From clusters to clinic: An 8-gene signature combined with mucinous component stratifies benefit of anti-CTLA-4 addition to anti-PD-1 in dMMR/MSI-H metastatic colorectal cancer
Year: 2026
Type: article
Abstract: Background Around 15-50% of patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) experience primary and secondary resistance to immune checkpoint inhibitors (ICI). We previously described three transcriptomic clusters (A, B, C) linked to progression-free survival (PFS), with cluster A ("Stromal HIGH – Proliferation LOW" ) associated with the shortest PFS. Here we combine gene signature and mucinous phenotype to predict the benefit from anti-CTLA-4 plus anti-PD-1. Methods We used 3'RNA-sequencing data from pre-treatment samples of two independent cohorts of patients with dMMR/MSI-H mCRC treated with anti-PD-1±anti-LAG-3 ("Mono") or anti-PD-1+anti-CTLA-4 ("Combo"). A rank-based k-Top Scoring Pairs (k-TSP) classifier was trained in Cohort 1 (103 patients) to predict assignment to Cluster A versus B/C and validated in Cohort 2 (87 patients). Patients receiving an anti-PD-L1 and with ECOG ≥2 were excluded. We defined a composite stratum crossing Cluster k-TSP (A vs B/C) with mucinous component (present vs absent). Results Cluster A was enriched for mucinous tumors and had shorter PFS in both cohorts. The k-TSP selected four gene pairs predictive of Cluster A (YPEL2>H2AZ1, H6PD>COX7A2, STAT5B>SNRPE, ZHX3>TRAPPC4) and was validated in Cohort 2 with 68.1% balanced accuracy. In the pooled population (163 patients), the composite stratum × treatment interaction improved model fit (likelihood-ratio p≈0.04). Patients with Cluster k-TSP A + mucinous (25/163, 15.3%) derived advantage from Combo versus Mono: adjusted 24-month PFS 72.2% vs 13.8% (HR 0.10, 95% CI 0.02–0.39; p<0.001). Conclusions An 8-Gene signature combined with mucinous component identifies a subgroup that preferentially benefits from anti-PD-1+CTLA-4, warranting prospective validation to guide regimen selection in dMMR/MSI-H mCRC.
Source: European Journal of Cancer
Authors: Margherita Ambrosini, Claire Gallois, Annalice Gandini, Aurélie Lecanu, Emily Alouani, Filippo Pietrantonio, Francesca Bergamo, Chiara Cremolini, Thibault Mazard, David Tougeron, Rosine Guimbaud, Sara Lonardi, Janick Selves, Sophie Mouillet-Richard, Jean-Francois Emile, Julien Taieb, Pierre Laurent-Puig
Institutions: Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Fondazione IRCCS Istituto Nazionale dei Tumori, Inserm, Université Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, La Ligue Contre le Cancer, Centre National de la Recherche Scientifique, Université de Tours, Centre Hospitalier Universitaire de Tours, Hôpital Rangueil, Istituto Oncologico Veneto, University of Pisa, Université de Montpellier, Institut de Recherche en Cancérologie de Montpellier, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Universitaire de Toulouse, Université Paris-Saclay, Hôpital Ambroise-Paré, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,270
Funders: Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Association pour la Recherche sur le Cancer, Merck KGaA, Jazz Pharmaceuticals, Les Laboratories Pierre Fabre, BeiGene, Incyte, Advanced Accelerator Applications, Seagen, Natera, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, Astellas Pharma, Shionogi, Institut National Du Cancer, Servier, Ono Pharmaceutical, Ipsen, Italfarmaco, Nordic Pharma Group, Genentech, Daiichi Sankyo Europe
Award: G6212683837
OpenAlex ID: W7149947797