Pub Date : 2025-12-26DOI: 10.1016/j.ejca.2025.116201
Hildur Helgadottir , Lars Ny , Gustav J. Ullenhag , Rasmus Mikiver , Karolin Isaksson , Roger Olofsson Bagge
Background
In patients with stage III cutaneous melanoma, adjuvant treatments with PD-1 and BRAF+MEK inhibitors were approved based on improved recurrence-free survival. However, as the treatments have significant side effects and costs, the effect on overall survival remains a matter of great importance.
Methods
Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage IIIB-D melanoma in 2016–2020. Patients under the age of 75 years, that had a positive sentinel lymph node (SLN) were included. Patients were divided into two cohorts, depending on if the SLN biopsy was performed before or from September 2018 (pre- and post-cohort), based on the timepoint when adjuvant treatment was introduced. Patients were followed for survival until the end of 2024.
Results
The five-year overall survival rates were, 67.3 % (95 % CI 62.0–72.9) in the pre-cohort (n = 287) and 70.1 % (95 % CI 65.3–75.2) in the post-cohort (n = 349), with hazard ratio adjusted for age, sex and tumor stage of 0.96 (95 % CI 0.73–1.27), P=0.791. In the post-cohort 72.8 % received adjuvant treatment, the majority with PD-1 inhibitors where treatment exposure was highest in those < 60 years (80.2 %), males (78.3 %) and those having thicker primary melanomas (75.4 %). No significant overall or melanoma-specific survival differences were observed when comparing the pre- and the post-cohort in different subgroups.
Conclusions
In this nationwide, population and registry-based study there was no overall survival benefit observed five years after the introduction of adjuvant treatment for patients with stage III melanoma. These findings encourage a careful assessment of the current recommendation on adjuvant treatment.
{"title":"Five-year survival after introduction of adjuvant treatment in stage III melanoma: A nationwide registry-based study","authors":"Hildur Helgadottir , Lars Ny , Gustav J. Ullenhag , Rasmus Mikiver , Karolin Isaksson , Roger Olofsson Bagge","doi":"10.1016/j.ejca.2025.116201","DOIUrl":"10.1016/j.ejca.2025.116201","url":null,"abstract":"<div><h3>Background</h3><div>In patients with stage III cutaneous melanoma, adjuvant treatments with PD-1 and BRAF+MEK inhibitors were approved based on improved recurrence-free survival. However, as the treatments have significant side effects and costs, the effect on overall survival remains a matter of great importance.</div></div><div><h3>Methods</h3><div>Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry for patients diagnosed with stage IIIB-D melanoma in 2016–2020. Patients under the age of 75 years, that had a positive sentinel lymph node (SLN) were included. Patients were divided into two cohorts, depending on if the SLN biopsy was performed before or from September 2018 (pre- and post-cohort), based on the timepoint when adjuvant treatment was introduced. Patients were followed for survival until the end of 2024.</div></div><div><h3>Results</h3><div>The five-year overall survival rates were, 67.3 % (95 % CI 62.0–72.9) in the pre-cohort (n = 287) and 70.1 % (95 % CI 65.3–75.2) in the post-cohort (n = 349), with hazard ratio adjusted for age, sex and tumor stage of 0.96 (95 % CI 0.73–1.27), <em>P=</em>0.791. In the post-cohort 72.8 % received adjuvant treatment, the majority with PD-1 inhibitors where treatment exposure was highest in those < 60 years (80.2 %), males (78.3 %) and those having thicker primary melanomas (75.4 %). No significant overall or melanoma-specific survival differences were observed when comparing the pre- and the post-cohort in different subgroups.</div></div><div><h3>Conclusions</h3><div>In this nationwide, population and registry-based study there was no overall survival benefit observed five years after the introduction of adjuvant treatment for patients with stage III melanoma. These findings encourage a careful assessment of the current recommendation on adjuvant treatment.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116201"},"PeriodicalIF":7.1,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917358","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116199
Pieter Maerten , Gilles Defraene , Albert Wolthuis , Cédric Schraepen , Gabriele Bislenghi , Gert De Hertogh , Lynn Debrun , Evelien Dierick , Raphaëla Dresen , Philippe Leclercq , Freddy Penninckxc , Gertjan Rasschaert , Xavier Sagaert , Sabine Tejpar , Filip Van Herpe , Jeroen Dekervel , Eric Van Cutsem , André D’Hoore , Karin Haustermans
Background
The management of locally advanced rectal cancer has significantly evolved over the past 25-years, most recently with the adoption of total neoadjuvant therapy (TNT). Nevertheless, optimal treatment selection for individual patients remains challenging. This study evaluated recurrence patterns in rectal cancer to improve risk stratification and guide neoadjuvant treatment decisions in the TNT era.
Methods
We conducted a prospective cohort study including 850 rectal cancer patients treated with neoadjuvant radio- and chemotherapy over a 25-year period.
Findings
After a median follow-up of 12 years, 5-year overall survival (OS) and disease-free survival (DFS) were 86.8 % and 75.5 %. Recurrence occurred in 167 patients (19.6 %), including 31 (3.6 %) with locoregional recurrence (LRR), 158 (18.6 %) with distant metastases (DM) and 22 (2.6 %) with both. Five-year recurrence-free survival (RFS), DM-free survival (DMFS) and LRR-free survival (LRFS) were 76.9 %, 77.8 % and 85.3 %. Mesorectal fascia involvement (p = 0.006) and extra-mural vascular invasion (p = 0.028) were associated with recurrence on univariable analysis, although their impact diminished after adjusting for neoadjuvant treatment. Independent predictors of DM were lymphovascular invasion (p < 0.001), perineural invasion (p = 0.004), positive circumferential resection margin (p = 0.046) and higher lymph node ratio (LN-ratio) (p < 0.001). Tumor diameter (p = 0.025) and LN-ratio (p = 0.047) independently predicted LRR. Early recurrence was associated with worse OS, although post-recurrence survival did not differ significantly.
Conclusion
Histopathological features and tumor response to neoadjuvant therapy are strong predictors of recurrence risk in rectal cancer. Identifying reliable baseline biomarkers of treatment response is essential to refine patient risk stratification and personalize neoadjuvant treatment strategies in the TNT era.
