Early-onset BRAF -mutant metastatic colorectal cancer: A distinct clinical and molecular signature.
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Le résumé fourni par la source
e15533 Background: BRAF V600E–mutant metastatic colorectal cancer (mCRC) is associated with poor prognosis and marked biological heterogeneity. Age at disease onset has emerged as a clinically relevant factor in colorectal cancer, but its influence on the biology of BRAF-mutant mCRC remains unclear. We examined whether early-onset (EO) and average-onset (AO) BRAF-mutant mCRC are biologically and clinically distinct subtypes. Methods: In a cohort of 1,209 metastatic colorectal cancer patients profiled by comprehensive next-generation sequencing and microsatellite stable (MSS), 234 BRAF V600E–mutant cases were identified. Patients were classified as early-onset (EO, ≤50 years; n = 73) or average-onset (AO, > 50 years; n = 161). Clinical characteristics, primary tumor location, first-line treatment, tumor mutational burden (TMB), co-mutation profiles, and overall survival (OS) were compared. Results: EO and AO patients had similar sex distribution and performance status. Primary tumor location differed significantly: EO tumors were more frequently left-sided and rectal (left-sided 77.5%, rectal 57.1%), whereas AO tumors were predominantly right-sided (51.0%, p = 0.00017). EO patients more often received intensive first-line therapy (FOLFOXIRI ± anti-VEGF: 47.9% vs 29.2%, p = 0.0087), but despite more intensive upfront treatment, they experienced significantly shorter OS (median 18.5 vs 26.1 months; log-rank p = 0.048). Molecular profiling revealed marked differences. EO tumors had significantly lower TMB (median 6.2 mut/Mb, IQR 4.0–8.9) compared with AO tumors (median 9.8 mut/Mb, IQR 6.1–14.7; p < 0.001) and fewer hypermutated cases. EO tumors were enriched for oncogenic alterations, including TP53 (82%), PIK3CA (48%), FBXW7 (26%) and PTEN (21%), consistent with a MAPK/PI3K-driven, genomically stable phenotype. In contrast, AO tumors showed higher frequencies of RNF43 (31%), APC (58%) and ARID1A (34%), consistent with a serrated, hypermutated molecular phenotype. Conclusions: Age at onset divides BRAF-mutant mCRC into two biologically and clinically distinct diseases. EO-BRAF tumours exhibit an oncogenic-driven, low-TMB profile associated with poorer survival despite more intensive chemotherapy, whereas AO-BRAF tumours show a serrated, hypermutated phenotype with longer survival. These findings emphasise intrinsic biological heterogeneity within BRAF-mutant mCRC and support age-informed molecular stratification in future clinical trials.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Early-onset <i>BRAF</i> -mutant metastatic colorectal cancer: A distinct clinical and molecular signature.
- Date Crossref
- 01/06/2026
- Éditeur
- American Society of Clinical Oncology (ASCO)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Cagliari Medical Oncology Unit pays non établi dans la noticeUniversité ou école supérieure
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Fondazione IRCCS Istituto Nazionale dei Tumori pays non établi dans la noticeÉtablissement de santé
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University of Pisa Unit of Medical Oncology 2 pays non établi dans la noticeUniversité ou école supérieure
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Azienda Ospedaliera Universitaria Pisana pays non établi dans la noticeÉtablissement de santé
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Istituto Oncologico Veneto pays non établi dans la noticeÉtablissement de santé
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Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
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Istituto Nazionale Tumori pays non établi dans la noticeInstitution
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Oncology Unit 1 pays non établi dans la noticeInstitution
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Veneto Institute of Oncology (IOV-IRCCS) Department of Oncology pays non établi dans la noticeStructure de recherche
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Medical Oncology Department pays non établi dans la noticeInstitution
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University of Padua Department of Surgery pays non établi dans la noticeUniversité ou école supérieure
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Veneto Institute of Oncology IOV–IRCCS Medical Oncology 1 pays non établi dans la noticeStructure de recherche
Medical Oncology Unit — University of Cagliari, Fondazione IRCCS Istituto Nazionale dei Tumori et Unit of Medical Oncology 2 — University of Pisa, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.