal,Freddie C Hamdy
ImportanceCribriform prostate cancer is associated with poor outcomes; however, its optimal treatment strategy remains unclear in the absence of randomized data.ObjectiveTo retrospectively analyze the results of the PROTECT randomized clinical trial to establish the association between cribriform-positive and cribriform-negative prostate cancer and 15-year risk of metastasis in patients who underwent active monitoring, surgery, or radiotherapy.Design, Setting, and ParticipantsBetween 1999 and 2009, the PROTECT phase 3 randomized clinical trial enrolled 1643 men with clinically localized prostate cancer who were randomly assigned to receive active monitoring, surgery, or radiotherapy with neoadjuvant androgen deprivation therapy (ADT). In this secondary analysis of the PROTECT trial, a centralized histopathologic review was conducted on available diagnostic biopsy slides to classify patients as cribriform-positive if they had invasive cribriform carcinoma and/or intraductal carcinoma. Data were collected from January 25, 2024, to October 11, 2024, and were analyzed from October 14, 2024, to January 30, 2025.ExposuresAge, prostate-specific antigen (PSA), Gleason score, and cribriform status.Main Outcomes and MeasuresThe primary outcome was progression to metastatic disease (bony, visceral, or lymph node metastases on imaging or PSA >100 ng/mL). Multivariable Cox proportional hazards regression models, adjusted for randomization variables, were incorporated to assess 15-year metastasis risk. Cumulative incidence curves were compared using the Gray test. Both intention-to-treat and per-protocol analyses were performed.ResultsAmong 712 men (mean [SD] age, 62.0 [5.0] years) whose biopsies were retrospectively reviewed, 93 (13.1%) had cribriform-positive disease and 42 (5.9%) developed metastasis. In the intention-to-treat cohort, cribriform-positive disease significantly increased the risk of metastasis (hazard ratio [HR], 3.61 [95% CI, 1.60-8.11]; P = .003). Radiotherapy with neoadjuvant ADT significantly reduced metastasis risk (HR, 0.35 [95% CI, 0.16-0.78]; P = .04) (15-year cumulative incidence in patients with cribriform-positive disease, 8%), while surgery delayed metastasis but did not significantly improve long-term outcomes compared with active monitoring (HR, 0.52 [95% CI, 0.25-1.08]; P = .09) (15-year cumulative incidence in patients with cribriform-positive disease, 26% for surgery and 25% for active monitoring). Among patients with cribriform-negative disease, incidence of metastasis was low and did not differ by treatment. Similar per-protocol results were noted.Conclusions and RelevanceThe findings of this secondary analysis of the PROTECT randomized clinical trial suggest that cribriform morphology was a strong, independent predictor of 15-year metastasis among patients with prostate cancer and that radiotherapy with neoadjuvant ADT was associated with a reduced long-term risk of metastasis. Conversely, outcomes were favorable for most
{"title":"Active Monitoring, Surgery, and Radiotherapy for Cribriform-Positive and Cribriform-Negative Prostate Cancer: A Secondary Analysis of the PROTECT Randomized Clinical Trial.","authors":"Nikita Sushentsev,Anne Y Warren,Richard Colling,Clare Verrill,Ekaterina Pazukhina,Oleg Blyuss,Tyler M Seibert,Tristan Barrett,Ian G Mills,Richard J Bryant,Jenny L Donovan,David E Neal,Freddie C Hamdy","doi":"10.1001/jamaoncol.2025.4125","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.4125","url":null,"abstract":"ImportanceCribriform prostate cancer is associated with poor outcomes; however, its optimal treatment strategy remains unclear in the absence of randomized data.ObjectiveTo retrospectively analyze the results of the PROTECT randomized clinical trial to establish the association between cribriform-positive and cribriform-negative prostate cancer and 15-year risk of metastasis in patients who underwent active monitoring, surgery, or radiotherapy.Design, Setting, and ParticipantsBetween 1999 and 