Pub Date : 2025-11-14DOI: 10.1016/j.ejca.2025.116111
Hyun-Jin Kim , Joo-Hyun Park , Jung Yong Hong , Kyungdo Han , Jay J. Shen , Joon Oh Park , Young Suk Park , Ho Yeong Lim
Background and aims
The incidence of young-onset pancreatic cancer is rapidly increasing worldwide. However, the association between body mass index (BMI), particularly overweight and mild obesity, and the risk of young-onset pancreatic cancer remains poorly defined. This study aimed to investigate the dose–response relationship between BMI and the risk of young-onset pancreatic cancer.
Methods
This nationwide cohort study included 6,315,055 adults aged 20–39 years who underwent national health screenings between 2009 and 2012. BMI categories were defined according to World Health Organization Asia-Pacific guidelines. Participants were followed until December 2020. Multivariable-adjusted Cox proportional hazards models estimated pancreatic cancer risk.
Results
During 59,159,572 person-years of follow-up, 1533 incident pancreatic cancer cases were identified. Compared with individuals with normal weight status, individuals with overweight or class I obesity had a significantly higher risk of pancreatic cancer (adjusted hazard ratio [aHR], 1.389; 95 % CI, 1.210–1.595 and aHR, 1.388; 95 % CI, 1.213–1.588, respectively). Individuals with class II obesity had the highest risk (aHR, 1.958; 95 % CI, 1.585–2.421), whereas underweight individuals had no significantly increased risk (aHR, 1.068; 95 % CI, 0.840–1.360).These associations did not differ significantly across subgroups defined by age, sex, smoking status, alcohol intake, physical activity, or diabetes (all P > 0.05 for interaction).
Conclusions
Overweight and class I obesity during early adulthood may serve as previously underrecognized yet modifiable risk factors for young-onset pancreatic cancer. Proactive weight-control interventions among young adults, starting from overweight status, may help reduce the increasing burden of pancreatic cancer in younger populations.
{"title":"Increased risk of young-onset pancreatic cancer among adults aged 20–39 years with overweight or obesity, but not underweight: A nationwide cohort study","authors":"Hyun-Jin Kim , Joo-Hyun Park , Jung Yong Hong , Kyungdo Han , Jay J. Shen , Joon Oh Park , Young Suk Park , Ho Yeong Lim","doi":"10.1016/j.ejca.2025.116111","DOIUrl":"10.1016/j.ejca.2025.116111","url":null,"abstract":"<div><h3>Background and aims</h3><div>The incidence of young-onset pancreatic cancer is rapidly increasing worldwide. However, the association between body mass index (BMI), particularly overweight and mild obesity, and the risk of young-onset pancreatic cancer remains poorly defined. This study aimed to investigate the dose–response relationship between BMI and the risk of young-onset pancreatic cancer.</div></div><div><h3>Methods</h3><div>This nationwide cohort study included 6,315,055 adults aged 20–39 years who underwent national health screenings between 2009 and 2012. BMI categories were defined according to World Health Organization Asia-Pacific guidelines. Participants were followed until December 2020. Multivariable-adjusted Cox proportional hazards models estimated pancreatic cancer risk.</div></div><div><h3>Results</h3><div>During 59,159,572 person-years of follow-up, 1533 incident pancreatic cancer cases were identified. Compared with individuals with normal weight status, individuals with overweight or class I obesity had a significantly higher risk of pancreatic cancer (adjusted hazard ratio [aHR], 1.389; 95 % CI, 1.210–1.595 and aHR, 1.388; 95 % CI, 1.213–1.588, respectively). Individuals with class II obesity had the highest risk (aHR, 1.958; 95 % CI, 1.585–2.421), whereas underweight individuals had no significantly increased risk (aHR, 1.068; 95 % CI, 0.840–1.360).These associations did not differ significantly across subgroups defined by age, sex, smoking status, alcohol intake, physical activity, or diabetes (all <em>P</em> > 0.05 for interaction).</div></div><div><h3>Conclusions</h3><div>Overweight and class I obesity during early adulthood may serve as previously underrecognized yet modifiable risk factors for young-onset pancreatic cancer. Proactive weight-control interventions among young adults, starting from overweight status, may help reduce the increasing burden of pancreatic cancer in younger populations.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116111"},"PeriodicalIF":7.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667755","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 : 2025-11-14DOI: 10.1016/j.ejca.2025.116109
Teng-Yu Lee , Sheng-Shun Yang , Pei-Chien Tsai , Chung-Feng Huang , Chi-Yi Chen , Chao-Hung Hung , Chien-Hung Chen , Chi-Ming Tai , Pin-Nan Cheng , Hsing-Tao Kuo , Kuo-Chih Tseng , Lein-Ray Mo , Ching-Chu Lo , Yi-Hsiang Huang , Han-Chieh Lin , Pei-Lun Lee , Ming-Jong Bair , Te-Sheng Chang , Chun-Yen Lin , Szu-Jen Wang , Ming-Lung Yu
Background
The survival benefit of direct-acting antiviral (DAA) in hepatitis C virus (HCV)-infected patients with or without active hepatocellular carcinoma (HCC) remains debated. This study aimed to clarify this issue.
Methods
This retrospective nationwide cohort study utilized data from the Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) to identify adults with HCC who received DAA therapy for HCV between December 2013 and December 2020. Patients with other viral infections, prior liver transplantation, non-HCC malignancies, or terminal-stage HCC were excluded. The primary outcome was overall survival (OS). The adjusted odds ratio (aOR) for sustained virological response (SVR) and the adjusted hazard ratio (aHR) for OS were calculated.