{"title":"Long-term recurrence patterns in rectal cancer after neoadjuvant therapy: 25-years of real-world data","authors":"Pieter Maerten , Gilles Defraene , Albert Wolthuis , Cédric Schraepen , Gabriele Bislenghi , Gert De Hertogh , Lynn Debrun , Evelien Dierick , Raphaëla Dresen , Philippe Leclercq , Freddy Penninckxc , Gertjan Rasschaert , Xavier Sagaert , Sabine Tejpar , Filip Van Herpe , Jeroen Dekervel , Eric Van Cutsem , André D’Hoore , Karin Haustermans","doi":"10.1016/j.ejca.2025.116199","DOIUrl":"10.1016/j.ejca.2025.116199","url":null,"abstract":"<div><h3>Background</h3><div>The management of locally advanced rectal cancer has significantly evolved over the past 25-years, most recently with the adoption of total neoadjuvant therapy (TNT). Nevertheless, optimal treatment selection for individual patients remains challenging. This study evaluated recurrence patterns in rectal cancer to improve risk stratification and guide neoadjuvant treatment decisions in the TNT era.</div></div><div><h3>Methods</h3><div>We conducted a prospective cohort study including 850 rectal cancer patients treated with neoadjuvant radio- and chemotherapy over a 25-year period.</div></div><div><h3>Findings</h3><div>After a median follow-up of 12 years, 5-year overall survival (OS) and disease-free survival (DFS) were 86.8 % and 75.5 %. Recurrence occurred in 167 patients (19.6 %), including 31 (3.6 %) with locoregional recurrence (LRR), 158 (18.6 %) with distant metastases (DM) and 22 (2.6 %) with both. Five-year recurrence-free survival (RFS), DM-free survival (DMFS) and LRR-free survival (LRFS) were 76.9 %, 77.8 % and 85.3 %. Mesorectal fascia involvement (p = 0.006) and extra-mural vascular invasion (p = 0.028) were associated with recurrence on univariable analysis, although their impact diminished after adjusting for neoadjuvant treatment. Independent predictors of DM were lymphovascular invasion (p < 0.001), perineural invasion (p = 0.004), positive circumferential resection margin (p = 0.046) and higher lymph node ratio (LN-ratio) (p < 0.001). Tumor diameter (p = 0.025) and LN-ratio (p = 0.047) independently predicted LRR. Early recurrence was associated with worse OS, although post-recurrence survival did not differ significantly.</div></div><div><h3>Conclusion</h3><div>Histopathological features and tumor response to neoadjuvant therapy are strong predictors of recurrence risk in rectal cancer. Identifying reliable baseline biomarkers of treatment response is essential to refine patient risk stratification and personalize neoadjuvant treatment strategies in the TNT era.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116199"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877631","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116196
Louis Jansen , Marcel Mayer , Andreas Stang , Hiltraud Kajueter , Florian Oesterling , Andras Szentkiralyi , Sofia Kourou , Philipp Wolber , Julia van de Loo , Lena Hieggelke , Alexander Quaas , Jens Peter Klussmann , Lisa Nachtsheim
Background
Primary salivary gland carcinomas (SGC) are rare tumors comprising 5 % of head and neck cancers. While most published studies on SGC in Germany focus on state-level data, nationwide population-based data on incidence, demographics, and outcomes have not been reported.
Objectives
This study aimed to provide a nationwide overview of the incidence, clinicopathologic characteristics, and survival of patients with primary SGC of the major salivary glands in Germany.
Design and methods
Data were extracted from the German Centre for Cancer Registry Data (ZfKD), covering all 16 federal states, for the period 2009–2022. Patients with primary malignant neoplasms of the major salivary glands were included. Crude and age standardized incidence rates were calculated. Relative survival was estimated using the period approach, stratified by demographic and tumor characteristics.
Results
We identified 10,808 SGC cases. The most frequent subtypes were adenocarcinoma not otherwise specified (ANOS) (18.4 %), mucoepidermoid (MEC, 13.5 %), adenoid cystic (ACC, 13.3 %), acinic cell (Acin, 10.4 %), and salivary duct carcinoma (SDC, 5.7 %). The mean age-standardized incidence rate was 5.2/1000,000 person-years, 5.8 for men and 4.8 for women, and increased slightly over observation period. A decline in ANOS and increase in SDC incidence were observed, primarily among men. The five-year relative survival was 70 %, with a pronounced disparity observed between male (62 %) and female (80 %) patients. Survival declined with advanced tumor status, nodal involvement, and distant metastasis.
Conclusion
To date, this represents the largest epidemiological investigation of major SGC worldwide. Over the observation period, the incidence of major SGC has slightly increased in Germany. Men showed a distinctly more unfavorable prognosis than women and were more likely to be diagnosed with aggressive entities like ANOS and SDC.
