Daniela Ottaviani, Mihaela Ola, Alessandra Allotta, Yasmine Maati Chaibi, Seán Hickey, Petra Jagust, Nicola Cosgrove, Sinéad Cocchiglia, Fiona Bane, Ramón Fallon, Gordon Daly, Aisling Hegarty, Lance Hudson, Katherine Sheehan, Shannon Kalsi, Stephen Shovlin, Aoibhín Powell, Ash Bahl, Ed Ainscow, Steffi Oesterreich, Adrian V Lee, Fergus J Couch, Arnold D K Hill, Damir Varešlija, Leonie Young
Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation, and plays multiple roles in RNA splicing, DNA damage-response, cell cycle and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA-sequencing, ChIP-sequencing and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.
{"title":"Targeting CDK12 disrupts estrogen-receptor chromatin recruitment and ER-MED1 transcription in advanced ER+ breast cancer","authors":"Daniela Ottaviani, Mihaela Ola, Alessandra Allotta, Yasmine Maati Chaibi, Seán Hickey, Petra Jagust, Nicola Cosgrove, Sinéad Cocchiglia, Fiona Bane, Ramón Fallon, Gordon Daly, Aisling Hegarty, Lance Hudson, Katherine Sheehan, Shannon Kalsi, Stephen Shovlin, Aoibhín Powell, Ash Bahl, Ed Ainscow, Steffi Oesterreich, Adrian V Lee, Fergus J Couch, Arnold D K Hill, Damir Varešlija, Leonie Young","doi":"10.1093/jnci/djaf295","DOIUrl":"https://doi.org/10.1093/jnci/djaf295","url":null,"abstract":"Background Cyclin-dependent kinase 12 (CDK12) regulates general gene transcription elongation, and plays multiple roles in RNA splicing, DNA damage-response, cell cycle and genomic stability. However, transcriptional partners that guide CDK12-specific gene programs have not been identified. Genomic alterations in CDK12 have been observed in multiple cancers, exhibiting both pro-tumorigenic and tumor-suppressive functions, suggesting a context-dependent mechanism of action. Methods CDK12 copy number alterations and gene expression levels were analyzed in matched primary and brain metastatic patient tumors. Clinical significance was assessed by immunohistochemistry in a large cohort of primary breast cancer patient tumors. RNA-sequencing, ChIP-sequencing and molecular studies were conducted to explore CDK12’s mechanism of action, and pharmacological studies were performed both in vitro and in vivo using models of advanced (endocrine-resistant and metastatic) estrogen receptor positive (ER+) disease. Results CDK12 amplifications and gene overexpression were observed in brain metastatic tumors. In ER+ primary patient tumors, high CDK12 protein expression significantly associated with poor overall survival, particularly within the ER+/HER2-negative group. In ER+ endocrine resistant models, CDK12 regulated estrogen signaling pathways, with ER/MED1 identified as the master transcriptional complex directing CDK12-specific pro-tumorigenic gene programs. Pharmacological inhibition of CDK12 significantly reduced viability in endocrine resistant and metastatic cell and organoid models in vitro, and decreased metastatic spread in vivo. Conclusion This work describes a novel mechanism for CDK12, suggesting a potential vulnerability in ER+ breast cancer. These findings provide a basis for further investigation into the role of CDK12 inhibition as a therapeutic approach, particularly in advanced disease settings.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"97 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paloma R Mitra, Ting Zhang, Hyokyoung G Hong, Demetrius Albanes, Stephanie J Weinstein, Steven C Moore, Rachael Z Stolzenberg-Solomon, Sabine Naudin
Background Evidence supports a modest positive association between alcohol intake and pancreatic ductal adenocarcinoma (PDAC), however knowledge regarding mechanisms underlying the association is scarce. Investigation of lipidomic metabolites may provide mechanistic insights into this association. Methods We measured 611 lipid species across 14 lipid classes in serum samples collected up to 24 years before PDAC diagnosis in two nested case-control studies (706 matched sets) within American and Finnish cohorts. We conducted cross-sectional analyses using multivariable linear regressions to examine associations between log-transformed self-reported alcohol intake and log-transformed lipid concentrations among controls within each cohort. The identified alcohol-associated lipids in both cohorts were then evaluated for PDAC risk using multivariable conditional logistic regressions and fixed-effects meta-analyses to estimate overall odds ratios (ORs) across the two cohorts. Results Alcohol intake was associated with 21 lipid species, 11 class-specific fatty acids (FA), 3 total FA, and 1 lipid class at Bonferroni significance thresholds with similar directions of associations in both cohorts. Among them, total pentadecanoic acid (FA150) and seven lipid species—TAG(49:3-FA18:2), TAG(51:3-FA18:2), TAG(49:2-FA18:2), TAG(51:3-FA15:0), TAG(51:2-FA18:2), TAG(51:2-FA15:0) and PC(15:0-18:2)—were inversely associated with alcohol intake and with PDAC risk at false discovery rate <0.10, with overall ORs ranging from 0.82 to 0.86, without evidence of heterogeneity by smoking habits. Conclusion Findings from two prospective cohorts identified seven lipid species and one FA inversely associated with both alcohol intake and PDAC risk. These results suggest that alcohol intake may be positively associated with PDAC through down-regulation of circulating lipids years before PDAC diagnosis.