Findings
A total of 2205 patients were included: 1771 (80.3 %) without active HCC and 434 (19.7 %) with active HCC. SVR was independently associated with improved OS (aHR 0.45, 95 % CI: 0.31–0.66; p < 0.001). In Barcelona Clinic Liver Cancer (BCLC) stage 0/A, the 3-year OS rate was significantly higher in the SVR group amongst patients with active HCC (71.7 %, 95 % CI 64.6–77.7 % vs. 39.9 %, 95 % CI 15.6–63.5 %; p = 0.007) but non-significantly higher amongst those without active HCC (84.2 %, 95 % CI 81.7–86.4 % vs. 70.0 %, 95 % CI 44.2–85.6 %; p = 0.181). In BCLC stage B/C, the 3-year OS rate was significantly higher in the SVR group amongst patients without active HCC (76.2 %, 95 % CI 70.2–81.2 % vs. 24.7 %, 95 % CI 5.3–51.3 %; p < 0.001) but not amongst those with active HCC (58.6 %, 95 % CI 47.9–67.7 % vs. 57.1 %, 95 % CI 17.2–83.7 %; p = 0.922).
Conclusion
For BCLC stage 0/A HCC, early DAA initiation is recommended, even with active HCC. In BCLC stage B/C, DAA therapy appears most beneficial after tumor control.
{"title":"Survival impact of hepatitis C virus eradication in patients with or without active hepatocellular carcinoma: A nationwide cohort study","authors":"Teng-Yu Lee , Sheng-Shun Yang , Pei-Chien Tsai , Chung-Feng Huang , Chi-Yi Chen , Chao-Hung Hung , Chien-Hung Chen , Chi-Ming Tai , Pin-Nan Cheng , Hsing-Tao Kuo , Kuo-Chih Tseng , Lein-Ray Mo , Ching-Chu Lo , Yi-Hsiang Huang , Han-Chieh Lin , Pei-Lun Lee , Ming-Jong Bair , Te-Sheng Chang , Chun-Yen Lin , Szu-Jen Wang , Ming-Lung Yu","doi":"10.1016/j.ejca.2025.116109","DOIUrl":"10.1016/j.ejca.2025.116109","url":null,"abstract":"<div><h3>Background</h3><div>The survival benefit of direct-acting antiviral (DAA) in hepatitis C virus (HCV)-infected patients with or without active hepatocellular carcinoma (HCC) remains debated. This study aimed to clarify this issue.</div></div><div><h3>Methods</h3><div>This retrospective nationwide cohort study utilized data from the Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) to identify adults with HCC who received DAA therapy for HCV between December 2013 and December 2020. Patients with other viral infections, prior liver transplantation, non-HCC malignancies, or terminal-stage HCC were excluded. The primary outcome was overall survival (OS). The adjusted odds ratio (aOR) for sustained virological response (SVR) and the adjusted hazard ratio (aHR) for OS were calculated.</div></div><div><h3>Findings</h3><div>A total of 2205 patients were included: 1771 (80.3 %) without active HCC and 434 (19.7 %) with active HCC. SVR was independently associated with improved OS (aHR 0.45, 95 % CI: 0.31–0.66; <em>p</em> < 0.001). In Barcelona Clinic Liver Cancer (BCLC) stage 0/A, the 3-year OS rate was significantly higher in the SVR group amongst patients with active HCC (71.7 %, 95 % CI 64.6–77.7 % vs. 39.9 %, 95 % CI 15.6–63.5 %; <em>p</em> = 0.007) but non-significantly higher amongst those without active HCC (84.2 %, 95 % CI 81.7–86.4 % vs. 70.0 %, 95 % CI 44.2–85.6 %; <em>p</em> = 0.181). In BCLC stage B/C, the 3-year OS rate was significantly higher in the SVR group amongst patients without active HCC (76.2 %, 95 % CI 70.2–81.2 % vs. 24.7 %, 95 % CI 5.3–51.3 %; <em>p</em> < 0.001) but not amongst those with active HCC (58.6 %, 95 % CI 47.9–67.7 % vs. 57.1 %, 95 % CI 17.2–83.7 %; <em>p</em> = 0.922).</div></div><div><h3>Conclusion</h3><div>For BCLC stage 0/A HCC, early DAA initiation is recommended, even with active HCC. In BCLC stage B/C, DAA therapy appears most beneficial after tumor control.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116109"},"PeriodicalIF":7.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570303","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 : 2025-11-13DOI: 10.1016/j.ejca.2025.116105
Lena Weiss , Sebastian Stintzing , Dominik Paul Modest , Arndt Stahler , Ludwig Fischer von Weikersthal , Anke Reinacher-Schick , Thomas Decker , Victoria Probst , Kathrin Heinrich , Ingo Schwaner , Florian Kaiser , Rudolf Pihusch , Martin Fuchs , Swantje Held , Annabel Alig , Birgit Gruenberger , Gerald Werner Prager , David Tougeron , Julien Taieb , Volker Heinemann
Background
Both BRAFV600E-mutation and right-sided primary tumor location (PTL), have been associated with poor prognosis in metastatic colorectal cancer (mCRC). The present pooled analysis of individual patient data evaluates the efficacy of first-line chemotherapy combined with anti-EGFR- or anti-VEGF-directed therapy in BRAFV600E-mut mCRC together with PTL.
Methods
We conducted a pooled analysis of seven first-line AIO-studies (FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including patients with BRAFV600E-mut and RAS-wild-type mCRC.
Results
Among 209 evaluable patients, left-sided primary tumors (LSPT) were observed in 98 (46.9 %) compared to 111 (53.1 %) patients with right-sided primary tumors (RSPT).