2009, the PROTECT phase 3 randomized clinical trial enrolled 1643 men with clinically localized prostate cancer who were randomly assigned to receive active monitoring, surgery, or radiotherapy with neoadjuvant androgen deprivation therapy (ADT). In this secondary analysis of the PROTECT trial, a centralized histopathologic review was conducted on available diagnostic biopsy slides to classify patients as cribriform-positive if they had invasive cribriform carcinoma and/or intraductal carcinoma. Data were collected from January 25, 2024, to October 11, 2024, and were analyzed from October 14, 2024, to January 30, 2025.ExposuresAge, prostate-specific antigen (PSA), Gleason score, and cribriform status.Main Outcomes and MeasuresThe primary outcome was progression to metastatic disease (bony, visceral, or lymph node metastases on imaging or PSA >100 ng/mL). Multivariable Cox proportional hazards regression models, adjusted for randomization variables, were incorporated to assess 15-year metastasis risk. Cumulative incidence curves were compared using the Gray test. Both intention-to-treat and per-protocol analyses were performed.ResultsAmong 712 men (mean [SD] age, 62.0 [5.0] years) whose biopsies were retrospectively reviewed, 93 (13.1%) had cribriform-positive disease and 42 (5.9%) developed metastasis. In the intention-to-treat cohort, cribriform-positive disease significantly increased the risk of metastasis (hazard ratio [HR], 3.61 [95% CI, 1.60-8.11]; P = .003). Radiotherapy with neoadjuvant ADT significantly reduced metastasis risk (HR, 0.35 [95% CI, 0.16-0.78]; P = .04) (15-year cumulative incidence in patients with cribriform-positive disease, 8%), while surgery delayed metastasis but did not significantly improve long-term outcomes compared with active monitoring (HR, 0.52 [95% CI, 0.25-1.08]; P = .09) (15-year cumulative incidence in patients with cribriform-positive disease, 26% for surgery and 25% for active monitoring). Among patients with cribriform-negative disease, incidence of metastasis was low and did not differ by treatment. Similar per-protocol results were noted.Conclusions and RelevanceThe findings of this secondary analysis of the PROTECT randomized clinical trial suggest that cribriform morphology was a strong, independent predictor of 15-year metastasis among patients with prostate cancer and that radiotherapy with neoadjuvant ADT was associated with a reduced long-term risk of metastasis. Conversely, outcomes were favorable for most ","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"54 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296091","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 : 2025-10-09DOI: 10.1001/jamaoncol.2025.3863
Rivalin Aho Glele, Elizabeth A. M. Feijen, Brice Fresneau, Raoul C. Reulen, Rodrigue S. Allodji, Giao Vu-Bezin, Boris Schwartz, Neige Journy, Véronique Minard-Colin, Francesca Bagnasco, Edit Bardi, Fabiën N. Belle, Julianne Byrne, Elvira C. van Dalen, Jop C. Teepen, Desiree Grabow, Peter Kaatsch, Lars Hjorth, Momcilo Jankovic, Claudia E. Kuehni, Gillian Levitt, Cristina Veres, Isabelle Aerts, Lorna Zadravec Zaletel, Helena J. H. van der Pal, Cecile Ronckers, Carlotta Sacerdote, Roderick Skinner, Zsuzsanna Jakab, Gisela Michel, Monica Terenziani, Nadia Haddy, Isabelle Thierry-Chef, Elisabeth Cardis, Ibrahima Diallo, David L. Winter, Leontien C. M. Kremer, Mike M. Hawkins, Florent de Vathaire
ImportanceSubstantial improvements in childhood cancer survival have created a critical need to address serious long-term health complications, such as valvular heart disease (VHD).ObjectiveTo identify treatment-related risk factors for VHD in a large European cohort of long-term childhood cancer survivors.Design, Setting, and ParticipantsThis nested case-control study used data from the PanCareSurFup (PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies) and ProCardio cohorts, including detailed radiation dose reconstruction and chemotherapy exposure, for childhood cancer survivors from 7 European