{"title":"Incidence and survival of primary major salivary gland carcinoma in Germany over the last decade: A nationwide population-based study","authors":"Louis Jansen , Marcel Mayer , Andreas Stang , Hiltraud Kajueter , Florian Oesterling , Andras Szentkiralyi , Sofia Kourou , Philipp Wolber , Julia van de Loo , Lena Hieggelke , Alexander Quaas , Jens Peter Klussmann , Lisa Nachtsheim","doi":"10.1016/j.ejca.2025.116196","DOIUrl":"10.1016/j.ejca.2025.116196","url":null,"abstract":"<div><h3>Background</h3><div>Primary salivary gland carcinomas (SGC) are rare tumors comprising 5 % of head and neck cancers. While most published studies on SGC in Germany focus on state-level data, nationwide population-based data on incidence, demographics, and outcomes have not been reported.</div></div><div><h3>Objectives</h3><div>This study aimed to provide a nationwide overview of the incidence, clinicopathologic characteristics, and survival of patients with primary SGC of the major salivary glands in Germany.</div></div><div><h3>Design and methods</h3><div>Data were extracted from the German Centre for Cancer Registry Data (ZfKD), covering all 16 federal states, for the period 2009–2022. Patients with primary malignant neoplasms of the major salivary glands were included. Crude and age standardized incidence rates were calculated. Relative survival was estimated using the period approach, stratified by demographic and tumor characteristics.</div></div><div><h3>Results</h3><div>We identified 10,808 SGC cases. The most frequent subtypes were adenocarcinoma not otherwise specified (ANOS) (18.4 %), mucoepidermoid (MEC, 13.5 %), adenoid cystic (ACC, 13.3 %), acinic cell (Acin, 10.4 %), and salivary duct carcinoma (SDC, 5.7 %). The mean age-standardized incidence rate was 5.2/1000,000 person-years, 5.8 for men and 4.8 for women, and increased slightly over observation period. A decline in ANOS and increase in SDC incidence were observed, primarily among men. The five-year relative survival was 70 %, with a pronounced disparity observed between male (62 %) and female (80 %) patients. Survival declined with advanced tumor status, nodal involvement, and distant metastasis.</div></div><div><h3>Conclusion</h3><div>To date, this represents the largest epidemiological investigation of major SGC worldwide. Over the observation period, the incidence of major SGC has slightly increased in Germany. Men showed a distinctly more unfavorable prognosis than women and were more likely to be diagnosed with aggressive entities like ANOS and SDC.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116196"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877712","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116191
Claudio Sini , Alessandro Russo , Diego Cortinovis , Lucia Anna Muscarella , Marcello Tiseo , Emilio Bria , Salvatore Grisanti , Pierluigi Piovano , Antonello Veccia , Lorenzo Antonuzzo , Fabrizio Citarella , Sara Pilotto , Maria Lucia Reale , Daniele Pignataro , Elisa Roca , Lorenzo Calvetti , Pamela Pizzutilo , Gabriele Minuti , Giacomo Pelizzari , Greta Alì , Editta Baldini
Background
BRAF mutations identify a small subgroup of patients (pts) with non-small cell lung cancer (NSCLC). Dabrafenib/trametinib (D/T) combination is associated with high response rates and durable anti-tumor activity in BRAF-V600-mutants. Several open questions still remain unanswered in clinical practice, including the efficacy of treatments based on clinical and molecular characteristics, the activity in patients with brain metastases, the optimal sequence with immunotherapy-based therapies. Here we present outcomes among advanced BRAF-mutant NSCLC patients from the Italian ATLAS registry.
Methods
Patients with metastatic BRAF-mutated NSCLC were included. Clinical-pathological features, treatment effectiveness and safety outcomes were retrospectively collected from the Italian real-world ATLAS registry.
Results
A total of 244 BRAF-mutated NSCLC pts were enrolled, including 70 % V600E mutations. The median PFS of first line D/T was 19.8 months (95 % CI: 10.7–29.0), with a 2-year OS rate of 65.4 % and a PFS2 of 6.6 months (95 % CI: 0–14.3). The activity of D/T differs among sex (mPFS was 13.6 mos and 25.3 mos and 2-yr OS rate were 54.9 % and 72.3 % in males and females, respectively) and smoking status (mPFS was 18.4 mos, 25.6 mos and 24 mos in never, former and current smokers, respectively). Concomitant MET amplification was associated with a shorter median PFS (mPFS was 13.6 mos vs. 44.3 mos with and without MET amplification respectively) in pts treated with D/T as 1st line.
Conclusions
These data confirm the efficacy and safety of first line D/T in BRAF V600E-mutated pts in the real-world setting consistently with prior studies, suggesting a differential activity among key clinical-molecular subgroups.
{"title":"Braf-mutant metastatic non–small-cell lung cancer: Real world data from the Italian biomarker atlas database","authors":"Claudio Sini , Alessandro Russo , Diego Cortinovis , Lucia Anna Muscarella , Marcello Tiseo , Emilio Bria , Salvatore Grisanti , Pierluigi Piovano , Antonello Veccia , Lorenzo Antonuzzo , Fabrizio Citarella , Sara Pilotto , Maria Lucia Reale , Daniele Pignataro , Elisa Roca , Lorenzo Calvetti , Pamela Pizzutilo , Gabriele Minuti , Giacomo Pelizzari , Greta Alì , Editta Baldini","doi":"10.1016/j.ejca.2025.116191","DOIUrl":"10.1016/j.ejca.2025.116191","url":null,"abstract":"<div><h3>Background</h3><div><em>BRAF</em> mutations identify a small subgroup of patients (pts) with non-small cell lung cancer (NSCLC). Dabrafenib/trametinib (D/T) combination is associated with high response rates and durable anti-tumor activity in <em>BRAF</em>-V600-mutants. Several open questions still remain unanswered in clinical practice, including the efficacy of treatments based on clinical and molecular characteristics, the activity in patients with brain metastases, the optimal sequence with immunotherapy-based therapies. Here we present outcomes among advanced <em>BRAF</em>-mutant NSCLC patients from the Italian ATLAS registry.</div></div><div><h3>Methods</h3><div>Patients with metastatic BRAF-mutated NSCLC were included. Clinical-pathological features, treatment effectiveness and safety outcomes were retrospectively collected from the Italian real-world ATLAS registry.</div></div><div><h3>Results</h3><div>A total of 244 <em>BRAF</em>-mutated NSCLC pts were enrolled, including 70 % V600E mutations. The median PFS of first line D/T was 19.8 months (95 % CI: 10.7–29.0), with a 2-year OS rate of 65.4 % and a PFS2 of 6.6 months (95 % CI: 0–14.3). The activity of D/T differs among sex (mPFS was 13.6 mos and 25.3 mos and 2-yr OS rate were 54.9 % and 72.3 % in males and females, respectively) and smoking status (mPFS was 18.4 mos, 25.6 mos and 24 mos in never, former and current smokers, respectively). Concomitant <em>MET</em> amplification was associated with a shorter median PFS (mPFS was 13.6 mos vs. 44.3 mos with and without MET amplification respectively) in pts treated with D/T as 1st line.</div></div><div><h3>Conclusions</h3><div>These data confirm the efficacy and safety of first line D/T in BRAF V600E-mutated pts in the real-world setting consistently with prior studies, suggesting a differential activity among key clinical-molecular subgroups.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116191"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877625","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116197
Md Tamzid Islam , Fengwei Yang , Stephan Komladzei , Murshalina Akhter , Mihaela E. Sardiu , Yanming Li
Background
Glioblastoma (GBM) is a highly prevalent and aggressive type of brain tumor characterized by profound molecular complexity and poor prognosis. While conventional biomarker studies focus on highly significant genes or proteins associated with cancer outcomes, the contribution of gene–gene co-regulation to GBM progression remains unclear.