In the overall cohort, ORR was comparable (OR 0.85; 95 % CI 0.47–1.52), while median PFS was significantly shorter in patients receiving anti-EGFR-based therapy (HR 1.42; 95 % CI 1.05–1.91; P = 0.022), no major difference was observed with regard to OS (HR 0.96; 95 % CI 0.70–1.32; P = 0.80).
Patients with LSPT showed comparable PFS (HR 0.98; 95 % CI 0.63–1.51), but a numerical OS benefit (HR 0.71; 95 % CI, 0.45–1.14) with anti-EGFR- compared to anti-VEGF-based therapy. This effect was observed independent of sex. In contrast, patients with RSPT showed both, inferior PFS (HR 2.09; 95 % CI 1.35–3.22; P < 0.001) and OS (HR 1.31; 95 % CI, 0.84–2.05). These effects were observed in male and female patients.
Conclusions
The present analysis of BRAFV600E-mut mCRC suggests a survival benefit from anti-EGFR- or anti-VEGF-directed antibodies in patients with LSPT. This effect was not observed in RSPT, where patients showed a clearly greater benefit from bevacizumab.
brafv600e突变和右侧原发肿瘤位置（PTL）都与转移性结直肠癌（mCRC）的不良预后相关。本研究对单个患者数据进行了汇总分析，评估了一线化疗联合抗egfr或抗vegf靶向治疗BRAFV600E-mut mCRC合并PTL的疗效。方法：我们对7项一线aio研究（FIRE-3、FIRE-4、FIRE-4.5、CIOX、XELAVIRI、PANAMA、VOLFI）进行了汇总分析，包括BRAFV600E-mut和ras -野生型mCRC患者。结果209例可评估患者中，左侧原发肿瘤（LSPT） 98例（46.9 %），右侧原发肿瘤（RSPT） 111例（53.1 %）。在整个队列中，ORR具有可比性（OR 0.85; 95 % CI 0.47-1.52），而接受基于抗egfr治疗的患者的中位PFS显著缩短（HR 1.42; 95 % CI 1.05-1.91; P = 0.022），OS方面无显著差异（HR 0.96; 95 % CI 0.70-1.32; P = 0.80）。LSPT患者表现出相当的PFS (HR 0.98; 95 % CI 0.63-1.51)，但与基于抗vegf的治疗相比，抗egfr -的数值OS获益（HR 0.71; 95 % CI, 0.45-1.14）。这种效应与性别无关。相比之下，RSPT患者均表现出较差的PFS （HR 2.09; 95 % CI 1.35-3.22; P <； 0.001）和OS （HR 1.31; 95 % CI, 0.84-2.05）。这些影响在男性和女性患者中都有观察到。目前对BRAFV600E-mut mCRC的分析表明，抗egfr或抗vegf定向抗体可提高LSPT患者的生存期。在RSPT中没有观察到这种效应，患者明显表现出贝伐单抗更大的益处。
{"title":"First-line treatment efficacy of anti-EGFR versus anti-VEGF antibodies in BRAFV600E-mutated metastatic colorectal cancer according to primary tumor sidedness: A pooled analysis of seven clinical trials performed in the first-line treatment of mCRC (German AIO Study Group)","authors":"Lena Weiss , Sebastian Stintzing , Dominik Paul Modest , Arndt Stahler , Ludwig Fischer von Weikersthal , Anke Reinacher-Schick , Thomas Decker , Victoria Probst , Kathrin Heinrich , Ingo Schwaner , Florian Kaiser , Rudolf Pihusch , Martin Fuchs , Swantje Held , Annabel Alig , Birgit Gruenberger , Gerald Werner Prager , David Tougeron , Julien Taieb , Volker Heinemann","doi":"10.1016/j.ejca.2025.116105","DOIUrl":"10.1016/j.ejca.2025.116105","url":null,"abstract":"<div><h3>Background</h3><div>Both BRAF<sup>V600E</sup>-mutation and right-sided primary tumor location (PTL), have been associated with poor prognosis in metastatic colorectal cancer (mCRC). The present pooled analysis of individual patient data evaluates the efficacy of first-line chemotherapy combined with anti-EGFR- or anti-VEGF-directed therapy in BRAF<sup>V600E</sup>-mut mCRC together with PTL.</div></div><div><h3>Methods</h3><div>We conducted a pooled analysis of seven first-line AIO-studies (FIRE-3, FIRE-4, FIRE-4.5, CIOX, XELAVIRI, PANAMA, VOLFI) including patients with BRAF<sup>V600E</sup>-mut and RAS-wild-type mCRC.</div></div><div><h3>Results</h3><div>Among 209 evaluable patients, left-sided primary tumors (LSPT) were observed in 98 (46.9 %) compared to 111 (53.1 %) patients with right-sided primary tumors (RSPT).</div><div>In the overall cohort, ORR was comparable (OR 0.85; 95 % CI 0.47–1.52), while median PFS was significantly shorter in patients receiving anti-EGFR-based therapy (HR 1.42; 95 % CI 1.05–1.91; P = 0.022), no major difference was observed with regard to OS (HR 0.96; 95 % CI 0.70–1.32; P = 0.80).</div><div>Patients with LSPT showed comparable PFS (HR 0.98; 95 % CI 0.63–1.51), but a numerical OS benefit (HR 0.71; 95 % CI, 0.45–1.14) with anti-EGFR- compared to anti-VEGF-based therapy. This effect was observed independent of sex. In contrast, patients with RSPT showed both, inferior PFS (HR 2.09; 95 % CI 1.35–3.22; P < 0.001) and OS (HR 1.31; 95 % CI, 0.84–2.05). These effects were observed in male and female patients.</div></div><div><h3>Conclusions</h3><div>The present analysis of BRAF<sup>V600E</sup>-mut mCRC suggests a survival benefit from anti-EGFR- or anti-VEGF-directed antibodies in patients with LSPT. This effect was not observed in RSPT, where patients showed a clearly greater benefit from bevacizumab.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116105"},"PeriodicalIF":7.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519005","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 : 2025-11-13DOI: 10.1016/j.ejca.2025.116106
Arun A. Azad , Karim Fizazi , Nobuaki Matsubara , Fred Saad , Ugo De Giorgi , Jae Young Joung , Peter C.C. Fong , Robert J. Jones , Stefanie Zschäbitz , Jan Oldenburg , Neal D. Shore , Curtis Dunshee , Joan Carles , Andre P. Fay , Xun Lin , Liza DeAnnuntis , Nicola Di Santo , Michael A. Zielinski , Neeraj Agarwal