{"title":"Lipid biomarkers of habitual alcohol intake and associations with pancreatic cancer risk","authors":"Paloma R Mitra, Ting Zhang, Hyokyoung G Hong, Demetrius Albanes, Stephanie J Weinstein, Steven C Moore, Rachael Z Stolzenberg-Solomon, Sabine Naudin","doi":"10.1093/jnci/djaf288","DOIUrl":"https://doi.org/10.1093/jnci/djaf288","url":null,"abstract":"Background Evidence supports a modest positive association between alcohol intake and pancreatic ductal adenocarcinoma (PDAC), however knowledge regarding mechanisms underlying the association is scarce. Investigation of lipidomic metabolites may provide mechanistic insights into this association. Methods We measured 611 lipid species across 14 lipid classes in serum samples collected up to 24 years before PDAC diagnosis in two nested case-control studies (706 matched sets) within American and Finnish cohorts. We conducted cross-sectional analyses using multivariable linear regressions to examine associations between log-transformed self-reported alcohol intake and log-transformed lipid concentrations among controls within each cohort. The identified alcohol-associated lipids in both cohorts were then evaluated for PDAC risk using multivariable conditional logistic regressions and fixed-effects meta-analyses to estimate overall odds ratios (ORs) across the two cohorts. Results Alcohol intake was associated with 21 lipid species, 11 class-specific fatty acids (FA), 3 total FA, and 1 lipid class at Bonferroni significance thresholds with similar directions of associations in both cohorts. Among them, total pentadecanoic acid (FA150) and seven lipid species—TAG(49:3-FA18:2), TAG(51:3-FA18:2), TAG(49:2-FA18:2), TAG(51:3-FA15:0), TAG(51:2-FA18:2), TAG(51:2-FA15:0) and PC(15:0-18:2)—were inversely associated with alcohol intake and with PDAC risk at false discovery rate &lt;0.10, with overall ORs ranging from 0.82 to 0.86, without evidence of heterogeneity by smoking habits. Conclusion Findings from two prospective cohorts identified seven lipid species and one FA inversely associated with both alcohol intake and PDAC risk. These results suggest that alcohol intake may be positively associated with PDAC through down-regulation of circulating lipids years before PDAC diagnosis.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recognizing the need to improve care and outcomes for patients affected by cancer, federal agencies collaborated to identify current efforts and timely actions to support and empower cancer patients and caregivers. One important approach is to capture information directly from patients about their health, such as their symptoms and functioning. Patient-reported outcomes (PROs) can be used to inform clinical trials, in care delivery, and to examine treatment effectiveness and care quality. Across the Department of Health and Human Services and the Department of Veterans Affairs, multiple agencies have recognized the value of PROs for people with cancer and developed initiatives that complement extensive work spearheaded by academic and other non-governmental organizations. Given that there are efforts occurring within and across several federal agencies, there is a need to appraise and synergize federal efforts to support PRO adoption. Such an approach would promote methods to engage patients and caregivers, with specific efforts to address barriers for all cancer populations as well as encourage and support researchers, clinicians, and health systems to collect meaningful health information from all patients. This report describes the value of using PROs in research and healthcare settings to inform cancer care. Demonstrations of how federal agencies support PRO use are described. This manuscript is not exhaustive; and does not describe the extensive PRO work accomplished outside of the United States (US) government. Instead, it is intended to emphasize the independent commitment across federal agencies to support monitoring PROs for people with cancer to improve care and outcomes.