Methods
This study employs an application of integrative machine learning approach, utilizing a high-dimensional transcriptomic profile that considers gene-gene co-regulations to identify predictive gene networks involved in GBM occurrence and 1-year survival prediction. We further integrate these network models with both empirical protein-protein interaction (PPI) data and random walk-based information flow analysis across the PPI landscape.
Results
This dual-layered approach uncovers gene modules that bridge transcriptional co-regulation with functional connectivity at the protein level. This integration highlighted several hub genes, including both strong and weak (e.g. BSN, RHOC, ANXA1, CSF1R, and ITGAM), that emerged as key molecular connectors involved in critical GBM processes such as immune response and neuronal signaling. Notably, these hub genes also exhibited cross-disease associations with traits including gut microbiome composition, type 2 diabetes, coronary artery disease, and other cancers, underscoring their systemic biological relevance.
Conclusion
Overall, our findings through the computational approach underscore the significance of co-regulatory gene networks in GBM biology. It also demonstrates how integrating transcriptomic and protein-level interactions can refine prognostic modeling, advance biomarker discovery, and inform future therapeutic development.
{"title":"Integrative machine learning reveals hidden and emerging co-regulatory gene networks for multi-phase glioblastoma outcome prediction","authors":"Md Tamzid Islam , Fengwei Yang , Stephan Komladzei , Murshalina Akhter , Mihaela E. Sardiu , Yanming Li","doi":"10.1016/j.ejca.2025.116197","DOIUrl":"10.1016/j.ejca.2025.116197","url":null,"abstract":"<div><h3>Background</h3><div>Glioblastoma (GBM) is a highly prevalent and aggressive type of brain tumor characterized by profound molecular complexity and poor prognosis. While conventional biomarker studies focus on highly significant genes or proteins associated with cancer outcomes, the contribution of gene–gene co-regulation to GBM progression remains unclear.</div></div><div><h3>Methods</h3><div>This study employs an application of integrative machine learning approach, utilizing a high-dimensional transcriptomic profile that considers gene-gene co-regulations to identify predictive gene networks involved in GBM occurrence and 1-year survival prediction. We further integrate these network models with both empirical protein-protein interaction (PPI) data and random walk-based information flow analysis across the PPI landscape.</div></div><div><h3>Results</h3><div>This dual-layered approach uncovers gene modules that bridge transcriptional co-regulation with functional connectivity at the protein level. This integration highlighted several hub genes, including both strong and weak (e.g. BSN, RHOC, ANXA1, CSF1R, and ITGAM), that emerged as key molecular connectors involved in critical GBM processes such as immune response and neuronal signaling. Notably, these hub genes also exhibited cross-disease associations with traits including gut microbiome composition, type 2 diabetes, coronary artery disease, and other cancers, underscoring their systemic biological relevance.</div></div><div><h3>Conclusion</h3><div>Overall, our findings through the computational approach underscore the significance of co-regulatory gene networks in GBM biology. It also demonstrates how integrating transcriptomic and protein-level interactions can refine prognostic modeling, advance biomarker discovery, and inform future therapeutic development.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116197"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838636","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116198
Wei Guo , Liang Zhao , Xiaowei Chen , Shuhang Wang , Xiuli Tao , Lin Li , Qianqian Sun , Yushun Gao , Yousheng Mao , Kang Shao , Fang Lv , Liangze Zhang , Wendong Lei , Dali Wang , Zhishan Li , Kai Su , Bing Wang , Feiyue Feng , Xinjie Chen , Ning Wu , Shugeng Gao
Background
Neoadjuvant camrelizumab plus apatinib has shown a promising major pathological response (primary endpoint) and pathological complete response (a secondary endpoint) in patients with resectable stage IIA-IIIB non-small-cell lung cancer (NSCLC) in a previous single-arm phase 2 trial. Here, we present the 3-year survival outcomes and potential prognostic factors with extended follow-up.
Methods
This single-arm phase 2 study enrolled patients with resectable stage IIA-IIIB NSCLC (stage IIIB, T3N2 only, according to the eighth edition of the American Joint Commission on Cancer TNM staging classification). Patients received three cycles of neoadjuvant camrelizumab (200 mg, intravenously, q2w) and apatinib (250 mg, orally, qd, for 5 days followed by 2 days off) followed by surgery. At 4–8 weeks after surgery, patients received either adjuvant camrelizumab monotherapy for up to 12 cycles or other strategies at the investigator's discretion.
Results
With the median follow-up of 42.6 months, the 3-year event-free survival (EFS), disease-free survival and overall survival were 58.9 % (95 % CI 46.9–69.1), 61.5 % (95 % CI 48.6–72.1), and 92.3 % (95 % CI 83.6–96.5), respectively. Among the pathological responses, residual viable tumors of ≤ 20 % were more strongly associated with improved EFS (HR 0.30, 95 % CI 0.13–0.72). Additionally, metabolic response on PET/CT after neoadjuvant treatment and ctDNA clearance during the perioperative period were significantly associated with improved EFS (HR 0.23 [95 % CI 0.08–0.62] and HR 0.23 [95 % CI 0.09–0.59], respectively).
Conclusions
Neoadjuvant camrelizumab plus apatinib provides a potential sustained benefit for patients with resectable stage IIA-IIIB NSCLC. Metabolic response on PET/CT and perioperative ctDNA clearance might be potential biomarkers for predicting survival.