{"title":"Corrigendum to “Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: Safety analyses from the randomized, placebo-controlled, phase III TALAPRO-2 study” [Eur J Cancer 213 (December) (2024) 115078]","authors":"Arun A. Azad , Karim Fizazi , Nobuaki Matsubara , Fred Saad , Ugo De Giorgi , Jae Young Joung , Peter C.C. Fong , Robert J. Jones , Stefanie Zschäbitz , Jan Oldenburg , Neal D. Shore , Curtis Dunshee , Joan Carles , Andre P. Fay , Xun Lin , Liza DeAnnuntis , Nicola Di Santo , Michael A. Zielinski , Neeraj Agarwal","doi":"10.1016/j.ejca.2025.116106","DOIUrl":"10.1016/j.ejca.2025.116106","url":null,"abstract":"","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116106"},"PeriodicalIF":7.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556567","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 : 2025-11-12DOI: 10.1016/j.ejca.2025.116108
Timothée Olivier
In time-to-event analyses of clinical trials, some data will inevitably be missing at the time of data cut-off. The Kaplan–Meier estimator aims to address these "incomplete observations", which has become a cornerstone of statistical methods in oncology trials. However, for the Kaplan-Meier principles to apply, censoring must occur randomly. If patients drop out for reasons related to treatment, this may lead to a remaining patient population with a different underlying risk of experiencing the event, producing biased estimates referred to as informative censoring. Here, we introduce the concept of an "informative censoring area", defined as a time period over which informative censoring more likely occurred. We demonstrate how examining the evolution of censoring patterns over time can help distinguish between informative and non-informative censoring. Using two clinical trials as examples, we show that comparing data from different follow-up periods reveals distinct patterns: NADINA trial showed early censored patients progressively disappearing with longer follow-up, indicating non-informative censoring, while NATALEE trial demonstrated stable early censoring patterns over time, reinforcing concerns of informative censoring. This approach helps identify when early censoring remains significant even with longer follow-up. We conclude that studying the evolution of censoring patterns over time may help differentiate between informative and non-informative censoring, reinforcing the need for systematic data sharing including reasons for censoring in trials seeking regulatory approval.
{"title":"Identifying informative censoring from censoring patterns across successive follow-ups","authors":"Timothée Olivier","doi":"10.1016/j.ejca.2025.116108","DOIUrl":"10.1016/j.ejca.2025.116108","url":null,"abstract":"<div><div>In time-to-event analyses of clinical trials, some data will inevitably be missing at the time of data cut-off. The Kaplan–Meier estimator aims to address these \"incomplete observations\", which has become a cornerstone of statistical methods in oncology trials. However, for the Kaplan-Meier principles to apply, censoring must occur randomly. If patients drop out for reasons related to treatment, this may lead to a remaining patient population with a different underlying risk of experiencing the event, producing biased estimates referred to as informative censoring. Here, we introduce the concept of an \"informative censoring area\", defined as a time period over which informative censoring more likely occurred. We demonstrate how examining the evolution of censoring patterns over time can help distinguish between informative and non-informative censoring. Using two clinical trials as examples, we show that comparing data from different follow-up periods reveals distinct patterns: NADINA trial showed early censored patients progressively disappearing with longer follow-up, indicating non-informative censoring, while NATALEE trial demonstrated stable early censoring patterns over time, reinforcing concerns of informative censoring. This approach helps identify when early censoring remains significant even with longer follow-up. We conclude that studying the evolution of censoring patterns over time may help differentiate between informative and non-informative censoring, reinforcing the need for systematic data sharing including reasons for censoring in trials seeking regulatory approval.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116108"},"PeriodicalIF":7.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570733","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 : 2025-11-12DOI: 10.1016/j.ejca.2025.116102
Roberto Buonaiuto , Federica Martorana , Paola Marino , Federica Mangiacotti , Aldo Caltavituro , Francesco La Spina , Paola Trasacco , Alessandra Longobardi , Vittoria Molinaro , Maria Letizia Cataldo , Martina Pagliuca , Michelino De Laurentiis , Mario Giuliano , Grazia Arpino , Paolo Vigneri , Carmine De Angelis
Background
In early-stage breast cancer (eBC), the efficacy of neoadjuvant chemotherapy (NACT) may be compromised by dose delays or reductions. A reduced relative dose intensity (RDI, i.e. the ratio of the delivered to planned chemotherapy dose), can lead to diminished clinical outcomes, but real-world data are limited in this setting.
Methods
We retrospectively analyzed data from HER2-negative eBC patients who received NACT at two Italian centers. RDI was assessed categorically with a 85 % threshold and continuously. We assessed the association between RDI and pathological complete response (pCR) and event-free survival (EFS) using regression analysis.