{"title":"Multi-federal agency actions to integrate patient-reported outcomes into cancer research and care.","authors":"Ashley Wilder Smith,Christine Dymek,Terri S Armstrong,Batsheva Honig,Aaliyah Parker,Shannon Mcdevitt,Vida Passero,Ashley Gruszkowski,Vishal Bhatnagar","doi":"10.1093/jnci/djaf273","DOIUrl":"https://doi.org/10.1093/jnci/djaf273","url":null,"abstract":"Recognizing the need to improve care and outcomes for patients affected by cancer, federal agencies collaborated to identify current efforts and timely actions to support and empower cancer patients and caregivers. One important approach is to capture information directly from patients about their health, such as their symptoms and functioning. Patient-reported outcomes (PROs) can be used to inform clinical trials, in care delivery, and to examine treatment effectiveness and care quality. Across the Department of Health and Human Services and the Department of Veterans Affairs, multiple agencies have recognized the value of PROs for people with cancer and developed initiatives that complement extensive work spearheaded by academic and other non-governmental organizations. Given that there are efforts occurring within and across several federal agencies, there is a need to appraise and synergize federal efforts to support PRO adoption. Such an approach would promote methods to engage patients and caregivers, with specific efforts to address barriers for all cancer populations as well as encourage and support researchers, clinicians, and health systems to collect meaningful health information from all patients. This report describes the value of using PROs in research and healthcare settings to inform cancer care. Demonstrations of how federal agencies support PRO use are described. This manuscript is not exhaustive; and does not describe the extensive PRO work accomplished outside of the United States (US) government. Instead, it is intended to emphasize the independent commitment across federal agencies to support monitoring PROs for people with cancer to improve care and outcomes.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RE: Interval cervical cancers after self-sampling for human papillomavirus in the general population.","authors":"Penelope Gray,Joakim Dillner","doi":"10.1093/jnci/djaf297","DOIUrl":"https://doi.org/10.1093/jnci/djaf297","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"126 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Changing paradigms in colorectal cancer screening.","authors":"Partha Basu","doi":"10.1093/jnci/djaf267","DOIUrl":"https://doi.org/10.1093/jnci/djaf267","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guilherme Nader-Marta,Xiangying Chu,Satabhisa Mukhopadhyay,Vandana G Abramson,Adam Brufsky,Erica Michelle Stringer-Reasor,Susan Faye Dent,Tiffany A Traina,Lisa A Carey,Mothaffar F Rimawi,Jennifer M Specht,Kathy D Miller,Cesar Augusto Santa-Maria,Tathagata Dasgupta,Busem Binboğa Kurt,Michelle DeMeo,Ian E Krop,Nadine M Tung,Stuart J Schnitt,Nabihah Tayob,Erica L Mayer
BACKGROUNDTumor-infiltrating lymphocytes (TILs), assessed by visual examination (VE), are prognostic and predictive in early-stage triple-negative breast cancer (TNBC). Computational assessment (CA) may provide a complementary approach. We evaluated the prognostic value of TILs by VE and CA.METHODSTBCRC 030 was a randomized phase II trial enrolling patients with BRCA1/2-proficient stage I-III TNBC to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathologic response at surgery. TILs were visually scored on digitized pre-treatment biopsies per International TILs Working Group recommendations. CA used the 4D QPOR platform to generate TILs, immune heterogeneity index (IHI), and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden (RCB) 0/1 was assessed using ROC curves and odds ratios (ORs) with 95% CIs; all statistical tests were two-sided.RESULTSOf 139 response-evaluable patients, 121 had matched VE and CA data (59 cisplatin, 62 paclitaxel). Median VE TILs were higher in responders (40.0% vs. 10.0%, p = .002) and predicted response (OR 1.86, 95% CI 1.24-2.87, AUC 0.69, 95% CI 0.57-0.80). CA CmbI differed by response group and predicted RCB 0/1 (OR 3.20, 1.05-11.07; AUC 0.62, 0.51-0.73). CA TILs and IHI were not predictive. VE TILs and CA CmbI predicted response to paclitaxel (OR 2.91, 1.56-6.14; OR 9.17, 2.01-66.39, respectively), but not to cisplatin.CONCLUSIONVE TILs and CA CmbI were each associated with response to NAC in TNBC in the overall cohort and the paclitaxel arm. CA CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.