背景：在之前的一项单臂2期试验中，新辅助camrelizumab联合阿帕替尼在可切除的IIA-IIIB期非小细胞肺癌（NSCLC）患者中显示出有希望的主要病理反应（主要终点）和病理完全缓解（次要终点）。在这里，我们通过延长的随访，提出了3年的生存结果和潜在的预后因素。方法：这项单臂2期研究纳入了可切除的IIA-IIIB期NSCLC （IIIB期，T3N2，根据美国癌症TNM分期分类联合委员会第八版）患者。患者接受三个周期的新辅助camrelizumab（200 mg，静脉注射，q2w）和apatinib（250 mg，口服，qd，持续5天，休息2天），然后进行手术。在手术后4-8周，患者接受辅助camrelizumab单药治疗长达12个周期或研究者自行决定的其他策略。结果：中位随访42.6个月，3年无事件生存期（EFS）、无病生存期和总生存期分别为58.9 %（95 % CI 46.9-69.1）、61.5 %（95 % CI 48.6-72.1）和92.3 %（95 % CI 83.6-96.5）。在病理反应中，残余活肿瘤≤ 20 %与改善的EFS相关性更强（HR 0.30, 95% % CI 0.13-0.72）。此外，新辅助治疗后PET/CT上的代谢反应和围手术期ctDNA清除与EFS改善显著相关（HR分别为0.23[95 % CI 0.08-0.62]和HR 0.23[95 % CI 0.09-0.59]）。结论：新辅助camrelizumab联合阿帕替尼为可切除的IIA-IIIB期NSCLC患者提供了潜在的持续益处。PET/CT代谢反应和围手术期ctDNA清除率可能是预测生存的潜在生物标志物。
{"title":"Phase II trial of neoadjuvant camrelizumab and apatinib in resectable NSCLC: 3-year survival outcomes and dynamic circulating tumor DNA analyses","authors":"Wei Guo , Liang Zhao , Xiaowei Chen , Shuhang Wang , Xiuli Tao , Lin Li , Qianqian Sun , Yushun Gao , Yousheng Mao , Kang Shao , Fang Lv , Liangze Zhang , Wendong Lei , Dali Wang , Zhishan Li , Kai Su , Bing Wang , Feiyue Feng , Xinjie Chen , Ning Wu , Shugeng Gao","doi":"10.1016/j.ejca.2025.116198","DOIUrl":"10.1016/j.ejca.2025.116198","url":null,"abstract":"<div><h3>Background</h3><div>Neoadjuvant camrelizumab plus apatinib has shown a promising major pathological response (primary endpoint) and pathological complete response (a secondary endpoint) in patients with resectable stage IIA-IIIB non-small-cell lung cancer (NSCLC) in a previous single-arm phase 2 trial. Here, we present the 3-year survival outcomes and potential prognostic factors with extended follow-up.</div></div><div><h3>Methods</h3><div>This single-arm phase 2 study enrolled patients with resectable stage IIA-IIIB NSCLC (stage IIIB, T3N2 only, according to the eighth edition of the American Joint Commission on Cancer TNM staging classification). Patients received three cycles of neoadjuvant camrelizumab (200 mg, intravenously, q2w) and apatinib (250 mg, orally, qd, for 5 days followed by 2 days off) followed by surgery. At 4–8 weeks after surgery, patients received either adjuvant camrelizumab monotherapy for up to 12 cycles or other strategies at the investigator's discretion.</div></div><div><h3>Results</h3><div>With the median follow-up of 42.6 months, the 3-year event-free survival (EFS), disease-free survival and overall survival were 58.9 % (95 % CI 46.9–69.1), 61.5 % (95 % CI 48.6–72.1), and 92.3 % (95 % CI 83.6–96.5), respectively. Among the pathological responses, residual viable tumors of ≤ 20 % were more strongly associated with improved EFS (HR 0.30, 95 % CI 0.13–0.72). Additionally, metabolic response on PET/CT after neoadjuvant treatment and ctDNA clearance during the perioperative period were significantly associated with improved EFS (HR 0.23 [95 % CI 0.08–0.62] and HR 0.23 [95 % CI 0.09–0.59], respectively).</div></div><div><h3>Conclusions</h3><div>Neoadjuvant camrelizumab plus apatinib provides a potential sustained benefit for patients with resectable stage IIA-IIIB NSCLC. Metabolic response on PET/CT and perioperative ctDNA clearance might be potential biomarkers for predicting survival.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116198"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917407","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 : 2025-12-24DOI: 10.1016/j.ejca.2025.116200
Rasmus Haunstrup Døssing , Elisabeth Hesselberg , Anna Burton Clausen , Adam Andrzej Luczak , Mario Presti , Inge Marie Svane , Henrik Schmidt , Lars Bastholt , Marco Donia , Eva Ellebaek
Background
BRAF and MEK inhibitors (BRAFi/MEKi) induce high response rates and rapid tumor regression in BRAF-mutated metastatic melanoma. While responses last around 12 months, ≈ 24 % of patients in clinical trials achieve progression-free survival (PFS) beyond 3 years. The impact of discontinuing therapy after long-lasting responses remains incompletely characterized.
Methods
We conducted a retrospective nationwide cohort study using the Danish Metastatic Melanoma Database (DAMMED), to include patients with metastatic melanoma treated with BRAFi/MEKi for ≥ 2 years from 2014 to 2022. Survival outcomes were assessed using Kaplan-Meier analyses and the log-rank test.
Results
1367 patients initiated treatment with BRAFi/MEKi, 97 received therapy ≥ 2 years, and 37 patients discontinued treatment in the absence of disease progression between 2 and 3.5 years from treatment initiation. Among patients who discontinued, median overall survival was 125 months and median PFS post-discontinuation 14 months. After median follow-up of 49 months post-discontinuation, 24 of 37 patients (65 %) progressed, with 67 % who progressed within 12 months. Of those who progressed, 19 were reinduced with BRAFi/MEKi, achieving a 79 % response rate; mPFS post-reinduction was 25 months (median follow-up 29.4 months).
Conclusion
In this nationwide real-world cohort of patients with melanoma receiving prolonged BRAFi/MEKi treatment, a notable proportion of patients who discontinued treatment without progression became long-term survivors. Progression after discontinuation typically occurred within the first year, with BRAFi/MEKi-reinduction being highly effective. Treatment discontinuation could be a viable strategy for selected patients, provided close follow-up and prompt reinitiation upon progression. Identifying clinical or molecular features predictive of sustained tumor control remains essential.