Results
365 patients were included, comprising 218 triple-negative (TN) and 147 hormone receptor-positive (HR+) cases. In the TN cohort, 63.3 % of patients received a high RDI. High RDI was significantly associated with increased pCR rates in univariate and multivariate analyses (categorical RDI: OR 3.15, p < 0.001; continuous RDI: OR 1.05, p < 0.001). High RDI was associated with improved EFS in univariate analysis (categorical RDI: HR 0.48, p = 0.010; continuous RDI: HR 0.98, p = 0.011); however, this association was not retained in multivariate model adjusted for pCR, age, stage, and dose-dense chemotherapy. In the HR+ cohort, where 88.4 % of patients received a high RDI, no association was observed between RDI and pCR. Nevertheless, high RDI was significantly associated with improved EFS in univariate and multivariate models (categorical RDI: HR 0.29, p = 0.006; continuous RDI: HR 0.96, p = 0.004) adjusted for age, stage, and treatment schedule.
Conclusion
High RDI is associated with improved clinical outcomes in patients with HER2-negative eBC undergoing NACT. Maintaining an optimal RDI is crucial to maximize treatment efficacy in the curative setting.
背景：在早期乳腺癌（eBC）中，新辅助化疗（NACT）的疗效可能会因剂量延迟或减少而受到损害。相对剂量强度（RDI，即给药与计划化疗剂量的比例）降低可能导致临床结果降低，但在这种情况下，实际数据有限。方法：我们回顾性分析了在两个意大利中心接受NACT治疗的her2阴性eBC患者的数据。RDI以85% %的阈值进行分类评估，并持续进行评估。我们使用回归分析评估RDI与病理完全缓解（pCR）和无事件生存（EFS）之间的关系。结果：共纳入365例患者，其中三阴性（TN） 218例，激素受体阳性（HR+） 147例。在TN队列中，63.3 %的患者接受了高RDI。在单因素和多因素分析中，高RDI与pCR率增加显著相关（分类RDI: OR 3.15, p ）。结论：高RDI与接受NACT治疗的her2阴性eBC患者的临床预后改善相关。维持一个最佳的RDI是至关重要的，以最大限度地提高治疗效果。
{"title":"Association of neoadjuvant chemotherapy dose intensity with pathological complete response and event-free survival in HER2-negative early breast cancer","authors":"Roberto Buonaiuto , Federica Martorana , Paola Marino , Federica Mangiacotti , Aldo Caltavituro , Francesco La Spina , Paola Trasacco , Alessandra Longobardi , Vittoria Molinaro , Maria Letizia Cataldo , Martina Pagliuca , Michelino De Laurentiis , Mario Giuliano , Grazia Arpino , Paolo Vigneri , Carmine De Angelis","doi":"10.1016/j.ejca.2025.116102","DOIUrl":"10.1016/j.ejca.2025.116102","url":null,"abstract":"<div><h3>Background</h3><div>In early-stage breast cancer (eBC), the efficacy of neoadjuvant chemotherapy (NACT) may be compromised by dose delays or reductions. A reduced relative dose intensity (RDI, i.e. the ratio of the delivered to planned chemotherapy dose), can lead to diminished clinical outcomes, but real-world data are limited in this setting.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed data from HER2-negative eBC patients who received NACT at two Italian centers. RDI was assessed categorically with a 85 % threshold and continuously. We assessed the association between RDI and pathological complete response (pCR) and event-free survival (EFS) using regression analysis.</div></div><div><h3>Results</h3><div>365 patients were included, comprising 218 triple-negative (TN) and 147 hormone receptor-positive (HR+) cases. In the TN cohort, 63.3 % of patients received a high RDI. High RDI was significantly associated with increased pCR rates in univariate and multivariate analyses (categorical RDI: OR 3.15, <em>p</em> < 0.001; continuous RDI: OR 1.05, <em>p</em> < 0.001). High RDI was associated with improved EFS in univariate analysis (categorical RDI: HR 0.48, <em>p</em> = 0.010; continuous RDI: HR 0.98, <em>p</em> = 0.011); however, this association was not retained in multivariate model adjusted for pCR, age, stage, and dose-dense chemotherapy. In the HR+ cohort, where 88.4 % of patients received a high RDI, no association was observed between RDI and pCR. Nevertheless, high RDI was significantly associated with improved EFS in univariate and multivariate models (categorical RDI: HR 0.29, <em>p</em> = 0.006; continuous RDI: HR 0.96, <em>p</em> = 0.004) adjusted for age, stage, and treatment schedule.</div></div><div><h3>Conclusion</h3><div>High RDI is associated with improved clinical outcomes in patients with HER2-negative eBC undergoing NACT. Maintaining an optimal RDI is crucial to maximize treatment efficacy in the curative setting.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116102"},"PeriodicalIF":7.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145556497","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}
Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma with a high metastatic potential. We conducted a phase II clinical study of atezolizumab in ASPS patients to evaluate its efficacy, safety, and biomarkers associated with therapeutic response.
Patients and Methods
Eligible patients were aged ≥ 16 years and diagnosed with ASPS. Atezolizumab was administered at a dose of 1200 mg every 3 weeks. The primary endpoint was the objective response rate (ORR). Immune and genomic profiling of tissues was performed using immunohistochemistry, RNA sequencing, and whole-exome sequencing.
Results
Twenty patients were included in the study. The median age was 32.5 years, and 12 patients (60 %) received pazopanib. The overall ORR was 10 % (2 of 20). Two patients (10 %) achieved a complete response, which persisted for more than 1 year. Fourteen patients (70 %) had stable disease. The disease control rate was 80 %. Responders exhibited abundant infiltration of CD8+PD-1+ T cells, characterised by low expression of Tim-3 and LAG-3.