{"title":"Prognostic value of visually and computationally-assessed tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer (TBCRC-030).","authors":"Guilherme Nader-Marta,Xiangying Chu,Satabhisa Mukhopadhyay,Vandana G Abramson,Adam Brufsky,Erica Michelle Stringer-Reasor,Susan Faye Dent,Tiffany A Traina,Lisa A Carey,Mothaffar F Rimawi,Jennifer M Specht,Kathy D Miller,Cesar Augusto Santa-Maria,Tathagata Dasgupta,Busem Binboğa Kurt,Michelle DeMeo,Ian E Krop,Nadine M Tung,Stuart J Schnitt,Nabihah Tayob,Erica L Mayer","doi":"10.1093/jnci/djaf289","DOIUrl":"https://doi.org/10.1093/jnci/djaf289","url":null,"abstract":"BACKGROUNDTumor-infiltrating lymphocytes (TILs), assessed by visual examination (VE), are prognostic and predictive in early-stage triple-negative breast cancer (TNBC). Computational assessment (CA) may provide a complementary approach. We evaluated the prognostic value of TILs by VE and CA.METHODSTBCRC 030 was a randomized phase II trial enrolling patients with BRCA1/2-proficient stage I-III TNBC to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathologic response at surgery. TILs were visually scored on digitized pre-treatment biopsies per International TILs Working Group recommendations. CA used the 4D QPOR platform to generate TILs, immune heterogeneity index (IHI), and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden (RCB) 0/1 was assessed using ROC curves and odds ratios (ORs) with 95% CIs; all statistical tests were two-sided.RESULTSOf 139 response-evaluable patients, 121 had matched VE and CA data (59 cisplatin, 62 paclitaxel). Median VE TILs were higher in responders (40.0% vs. 10.0%, p = .002) and predicted response (OR 1.86, 95% CI 1.24-2.87, AUC 0.69, 95% CI 0.57-0.80). CA CmbI differed by response group and predicted RCB 0/1 (OR 3.20, 1.05-11.07; AUC 0.62, 0.51-0.73). CA TILs and IHI were not predictive. VE TILs and CA CmbI predicted response to paclitaxel (OR 2.91, 1.56-6.14; OR 9.17, 2.01-66.39, respectively), but not to cisplatin.CONCLUSIONVE TILs and CA CmbI were each associated with response to NAC in TNBC in the overall cohort and the paclitaxel arm. CA CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Will adaptive radiation therapy be the new state-of-the-ART in head and neck cancer?","authors":"Alisa Rybkin,Melissa R Young,Henry S Park","doi":"10.1093/jnci/djaf283","DOIUrl":"https://doi.org/10.1093/jnci/djaf283","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah J Westvold,Jessica B Long,Jane Fan,Madhav Kc,Terry Hyslop,Kerry Conlin,Sofia Jacobson,Andrea Silber,Shi-Yi Wang,Michael S Leapman,Ira Leeds,Lisa Spees,Stephanie B Wheeler,Cary P Gross,Kevin Oeffinger,Michaela A Dinan
BACKGROUNDCardiovascular disease (CVD) is the leading cause of non-cancer mortality in long-term cancer survivors. Population-level assessment of cancer-related exposures is limited with respect to long-term cardiovascular risk in older survivors, who have additional aging-related risks.METHODSThis was a SEER-Medicare retrospective cohort study of long-term (five-year) survivors of breast, prostate, colon, and rectal cancers who were aged 66+, diagnosed from 2003-2012, and received definitive treatment. The primary endpoint was late CVD, defined as MI, stroke, CHF/cardiomyopathy on an inpatient administrative claim or as SEER cause of death occurring 5-15 years post-diagnosis. Restricted mean survival time regression was used to assess predictors of shorter average time without CVD and develop a prediction rule for risk stratification. Survivors were assigned a risk score and stratified into tertiles.RESULTSIncluded were 95,100 survivors with a mean age of 74 (SD = 6) at diagnosis. Late CVD occurred in 23.2% of survivors. Older age, comorbidities, and prior CVD were associated with shorter time without CVD. In contrast, cancer-related factors were not associated, except for stage III breast cancer, and radiation plus ADT for prostate cancer. Across all cohorts, the high-risk strata had a 3- to 4-fold higher risk of CVD compared to the low-risk strata.CONCLUSIONSIn this cohort of older, long-term cancer survivors, cancer-related exposures were not independently associated with onset of CVD 5-15 years after diagnosis but may still contribute to latent cardiovascular risk. Given the limited impact of cancer-specific factors, cancer-agnostic risk prediction may be adequate to predict individual cardiovascular risk.