{"title":"Discontinuation of BRAF/MEK inhibitor therapy after long-lasting response: Clinical outcomes in advanced melanoma","authors":"Rasmus Haunstrup Døssing , Elisabeth Hesselberg , Anna Burton Clausen , Adam Andrzej Luczak , Mario Presti , Inge Marie Svane , Henrik Schmidt , Lars Bastholt , Marco Donia , Eva Ellebaek","doi":"10.1016/j.ejca.2025.116200","DOIUrl":"10.1016/j.ejca.2025.116200","url":null,"abstract":"<div><h3>Background</h3><div>BRAF and MEK inhibitors (BRAFi/MEKi) induce high response rates and rapid tumor regression in BRAF-mutated metastatic melanoma. While responses last around 12 months, ≈ 24 % of patients in clinical trials achieve progression-free survival (PFS) beyond 3 years. The impact of discontinuing therapy after long-lasting responses remains incompletely characterized.</div></div><div><h3>Methods</h3><div>We conducted a retrospective nationwide cohort study using the Danish Metastatic Melanoma Database (DAMMED), to include patients with metastatic melanoma treated with BRAFi/MEKi for ≥ 2 years from 2014 to 2022. Survival outcomes were assessed using Kaplan-Meier analyses and the log-rank test.</div></div><div><h3>Results</h3><div>1367 patients initiated treatment with BRAFi/MEKi, 97 received therapy ≥ 2 years, and 37 patients discontinued treatment in the absence of disease progression between 2 and 3.5 years from treatment initiation. Among patients who discontinued, median overall survival was 125 months and median PFS post-discontinuation 14 months. After median follow-up of 49 months post-discontinuation, 24 of 37 patients (65 %) progressed, with 67 % who progressed within 12 months. Of those who progressed, 19 were reinduced with BRAFi/MEKi, achieving a 79 % response rate; mPFS post-reinduction was 25 months (median follow-up 29.4 months).</div></div><div><h3>Conclusion</h3><div>In this nationwide real-world cohort of patients with melanoma receiving prolonged BRAFi/MEKi treatment, a notable proportion of patients who discontinued treatment without progression became long-term survivors. Progression after discontinuation typically occurred within the first year, with BRAFi/MEKi-reinduction being highly effective. Treatment discontinuation could be a viable strategy for selected patients, provided close follow-up and prompt reinitiation upon progression. Identifying clinical or molecular features predictive of sustained tumor control remains essential.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116200"},"PeriodicalIF":7.1,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838637","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 : 2025-12-19DOI: 10.1016/j.ejca.2025.116195
Noah Zimmermann , Julian Kött , Tim Zell , Ali Zeinal Abedini , Chiara L. Blomen , Stella Belz , Benjamin Deitert , Isabel Heidrich , Glenn Geidel , Alessandra Rünger , Daniel J. Smit , Michael Weichenthal , Selma Ugurel , Ulrike Leiter , Carola Berking , Ralf Gutzmer , Dirk Schadendorf , Imke von Wasielewski , Peter Mohr , Friedegund Meier , Christoffer Gebhardt
Background
Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT.
Methods
We analyzed 1296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016–2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists).
Results
Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 % CI 0.39–0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 % CI 0.19–0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 % CI 0.25–0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 % CI 0.27–0.87, p = 0.015).
Conclusion
Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.
背景：靶向治疗（TT）改善braf突变黑色素瘤的预后。临床前数据表明抗凝（AC）和血小板聚集抑制（PAI）可能具有抗肿瘤作用。我们评估了合并AC或PAI对接受TT患者预后的影响。方法：我们在前瞻性多中心ADOReg注册中分析了1296例不可切除的BRAF- iv期突变黑色素瘤患者，这些患者接受BRAF + MEK抑制剂治疗（2016-2024）。患者被分类为未接受抗血栓治疗（ATT; n = 1125）、PAI （n = 73；乙酰水杨酸或氯吡格雷）或AC （n = 98；直接口服抗凝剂、低分子肝素或维生素K拮抗剂）。结果：中位随访时间为1.3年。与没有ATT的患者相比，接受AC治疗的患者12个月无进展生存期（PFS; HR 0.55, 95% CI 0.39-0.78, p = 0.001）和总生存期（OS; HR 0.35, 95% CI 0.19-0.64, p = 0.001）显著改善。直接口服抗凝药物显示出最明显的PFS益处（HR 0.40, 95% CI 0.25-0.64, p ）。结论：在接受TT治疗的黑色素瘤患者中，伴随AC治疗，尤其是抑制xa因子的直接口服抗凝药物，与生存率的提高有关。这些发现支持前瞻性试验评估AC作为晚期黑色素瘤的伴随治疗。
{"title":"Enhanced overall and progression-free survival in advanced melanoma patients undergoing targeted therapy alongside antithrombotic treatment – Insights from a multicenter study involving 1296 patients from the prospective skin cancer registry ADOReg","authors":"Noah Zimmermann , Julian Kött , Tim Zell , Ali Zeinal Abedini , Chiara L. Blomen , Stella Belz , Benjamin Deitert , Isabel Heidrich , Glenn Geidel , Alessandra Rünger , Daniel J. Smit , Michael Weichenthal , Selma Ugurel , Ulrike Leiter , Carola Berking , Ralf Gutzmer , Dirk Schadendorf , Imke von Wasielewski , Peter Mohr , Friedegund Meier , Christoffer Gebhardt","doi":"10.1016/j.ejca.2025.116195","DOIUrl":"10.1016/j.ejca.2025.116195","url":null,"abstract":"<div><h3>Background</h3><div>Targeted therapies (TT) improve outcomes in BRAF-mutant melanoma. Pre-clinical data suggest that anticoagulation (AC) and platelet aggregation inhibition (PAI) may have antitumoral effects. We evaluated the impact of concomitant AC or PAI on outcomes in patients receiving TT.</div></div><div><h3>Methods</h3><div>We analyzed 1296 patients with unresectable stage III-IV BRAF-mutant melanoma treated with BRAF plus MEK inhibitors (2016–2024) in the prospective multicenter ADOReg registry. Patients were categorized as receiving no antithrombotic therapy (ATT; n = 1125), PAI (n = 73; acetylsalicylic acid or clopidogrel), or AC (n = 98; direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonists).</div></div><div><h3>Results</h3><div>Median follow-up was 1.3 years. Compared with patients without ATT, those receiving AC had significantly improved 12-month progression-free survival (PFS; HR 0.55, 95 % CI 0.39–0.78, p = 0.001) and overall survival (OS; HR 0.35, 95 % CI 0.19–0.64, p = 0.001). Direct oral anticoagulants showed the most pronounced PFS benefit (HR 0.40, 95 % CI 0.25–0.64, p < 0.001). PAI was not associated with a significant difference in PFS, but multivariable Cox regression indicated a reduced hazard of death (HR 0.48, 95 % CI 0.27–0.87, p = 0.015).</div></div><div><h3>Conclusion</h3><div>Concomitant AC, particularly factor Xa-inhibiting direct oral anticoagulants, was associated with improved survival in melanoma patients undergoing TT. These findings support prospective trials evaluating AC as concomitant therapy in advanced melanoma.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116195"},"PeriodicalIF":7.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833441","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 : 2025-12-19DOI: 10.1016/j.ejca.2025.116194
Maria Vittoria Dieci , Grazia Vernaci , Chiara Colangelo , Emilio Bria , Davide Massa , Elisabetta Di Liso , Carlo Alberto Giorgi , Tommaso Giarratano , Davide Napetti , Giorgio Bonomi , Francesca Zanghì , Michele Bottosso , Elisabetta Lazzarini , Laura Santarelli , Andrea Boscolo Bragadin , Stefano Indraccolo , Valentina Guarneri
Background
Outcomes and characteristics of endocrine-resistant, PIK3CA-mutated HR+ /HER2- advanced breast cancer patients in real-world are poorly investigated.