Conclusion
Atezolizumab was effective in some patients, regardless of prior treatment with pazopanib. Responders had significant PD-1 expressing CD8+ T cell infiltration before immune checkpoint inhibitor therapy. The degree of CD8+PD1+ T cells may be a potential biomarker for predicting responses to atezolizumab.
{"title":"Clinical, immunological, and genomic findings of atezolizumab in advanced alveolar soft part sarcoma: A phase II trial (ALBERT trial/NCCH1907)","authors":"Yuki Kojima , Keisuke Watanabe , Motoko Arakaki , Tadaaki Nishikawa , Yukari Hoshina , Kenta Anjo , Akihiro Hirakawa , Masahiko Ichimura , Makoto Endo , Ikuo Kudawara , Masanobu Takahashi , Genki Okumura , Shohei Koyama , Akihiko Yoshida , Kouya Shiraishi , Hitoshi Ichikawa , Kan Yonemori","doi":"10.1016/j.ejca.2025.116104","DOIUrl":"10.1016/j.ejca.2025.116104","url":null,"abstract":"<div><h3>Purpose</h3><div>Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma with a high metastatic potential. We conducted a phase II clinical study of atezolizumab in ASPS patients to evaluate its efficacy, safety, and biomarkers associated with therapeutic response.</div></div><div><h3>Patients and Methods</h3><div>Eligible patients were aged ≥ 16 years and diagnosed with ASPS. Atezolizumab was administered at a dose of 1200 mg every 3 weeks. The primary endpoint was the objective response rate (ORR). Immune and genomic profiling of tissues was performed using immunohistochemistry, RNA sequencing, and whole-exome sequencing.</div></div><div><h3>Results</h3><div>Twenty patients were included in the study. The median age was 32.5 years, and 12 patients (60 %) received pazopanib. The overall ORR was 10 % (2 of 20). Two patients (10 %) achieved a complete response, which persisted for more than 1 year. Fourteen patients (70 %) had stable disease. The disease control rate was 80 %. Responders exhibited abundant infiltration of CD8<sup>+</sup>PD-1<sup>+</sup> T cells, characterised by low expression of Tim-3 and LAG-3.</div></div><div><h3>Conclusion</h3><div>Atezolizumab was effective in some patients, regardless of prior treatment with pazopanib. Responders had significant PD-1 expressing CD8<sup>+</sup> T cell infiltration before immune checkpoint inhibitor therapy. The degree of CD8<sup>+</sup>PD1<sup>+</sup> T cells may be a potential biomarker for predicting responses to atezolizumab.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116104"},"PeriodicalIF":7.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519004","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 : 2025-11-10DOI: 10.1016/j.ejca.2025.116103
Rehsan Akdas , Enrico Schalk , Jannik Stemler , Stefan Schwartz , Uta Meyding-Lamadé , Jens P. Panse , William Krüger , Holger Rohde , Markus Ruhnke , Maximilian Christopeit , Klemens Angstwurm , Claus P. Heußel , Oliver A. Cornely , Daniel Teschner , Martin Schmidt-Hieber
Background
Infections of the central nervous system (CNS) occur in up to 15 % of patients with hematological or oncological diseases (HOD), particularly in high-risk populations. The most common causative agents are viruses or fungi. Prompt initiation of adequate diagnostic procedures and anti-infective treatment is crucial, as treatment delays increase mortality.
Methods
We present an update of our previous guideline published in 2016 on the management of CNS infections in patients with HOD. The grading of recommendation strength and level of evidence followed the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) standards, based on a systematic literature review and a stepwise consensus process involving experts in internal medicine, hematology, oncology, infectious diseases, neurology, microbiology, and radiology. This process included several web-based meetings by the guideline panel, whereas the final recommendations were approved by the assembly of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology in September 2024.
Findings and interpretation
Evidence-based recommendations on the diagnosis and treatment of CNS infections in adult patients with HOD are essential in daily clinical practice to improve outcomes for patients at high risk of morbidity and mortality.
{"title":"CNS infections in patients with hematological or oncological diseases (including cellular therapies) – 2024 update of the guideline of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)","authors":"Rehsan Akdas , Enrico Schalk , Jannik Stemler , Stefan Schwartz , Uta Meyding-Lamadé , Jens P. Panse , William Krüger , Holger Rohde , Markus Ruhnke , Maximilian Christopeit , Klemens Angstwurm , Claus P. Heußel , Oliver A. Cornely , Daniel Teschner , Martin Schmidt-Hieber","doi":"10.1016/j.ejca.2025.116103","DOIUrl":"10.1016/j.ejca.2025.116103","url":null,"abstract":"<div><h3>Background</h3><div>Infections of the central nervous system (CNS) occur in up to 15 % of patients with hematological or oncological diseases (HOD), particularly in high-risk populations. The most common causative agents are viruses or fungi. Prompt initiation of adequate diagnostic procedures and anti-infective treatment is crucial, as treatment delays increase mortality.</div></div><div><h3>Methods</h3><div>We present an update of our previous guideline published in 2016 on the management of CNS infections in patients with HOD. The grading of recommendation strength and level of evidence followed the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) standards, based on a systematic literature review and a stepwise consensus process involving experts in internal medicine, hematology, oncology, infectious diseases, neurology, microbiology, and radiology. This process included several web-based meetings by the guideline panel, whereas the final recommendations were approved by the assembly of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology in September 2024.</div></div><div><h3>Findings and interpretation</h3><div>Evidence-based recommendations on the diagnosis and treatment of CNS infections in adult patients with HOD are essential in daily clinical practice to improve outcomes for patients at high risk of morbidity and mortality.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"232 ","pages":"Article 116103"},"PeriodicalIF":7.1,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676912","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 : 2025-11-07DOI: 10.1016/j.ejca.2025.116101
Pascal Pujol , Lise Roca , Alain Lortholary , Christine Lasset , Louise Crivelli , Pascaline Berthet , Isabelle Tennevet , Thierry Petit , Nathalie Chabbert-Buffet , Paul Gesta , Claire Saule , Jean Chiesa , Tan Dat Nguyen , Audrey Mailliez , Nasrine Afdjei Callet , Catherine Noguès , Hélène Dreyfus , Capucine Delnatte , Fabienne Prieur , Laurence Gladieff , Suzette Delaloge
Background
Women carrying a germline BRCA1 or BRCA2 mutation (gBRCAm) have a 70 % lifetime risk of breast cancer (BC). Aromatase inhibitors (AI) decrease BC incidence in high-risk populations but have not been specifically assessed in gBRCAm carriers.