{"title":"Cardiovascular risk in long-term survivors of breast, prostate, colon, and rectal cancer.","authors":"Sarah J Westvold,Jessica B Long,Jane Fan,Madhav Kc,Terry Hyslop,Kerry Conlin,Sofia Jacobson,Andrea Silber,Shi-Yi Wang,Michael S Leapman,Ira Leeds,Lisa Spees,Stephanie B Wheeler,Cary P Gross,Kevin Oeffinger,Michaela A Dinan","doi":"10.1093/jnci/djaf243","DOIUrl":"https://doi.org/10.1093/jnci/djaf243","url":null,"abstract":"BACKGROUNDCardiovascular disease (CVD) is the leading cause of non-cancer mortality in long-term cancer survivors. Population-level assessment of cancer-related exposures is limited with respect to long-term cardiovascular risk in older survivors, who have additional aging-related risks.METHODSThis was a SEER-Medicare retrospective cohort study of long-term (five-year) survivors of breast, prostate, colon, and rectal cancers who were aged 66+, diagnosed from 2003-2012, and received definitive treatment. The primary endpoint was late CVD, defined as MI, stroke, CHF/cardiomyopathy on an inpatient administrative claim or as SEER cause of death occurring 5-15 years post-diagnosis. Restricted mean survival time regression was used to assess predictors of shorter average time without CVD and develop a prediction rule for risk stratification. Survivors were assigned a risk score and stratified into tertiles.RESULTSIncluded were 95,100 survivors with a mean age of 74 (SD = 6) at diagnosis. Late CVD occurred in 23.2% of survivors. Older age, comorbidities, and prior CVD were associated with shorter time without CVD. In contrast, cancer-related factors were not associated, except for stage III breast cancer, and radiation plus ADT for prostate cancer. Across all cohorts, the high-risk strata had a 3- to 4-fold higher risk of CVD compared to the low-risk strata.CONCLUSIONSIn this cohort of older, long-term cancer survivors, cancer-related exposures were not independently associated with onset of CVD 5-15 years after diagnosis but may still contribute to latent cardiovascular risk. Given the limited impact of cancer-specific factors, cancer-agnostic risk prediction may be adequate to predict individual cardiovascular risk.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While large socioeconomic inequalities in cancer outcomes exist between- and within-countries, financial and human resources are increasingly allocated to medical interventions that have minimal impact or that cause harm, including overdiagnosis and overtreatment. Underuse and overuse of medical cancer care stem from similar underlying mechanisms, including environmental, social, economic, and cultural factors, as well as healthcare system organization and medical practices, and their coexistence represents two opposing yet interconnected aspects of healthcare inefficiency. Identifying and measuring low-value in cancer prevention and care is challenging. However, emerging evidence shows that the magnitude and consequences of underuse and overuse are vast, shaping the current epidemiological landscape of cancer, causing physical, psychological, and social harm to millions of individuals and posing significant challenges to the sustainability of health systems. In this paper, we propose a novel perspective and a comprehensive roadmap that examines inefficiencies of health systems through the lens of simultaneous underuse of cancer care by underserved populations and overuse by groups with greater access to healthcare system.