Here, we explored the role of circulating PIK3CA mutations in endocrine-resistant patients in the ongoing prospective, multicentric CHAMBER study.
Methods
PIK3CA was analyzed by NGS panel covering the full exonic region of PIK3CA gene.
Endocrine resistance was defined as: i) primary: relapse during the first 2 years of adjuvant ET, or ii) secondary: relapse after 2 years of starting or within 1 year of completing ET.
Overall survival (OS) was calculated from the start of first-line to death from any cause. Progression free survival 1 (PFS1) was calculated from the start of first-line to progression or death.
Results
Among the overall CHAMBER population, 22 % patients met the criteria for endocrine-resistance (74/337).
The study population consisted in 95 % women and 5 % men; median age at diagnosis was 50 years (IQR 44–63); 75 % of the women was postmenopausal;86 % of the total population presented with a secondary endocrine-resistance, 64 % had visceral relapse, 74 % had less than 3 metastatic sites, 79 % had received first-line CDK4/6 inhibitor.
PIK3CA status was available for 63/74 pts, with a 29 % prevalence of mutation.
PIK3CAmut was a negative prognostic factor for OS (median 65 [wt] vs 36 months [mut], log-rank p 0.024 HR 2.61 [95 % CI 1.10–6.22]) and PFS1 (median 22 [wt] vs 10 months [mut], log-rank p 0.012, HR 2.24 [95 % CI 1.18–4.26]).
Conclusion
The co-occurrence of endocrine-resistance and PIK3CAmut identifies a population with unfavorable prognosis, reinforcing the rationale of escalated therapies.
现实世界中，内分泌抵抗、pik3ca突变的HR+ /HER2晚期乳腺癌患者的结局和特征研究很少。在这里，我们在正在进行的前瞻性多中心CHAMBER研究中探讨了循环PIK3CA突变在内分泌抵抗患者中的作用。方法采用覆盖PIK3CA基因全外显子区域的NGS面板对spik3ca进行分析。内分泌抵抗被定义为：i)原发性：在辅助ET治疗的前2年内复发，或ii)继发性：在开始ET治疗后2年或完成ET治疗后1年内复发。总生存期（OS）从一线开始计算到任何原因死亡。从一线开始至进展或死亡计算无进展生存期1 （PFS1）。结果在总体CHAMBER人群中，22 %的患者符合内分泌抵抗标准（74/337）。研究人群包括95% %的女性和5% %的男性；诊断时中位年龄为50岁（IQR 44-63）；75% %的妇女绝经后；86% %的患者出现继发性内分泌抵抗，64% %的患者内脏复发，74% %的患者转移部位少于3个，79% %的患者接受了一线CDK4/6抑制剂治疗。63/74名患者有PIK3CA状态，突变发生率为29% %。PIK3CAmut是OS（中位65 [wt] vs 36个月[mut]， log-rank p 0.024 HR 2.61[95 % CI 1.10-6.22]）和PFS1（中位22 [wt] vs 10个月[mut]， log-rank p 0.012, HR 2.24[95 % CI 1.18-4.26]）的负面预后因素。结论内分泌抵抗和PIK3CAmut的共同出现是一个预后不良的人群，加强了升级治疗的理由。
{"title":"PIK3CA mutations and first-line outcomes in endocrine-resistant HR+/HER2- metastatic breast cancer: A multicentric real-world study.","authors":"Maria Vittoria Dieci , Grazia Vernaci , Chiara Colangelo , Emilio Bria , Davide Massa , Elisabetta Di Liso , Carlo Alberto Giorgi , Tommaso Giarratano , Davide Napetti , Giorgio Bonomi , Francesca Zanghì , Michele Bottosso , Elisabetta Lazzarini , Laura Santarelli , Andrea Boscolo Bragadin , Stefano Indraccolo , Valentina Guarneri","doi":"10.1016/j.ejca.2025.116194","DOIUrl":"10.1016/j.ejca.2025.116194","url":null,"abstract":"<div><h3>Background</h3><div>Outcomes and characteristics of endocrine-resistant, PIK3CA-mutated HR+ /HER2- advanced breast cancer patients in real-world are poorly investigated.</div><div>Here, we explored the role of circulating PIK3CA mutations in endocrine-resistant patients in the ongoing prospective, multicentric CHAMBER study.</div></div><div><h3>Methods</h3><div>PIK3CA was analyzed by NGS panel covering the full exonic region of PIK3CA gene.</div><div>Endocrine resistance was defined as: i) primary: relapse during the first 2 years of adjuvant ET, or ii) secondary: relapse after 2 years of starting or within 1 year of completing ET.</div><div>Overall survival (OS) was calculated from the start of first-line to death from any cause. Progression free survival 1 (PFS1) was calculated from the start of first-line to progression or death.</div></div><div><h3>Results</h3><div>Among the overall CHAMBER population, 22 % patients met the criteria for endocrine-resistance (74/337).</div><div>The study population consisted in 95 % women and 5 % men; median age at diagnosis was 50 years (IQR 44–63); 75 % of the women was postmenopausal;86 % of the total population presented with a secondary endocrine-resistance, 64 % had visceral relapse, 74 % had less than 3 metastatic sites, 79 % had received first-line CDK4/6 inhibitor.</div><div>PIK3CA status was available for 63/74 pts, with a 29 % prevalence of mutation.</div><div>PIK3CAmut was a negative prognostic factor for OS (median 65 [wt] vs 36 months [mut], log-rank p 0.024 HR 2.61 [95 % CI 1.10–6.22]) and PFS1 (median 22 [wt] vs 10 months [mut], log-rank p 0.012, HR 2.24 [95 % CI 1.18–4.26]).</div></div><div><h3>Conclusion</h3><div>The co-occurrence of endocrine-resistance and PIK3CAmut identifies a population with unfavorable prognosis, reinforcing the rationale of escalated therapies.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116194"},"PeriodicalIF":7.1,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801951","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 : 2025-12-18DOI: 10.1016/j.ejca.2025.116193
Xiao Zhang , Jiaolin Zhou , Jianhao Geng , Yongheng Li , Fei Huang , Wenlong Shu , Wei Fu , Xin Zhou , Guoju Wu , Wenzhuo Jia , Jian Cui , Zhenjun Wang , Jiagang Han , Bohao Shi , Lifeng Li , Jinqiu Rui , Huadan Xue , Ke Hu , Tao Xu , Weijie Chen , Guole Lin
Background
Accurate risk stratification is essential to optimize neoadjuvant therapy for locally advanced rectal cancer (LARC) in the era of precision medicine. This study assessed the feasibility and safety of a circulating tumor DNA (ctDNA)-guided neoadjuvant strategy.