Methods
LIBER was a randomized, double-blind, placebo-controlled, phase III trial. Post-menopausal women aged between 40 and 70 years carrying a gBRCAm were randomly allocated either 5 years of letrozole (2.5 mg/day) or placebo. Women with prior BC in remission for more than 5 years ago were eligible to assess the risk of second BC. Randomization was stratified by type of gBRCAm (BRCA1 versus BRCA2), previous bilateral oophorectomy, and prior BC. The primary endpoint was the 5-year incidence of invasive BC. Safety and quality of life were analyzed.
Results
Between 2008 and 2013, 170 women were randomized: 86 to placebo and 84 to letrozole. At 5 years, treatment adherence was 73.5 % with placebo and 76.7 % with letrozole. After a median follow-up of 72.7 months (95 % CI 71.5–78.5), the 5-year incidence of invasive BC was 13.1 % with placebo and 7.8 % with letrozole: hazard ratio, 0.70 (95 % CI 0.29–1.66), p = 0.416. Safety events and quality of life did not statistically differ in the arm.
Conclusion
Due to the underpowered nature of the trial and the observed trend, it cannot be ruled out that using AI to prevent invasive breast cancer could be effective for BRCA1/2 carriers overall, or for specific subgroups within a larger sample size. Further randomised controlled trials are needed to determine the potential benefits of AI for gBRCA1/2m carriers.
携带种系BRCA1或BRCA2突变（gBRCAm）的女性患乳腺癌（BC）的终生风险为70% %。芳香酶抑制剂（AI）可降低高危人群的BC发病率，但尚未在gBRCAm携带者中进行专门评估。方法sliber是一项随机、双盲、安慰剂对照的III期临床试验。年龄在40 - 70岁之间携带gBRCAm的绝经后妇女被随机分配5年来曲唑（2.5 mg/天）或安慰剂。既往BC缓解超过5年的女性有资格评估第二次BC的风险。随机分组根据gBRCAm类型（BRCA1 vs BRCA2）、既往双侧卵巢切除术和既往BC进行分层。主要终点是浸润性BC的5年发病率。对安全性和生活质量进行了分析。结果在2008年至2013年期间，170名女性被随机分配：86名服用安慰剂，84名服用来曲唑。5年时，安慰剂组的治疗依从性为73.5 %，来曲唑组为76.7 %。中位随访72.7个月后（95 % CI 71.5-78.5），安慰剂组5年浸润性BC发病率为13.1 %，来曲唑组为7.8 %：风险比为0.70(95 % CI 0.29-1.66), p = 0.416。两组的安全事件和生活质量没有统计学差异。由于该试验的有效性不足和观察到的趋势，不能排除使用人工智能预防浸润性乳腺癌可能对BRCA1/2携带者整体有效，或者对更大样本量内的特定亚组有效。需要进一步的随机对照试验来确定人工智能对gBRCA1/2m携带者的潜在益处。
{"title":"Letrozole to prevent breast cancer in postmenopausal women with BRCA1/2 mutations (LIBER study)","authors":"Pascal Pujol , Lise Roca , Alain Lortholary , Christine Lasset , Louise Crivelli , Pascaline Berthet , Isabelle Tennevet , Thierry Petit , Nathalie Chabbert-Buffet , Paul Gesta , Claire Saule , Jean Chiesa , Tan Dat Nguyen , Audrey Mailliez , Nasrine Afdjei Callet , Catherine Noguès , Hélène Dreyfus , Capucine Delnatte , Fabienne Prieur , Laurence Gladieff , Suzette Delaloge","doi":"10.1016/j.ejca.2025.116101","DOIUrl":"10.1016/j.ejca.2025.116101","url":null,"abstract":"<div><h3>Background</h3><div>Women carrying a germline BRCA1 or BRCA2 mutation (gBRCAm) have a 70 % lifetime risk of breast cancer (BC). Aromatase inhibitors (AI) decrease BC incidence in high-risk populations but have not been specifically assessed in gBRCAm carriers.</div></div><div><h3>Methods</h3><div>LIBER was a randomized, double-blind, placebo-controlled, phase III trial. Post-menopausal women aged between 40 and 70 years carrying a gBRCAm were randomly allocated either 5 years of letrozole (2.5 mg/day) or placebo. Women with prior BC in remission for more than 5 years ago were eligible to assess the risk of second BC. Randomization was stratified by type of gBRCAm (BRCA1 versus BRCA2), previous bilateral oophorectomy, and prior BC. The primary endpoint was the 5-year incidence of invasive BC. Safety and quality of life were analyzed.</div></div><div><h3>Results</h3><div>Between 2008 and 2013, 170 women were randomized: 86 to placebo and 84 to letrozole. At 5 years, treatment adherence was 73.5 % with placebo and 76.7 % with letrozole. After a median follow-up of 72.7 months (95 % CI 71.5–78.5), the 5-year incidence of invasive BC was 13.1 % with placebo and 7.8 % with letrozole: hazard ratio, 0.70 (95 % CI 0.29–1.66), p = 0.416. Safety events and quality of life did not statistically differ in the arm.</div></div><div><h3>Conclusion</h3><div>Due to the underpowered nature of the trial and the observed trend, it cannot be ruled out that using AI to prevent invasive breast cancer could be effective for BRCA1/2 carriers overall, or for specific subgroups within a larger sample size. Further randomised controlled trials are needed to determine the potential benefits of AI for gBRCA1/2m carriers.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"231 ","pages":"Article 116101"},"PeriodicalIF":7.1,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517798","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 : 2025-11-06DOI: 10.1016/j.ejca.2025.116098