{"title":"Cancer care underuse, overuse, and inequalities","authors":"Salvatore Vaccarella, Paolo Vineis","doi":"10.1093/jnci/djaf290","DOIUrl":"https://doi.org/10.1093/jnci/djaf290","url":null,"abstract":"While large socioeconomic inequalities in cancer outcomes exist between- and within-countries, financial and human resources are increasingly allocated to medical interventions that have minimal impact or that cause harm, including overdiagnosis and overtreatment. Underuse and overuse of medical cancer care stem from similar underlying mechanisms, including environmental, social, economic, and cultural factors, as well as healthcare system organization and medical practices, and their coexistence represents two opposing yet interconnected aspects of healthcare inefficiency. Identifying and measuring low-value in cancer prevention and care is challenging. However, emerging evidence shows that the magnitude and consequences of underuse and overuse are vast, shaping the current epidemiological landscape of cancer, causing physical, psychological, and social harm to millions of individuals and posing significant challenges to the sustainability of health systems. In this paper, we propose a novel perspective and a comprehensive roadmap that examines inefficiencies of health systems through the lens of simultaneous underuse of cancer care by underserved populations and overuse by groups with greater access to healthcare system.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thi Huyen Trang Nguyen,Somin Jeon,Junghyun Yoon,Boyoung Park
BACKGROUNDWe examined whether fasting blood glucose (FBG) mediates the associations between body mass index (BMI), waist circumference (WC), and breast cancer (BC) risk among postmenopausal women, while considering the temporal order of exposure, mediator, and disease onset.METHODSData from 2,093,578 postmenopausal women in the Korean National Breast Cancer Screening Program (2009-2010) were analyzed. Participants underwent at least one repeat screening (2011-2014) and were followed until 2021. Baseline BMI and WC served as exposures, and FBG levels, measured during 2011-2014, were examined as potential mediators. Associations among BMI, WC, FBG, and BC risk were evaluated using Cox proportional hazards regression and mediation analyses.RESULTSOver a median follow-up of 11.9 years, 17,120 women (0.82%) developed BC. Compared to lower values higher BMI (≥30 kg/m2) and WC (≥88 cm) were significantly associated with increased BC risk, with hazard ratios (HRs) of 1.82 (95% confidence interval [CI]=1.69-1.96) and 1.43 (95% CI = 1.37-1.49), respectively. Two-way decomposition mediation analysis indicated that FBG minimally mediated these associations, with natural indirect effect odds ratios near 1.00 and mediated effects ranged up to 2.23%. A four-way decomposition further confirmed that over 95% of the associations were attributable to the controlled direct effects of BMI and WC, while the pure indirect effect via FBG comprised approximately 5% of the total association.CONCLUSIONAlthough BMI and WC are robustly linked to BC risk, FBG plays a negligible mediating role. These findings suggest that obesity and glucose metabolism independently influence breast cancer risk.
背景：我们研究了空腹血糖（FBG）是否介导了绝经后妇女体重指数（BMI）、腰围（WC）和乳腺癌（BC）风险之间的关联，同时考虑了暴露、介质和疾病发病的时间顺序。方法分析韩国国家乳腺癌筛查项目（2009-2010）中2,093,578名绝经后妇女的数据。参与者至少进行了一次重复筛查（2011-2014年），并随访至2021年。基线BMI和WC作为暴露，2011-2014年期间测量的FBG水平作为潜在的介质进行了研究。使用Cox比例风险回归和中介分析评估BMI、WC、FBG和BC风险之间的关联。结果在中位11.9年的随访中，17120名女性（0.82%）发展为BC。与较低值相比，较高的BMI（≥30 kg/m2）和WC（≥88 cm）与BC风险增加显著相关，风险比（hr）分别为1.82（95%可信区间[CI]=1.69-1.96）和1.43 （95% CI = 1.37-1.49）。双向分解中介分析表明，FBG对这些关联的介导作用最小，自然间接效应比值比接近1.00，介导效应最高可达2.23%。四向分解进一步证实，超过95%的关联可归因于BMI和WC的可控直接影响，而通过FBG的纯间接影响约占总关联的5%。结论虽然BMI和WC与BC风险密切相关，但FBG的中介作用可以忽略不计。这些发现表明，肥胖和葡萄糖代谢独立影响乳腺癌风险。
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