Methods
This interim analysis included patients with mid-low rectal adenocarcinoma (cT3–4N0M0 or cT1–4N1–2M0) from the multicenter, randomized CINTS-R trial using a 2:1 allocation to an experimental or control group. The control group received conventional nCRT (long-course radiotherapy with concurrent capecitabine followed by one XELOX cycle). In the experimental group, treatment was stratified as follows: (1) ctDNA-defined high-risk patients received TNT, consisting of the same nCRT followed by five additional XELOX cycles (six in total); (2) ctDNA-defined low-risk patients proceeded directly to surgery after nCRT; and (3) patients with dMMR/MSI-H/TMB-H tumors received neoadjuvant tislelizumab (≥6 cycles). The analysis focuses on feasibility and safety outcomes.
Results
Between February 2023 and September 2024, 349 patients were randomized and 316 included in analysis (experimental: 210; control: 106). Among the experimental group, 115 were ctDNA-high-risk and 89 ctDNA-low-risk. High-risk patients were significantly older and more often male, with larger tumors, longer tumor-to-anal verge distance, greater circumferential involvement, and higher EMVI rates (all p ＜0.05). Serious adverse events (SAEs, CTCAE v5.0, grade 3–4) occurred in 10.0 % vs. 6.6 % of patients in the experimental and control groups (p = 0.316). Notably, 15.7 % of TNT-treated patients discontinued chemotherapy due to SAEs, whereas all nCRT recipients completed treatment.
Conclusion
This interim analysis demonstrates the feasibility and safety of a ctDNA-guided, risk-adapted neoadjuvant strategy for LARC. Final outcomes will further clarify its clinical efficacy.
{"title":"Feasibility of ctDNA-guided precision neoadjuvant therapy in locally advanced rectal cancer: Insights from the ongoing CINTS-R trial","authors":"Xiao Zhang , Jiaolin Zhou , Jianhao Geng , Yongheng Li , Fei Huang , Wenlong Shu , Wei Fu , Xin Zhou , Guoju Wu , Wenzhuo Jia , Jian Cui , Zhenjun Wang , Jiagang Han , Bohao Shi , Lifeng Li , Jinqiu Rui , Huadan Xue , Ke Hu , Tao Xu , Weijie Chen , Guole Lin","doi":"10.1016/j.ejca.2025.116193","DOIUrl":"10.1016/j.ejca.2025.116193","url":null,"abstract":"<div><h3>Background</h3><div>Accurate risk stratification is essential to optimize neoadjuvant therapy for locally advanced rectal cancer (LARC) in the era of precision medicine. This study assessed the feasibility and safety of a circulating tumor DNA (ctDNA)-guided neoadjuvant strategy.</div></div><div><h3>Methods</h3><div>This interim analysis included patients with mid-low rectal adenocarcinoma (cT3–4N0M0 or cT1–4N1–2M0) from the multicenter, randomized CINTS-R trial using a 2:1 allocation to an experimental or control group. The control group received conventional nCRT (long-course radiotherapy with concurrent capecitabine followed by one XELOX cycle). In the experimental group, treatment was stratified as follows: (1) ctDNA-defined high-risk patients received TNT, consisting of the same nCRT followed by five additional XELOX cycles (six in total); (2) ctDNA-defined low-risk patients proceeded directly to surgery after nCRT; and (3) patients with dMMR/MSI-H/TMB-H tumors received neoadjuvant tislelizumab (≥6 cycles). The analysis focuses on feasibility and safety outcomes.</div></div><div><h3>Results</h3><div>Between February 2023 and September 2024, 349 patients were randomized and 316 included in analysis (experimental: 210; control: 106). Among the experimental group, 115 were ctDNA-high-risk and 89 ctDNA-low-risk. High-risk patients were significantly older and more often male, with larger tumors, longer tumor-to-anal verge distance, greater circumferential involvement, and higher EMVI rates (all <em>p</em> ＜0.05). Serious adverse events (SAEs, CTCAE v5.0, grade 3–4) occurred in 10.0 % vs. 6.6 % of patients in the experimental and control groups (<em>p</em> = 0.316). Notably, 15.7 % of TNT-treated patients discontinued chemotherapy due to SAEs, whereas all nCRT recipients completed treatment.</div></div><div><h3>Conclusion</h3><div>This interim analysis demonstrates the feasibility and safety of a ctDNA-guided, risk-adapted neoadjuvant strategy for LARC. Final outcomes will further clarify its clinical efficacy.</div></div><div><h3>Trial registration</h3><div>ClinicalTrials.gov identifier: NCT05601505.</div></div>","PeriodicalId":11980,"journal":{"name":"European Journal of Cancer","volume":"234 ","pages":"Article 116193"},"PeriodicalIF":7.1,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801952","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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