countries, diagnosed between 1940 and 2009, who survived at least 5 years after cancer diagnosis. Case patients, defined as having symptomatic VHD, were matched with controls 1:2 by subcohort, sex, age at cancer diagnosis, and calendar year of initial diagnosis. Data were analyzed from October 2023 to June 2025.ExposuresDoses were calculated by performing a whole-body dosimetric reconstruction using a voxel-based anthropomorphic phantom with more than 200 delineated anatomic structures or substructures. Cumulative dose to cytotoxic agents was also assessed.Main Outcome and MeasureDevelopment of symptomatic VHD (grade ≥3 per the Common Terminology and Criteria for Adverse Events, version 4.03).ResultsOf the 225 cases, 136 participants (60.4%) were male, and 195 (86.7%) were diagnosed with VHD beyond 20 years from childhood cancer. Survivors receiving a mean heart radiation therapy (RT) dose of 5 to less than 15 Gy had an increased risk of VHD (odds ratio [OR], 4.7; 95% CI, 2.1-10.7) compared to those without heart RT, with higher risk when more than half of the heart was exposed. The heart RT dose response appeared exponential, with the OR being 104.1 (95% CI, 27.8-389.6) for mean heart dose of 30 Gy or more, increasing considerably with follow-up from 6.0 (95% CI, 1.4-26.5) after 5 to 19 years to 71.4 (95% CI, 20.4-250.0) after 30 or more years. Cumulative anthracycline doses of 400 mg/m2 or higher were also associated with increased VHD risk (OR, 3.8; 95% CI, 1.4-10.3), showing an exponential dose-response pattern. Cumulative exposure to platinum agents was associated with VHD risk in a linear manner. No statistically significant associations were found for other chemotherapy agents or radiation to the spleen.Conclusion and RelevanceIn this case-control study, heart RT, anthracyclines, and platinum agents were associated with increased VHD risk in childhood cancer survivors. Risks from both RT and anthracyclines were amplified with age and follow-up, underscoring the need for long-term cardiac surveillance.
{"title":"Risk Factors for Valvulopathy Among Childhood Cancer Survivors","authors":"Rivalin Aho Glele, Elizabeth A. M. Feijen, Brice Fresneau, Raoul C. Reulen, Rodrigue S. Allodji, Giao Vu-Bezin, Boris Schwartz, Neige Journy, Véronique Minard-Colin, Francesca Bagnasco, Edit Bardi, Fabiën N. Belle, Julianne Byrne, Elvira C. van Dalen, Jop C. Teepen, Desiree Grabow, Peter Kaatsch, Lars Hjorth, Momcilo Jankovic, Claudia E. Kuehni, Gillian Levitt, Cristina Veres, Isabelle Aerts, Lorna Zadravec Zaletel, Helena J. H. van der Pal, Cecile Ronckers, Carlotta Sacerdote, Roderick Skinner, Zsuzsanna Jakab, Gisela Michel, Monica Terenziani, Nadia Haddy, Isabelle Thierry-Chef, Elisabeth Cardis, Ibrahima Diallo, David L. Winter, Leontien C. M. Kremer, Mike M. Hawkins, Florent de Vathaire","doi":"10.1001/jamaoncol.2025.3863","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3863","url":null,"abstract":"ImportanceSubstantial improvements in childhood cancer survival have created a critical need to address serious long-term health complications, such as valvular heart disease (VHD).ObjectiveTo identify treatment-related risk factors for VHD in a large European cohort of long-term childhood cancer survivors.Design, Setting, and ParticipantsThis nested case-control study used data from the PanCareSurFup (PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies) and ProCardio cohorts, including detailed radiation dose reconstruction and chemotherapy exposure, for childhood cancer survivors from 7 European countries, diagnosed between 1940 and 2009, who survived at least 5 years after cancer diagnosis. Case patients, defined as having symptomatic VHD, were matched with controls 1:2 by subcohort, sex, age at cancer diagnosis, and calendar year of initial diagnosis. Data were analyzed from October 2023 to June 2025.ExposuresDoses were calculated by performing a whole-body dosimetric reconstruction using a voxel-based anthropomorphic phantom with more than 200 delineated