Anne-Sophie van der Werf – ’t Lam , James G. Dowty , Morrison Italia , Astrid C. Bakker , Fernande Koops , Fonnet Bleeker , Encarna Gomez – Garcia , Liselot P. van Hest , Hans J.P. Gille , Claire C. Cornips , Mirjam M. de Jong , Tom G.W. Letteboer , Floor A.M. Duijkers , Anja Wagner , Ellis L. Eikenboom , Christi J. van Asperen , Sanne W. Bajwa – ten Broeke , Aung K. Win , Mark A. Jenkins , Maartje Nielsen
Introduction
Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic variants (PVs) in DNA mismatch repair genes, including MSH6. Although MSH6-associated LS (MSH6-LS) is known to increase the risk of several cancers, precise risk estimates—particularly for non-colorectal cancers—remain uncertain. This limits personalised clinical guidance for MSH6-LS. This study aims to refine cancer risk estimates for individuals with pathogenic or likely pathogenic MSH6 variants.
Methods
A retrospective cohort study was conducted using data from 360 Dutch families, comprising 1117 MSH6 PV carriers identified between 1995 and 2020. Pedigree data were collected from multiple clinical centres. Cancer diagnoses were confirmed through medical records where available. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were calculated using segregation analysis, adjusted for ascertainment bias.
Results
By age 80, the cumulative CRC risk was 36 % for males (95 % CI: 25–48 %) and 21 % for females (95 % CI: 13–32 %). For endometrial cancer, the CR was 23 % in females (95 % CI: 15–43 %). At age 40, CRC risk remained low: 0.2 % in males and 0.9 % in females. Elevated lifetime risks were observed for ovarian cancer (6.4 %; HR 5.58), urinary tract cancers (10.1 % in males, 4.1 % in females; HR 2.52), and biliary tract cancers (4.9 % in males, 4.2 % in females; HR 2.76). No increased risk was found for prostate or breast cancer.
Conclusion
These refined, age- and sex-specific risk estimates for MSH6 PV carriers inform tailored surveillance strategies, supporting delayed CRC screening and individualised counselling on risk-reducing surgery for women.
{"title":"Cancer risks for MSH6 pathogenic variant carriers","authors":"Anne-Sophie van der Werf – ’t Lam , James G. Dowty , Morrison Italia , Astrid C. Bakker , Fernande Koops , Fonnet Bleeker , Encarna Gomez – Garcia , Liselot P. van Hest , Hans J.P. Gille , Claire C. Cornips , Mirjam M. de Jong , Tom G.W. Letteboer , Floor A.M. Duijkers , Anja Wagner , Ellis L. Eikenboom , Christi J. van Asperen , Sanne W. Bajwa – ten Broeke , Aung K. Win , Mark A. Jenkins , Maartje Nielsen","doi":"10.1016/j.ejca.2025.116098","DOIUrl":"10.1016/j.ejca.2025.116098","url":null,"abstract":"<div><h3>Introduction</h3><div>Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic variants (PVs) in DNA mismatch repair genes, including <em>MSH6</em>. Although <em>MSH6</em>-associated LS (<em>MSH6</em>-LS) is known to increase the risk of several cancers, precise risk estimates—particularly for non-colorectal cancers—remain uncertain. This limits personalised clinical guidance for <em>MSH6</em>-LS. This study aims to refine cancer risk estimates for individuals with pathogenic or likely pathogenic <em>MSH6</em> variants.</div></div><div><h3>Methods</h3><div>A retrospective cohort study was conducted using data from 360 Dutch families, comprising 1117 <em>MSH6</em> PV carriers identified between 1995 and 2020. Pedigree data were collected from multiple clinical centres. Cancer diagnoses were confirmed through medical records where available. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were calculated using segregation analysis, adjusted for ascertainment bias.</div></div><div><h3>Results</h3><div>By age 80, the cumulative CRC risk was 36 % for males (95 % CI: 25–48 %) and 21 % for females (95 % CI: 13–32 %). For endometrial cancer, the CR was 23 % in females (95 % CI: 15–43 %). At age 40, CRC risk remained low: 0.2 % in males and 0.9 % in females. Elevated lifetime risks were observed for ovarian cancer (6.4 %; HR 5.58), urinary tract cancers (10.1 % in males, 4.1 % in females; HR 2.52), and biliary tract cancers (4.9 % in males, 4.2 % in females; HR 2.76). No increased risk was found for prostate or breast cancer.</div></div><div><h3>Conclusion</h3><div>These refined, age- and sex-specific risk estimates for <em>MSH6</em> PV carriers inform tailored surveillance strategies, supporting delayed CRC screening and individualised counselling on risk-reducing surgery for women.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"231 ","pages":"Article 116098"},"PeriodicalIF":7.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517799","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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