anatomic structures or substructures. Cumulative dose to cytotoxic agents was also assessed.Main Outcome and MeasureDevelopment of symptomatic VHD (grade ≥3 per the Common Terminology and Criteria for Adverse Events, version 4.03).ResultsOf the 225 cases, 136 participants (60.4%) were male, and 195 (86.7%) were diagnosed with VHD beyond 20 years from childhood cancer. Survivors receiving a mean heart radiation therapy (RT) dose of 5 to less than 15 Gy had an increased risk of VHD (odds ratio [OR], 4.7; 95% CI, 2.1-10.7) compared to those without heart RT, with higher risk when more than half of the heart was exposed. The heart RT dose response appeared exponential, with the OR being 104.1 (95% CI, 27.8-389.6) for mean heart dose of 30 Gy or more, increasing considerably with follow-up from 6.0 (95% CI, 1.4-26.5) after 5 to 19 years to 71.4 (95% CI, 20.4-250.0) after 30 or more years. Cumulative anthracycline doses of 400 mg/m<jats:sup>2</jats:sup> or higher were also associated with increased VHD risk (OR, 3.8; 95% CI, 1.4-10.3), showing an exponential dose-response pattern. Cumulative exposure to platinum agents was associated with VHD risk in a linear manner. No statistically significant associations were found for other chemotherapy agents or radiation to the spleen.Conclusion and RelevanceIn this case-control study, heart RT, anthracyclines, and platinum agents were associated with increased VHD risk in childhood cancer survivors. Risks from both RT and anthracyclines were amplified with age and follow-up, underscoring the need for long-term cardiac surveillance.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"11 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246764","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 : 2025-10-09DOI: 10.1001/jamaoncol.2025.3792
James Heyward,Jodi B Segal
{"title":"Limitations in Quantitative Harm-Benefit Assessment in Immuno-Oncology-Reply.","authors":"James Heyward,Jodi B Segal","doi":"10.1001/jamaoncol.2025.3792","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3792","url":null,"abstract":"","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"26 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246875","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 : 2025-10-09DOI: 10.1001/jamaoncol.2025.3875
Katie M. O’Brien, Alexander P. Keil, Jack A. Taylor, Clarice R. Weinberg, Eric C. Polley, Siddhartha Yadav, Nicholas J. Boddicker, Chunling Hu, Christine B. Ambrosone, Hoda Anton-Culver, Paul L. Auer, Clara Bodelon, Kristen Brantley, Elizabeth S. Burnside, Fei Chen, Susan M. Domchek, A. Heather Eliassen, Christopher A. Haiman, James M. Hodge, Peter Kraft, James V. Lacey, Sara Lindstroem, Maria Elena Martinez, Katherine L. Nathanson, Susan L. Neuhausen, Janet E. Olson, Julie R. Palmer, Alpa V. Patel, Kathryn L. Penney, Kathryn J. Ruddy, Christopher G. Scott, Lauren R. Teras, Amy Trentham-Dietz, Celine M. Vachon, Jeffrey N. Weitzel, Song Yao, Gary Zirpoli, Fergus J. Couch, Dale P. Sandler
ImportanceInherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described.ObjectiveTo evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors.Design, Setting, and ParticipantsThis study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025.ExposuresPVs, breast cancer family history, self-reported race and ethnicity, and established risk factors.Main Outcomes and MeasuresBreast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated.ResultsA total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in <jats:italic>ATM</jats:italic>, <jats:italic>BRCA1</jats:italic>, <jats:italic>BRCA2</jats:italic>, <jats:italic>CHEK2</jats:italic>, and <jats:italic>PALB2</jats:italic> were strongly associated with breast cancer risk, with <jats:italic>BRCA1</jats:italic> and <jats:italic>PALB2</jats:italic> PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in <jats:italic>PALB2</jats:italic> PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for <jats:italic>PALB2</jats:italic> carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors.Conclusions and RelevanceIn this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefi
{"title":"Pathogenic Variants, Family History, and Cumulative Risk of Breast Cancer in US Women","authors":"Katie M. O’Brien, Alexander P. Keil, Jack A. Taylor, Clarice R. Weinberg, Eric C. Polley, Siddhartha Yadav, Nicholas J. Boddicker, Chunling Hu, Christine B. Ambrosone, Hoda Anton-Culver, Paul L. Auer, Clara Bodelon, Kristen Brantley, Elizabeth S. Burnside, Fei Chen, Susan M. Domchek, A. Heather Eliassen, Christopher A. Haiman, James M. Hodge, Peter Kraft, James V. Lacey, Sara Lindstroem, Maria Elena Martinez, Katherine L. Nathanson, Susan L. Neuhausen, Janet E. Olson, Julie R. Palmer, Alpa V. Patel, Kathryn L. Penney, Kathryn J. Ruddy, Christopher G. Scott, Lauren R. Teras, Amy Trentham-Dietz, Celine M. Vachon, Jeffrey N. Weitzel, Song Yao, Gary Zirpoli, Fergus J. Couch, Dale P. Sandler","doi":"10.1001/jamaoncol.2025.3875","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3875","url":null,"abstract":"ImportanceInherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described.ObjectiveTo evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors.Design, Setting, and ParticipantsThis study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025.ExposuresPVs, breast cancer family history, self-reported race and ethnicity, and established risk factors.Main Outcomes and MeasuresBreast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated.ResultsA total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in <jats:italic>ATM</jats:italic>, <jats:italic>BRCA1</jats:italic>, <jats:italic>BRCA2</jats:italic>, <jats:italic>CHEK2</jats:italic>, and <jats:italic>PALB2</jats:italic> were strongly associated with breast cancer risk, with <jats:italic>BRCA1</jats:italic> and <jats:italic>PALB2</jats:italic> PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in <jats:italic>PALB2</jats:italic> PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for <jats:italic>PALB2</jats:italic> carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors.Conclusions and RelevanceIn this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefi","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"15 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246761","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 : 2025-10-09DOI: 10.1001/jamaoncol.2025.3882
Mahendra Naidoo,Dragan Damianovich
{"title":"The View from the Other Chair-An Oncologist's Journey on Becoming a Patient.","authors":"Mahendra Naidoo,Dragan Damianovich","doi":"10.1001/jamaoncol.2025.3882","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3882","url":null,"abstract":"","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"23 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246873","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 : 2025-10-09DOI: 10.1001/jamaoncol.2025.3869
Lauren E. Merz, Yating Wang, Angel Cronin, Elad Sharon, Thomas P. Walsh, Stephen P. Hibbs, Christopher S. Lathan, Andrew Hantel
This cross-sectional study examines absolute neutrophil count–related racial and ethnic disparities in cancer clinical trial eligibility using Duffy null status.
本横断面研究使用Duffy无效状态检查绝对中性粒细胞计数与癌症临床试验资格的种族和民族差异。
{"title":"Duffy Null–Associated Absolute Neutrophil Counts and Cancer Clinical Trial Eligibility","authors":"Lauren E. Merz, Yating Wang, Angel Cronin, Elad Sharon, Thomas P. Walsh, Stephen P. Hibbs, Christopher S. Lathan, Andrew Hantel","doi":"10.1001/jamaoncol.2025.3869","DOIUrl":"https://doi.org/10.1001/jamaoncol.2025.3869","url":null,"abstract":"This cross-sectional study examines absolute neutrophil count–related racial and ethnic disparities in cancer clinical trial eligibility using Duffy null status.","PeriodicalId":14850,"journal":{"name":"JAMA Oncology","volume":"10 1","pages":""},"PeriodicalIF":28.4,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246763","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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