Sex and outcomes of patients with microsatellite instability-high andBRAFV600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors
Authors: Nasca Vincenzo , Zhao Joseph , Ros Javier , Lonardi Sara , Zwart Koen , Cohen Romain , Fakih Marwan , Jayachandran Priya , Roodhart Jeanine M L , Derksen Jeroen , Intini Rossana , Bergamo Francesca , Mazzoli Giacomo , Ghelardi Filippo , Ligero Marta , Jonnagaddala Jitendra , Hawkins Nicholas , Ward Robyn L , Wankhede Durgesh , Brenner Hermann , Hoffmeister Michael , Vitellaro Marco , Salvatore Lisa , Gallois Claire , Laurent-Puig Pierre , Cremolini Chiara , Overman Michael J , Taieb Julien , Tougeron David , Andre Thierry , Kather Jakob Nikolas , Sundar Raghav , Carmona Javier , Elez Elena , Koopman Miriam , Pietrantonio Filippo 
Published: February 2025

BackgroundImmune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.MethodsIn this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients’ outcomes, overall and according toRAS-BRAFmutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We then investigated these associations also in two independent cohorts of patients with early-stage or advanced MSI-H CRC unexposed to ICIs. Finally, we explored two public microarray and RNA-seq datasets from patients with non-metastatic or metastatic MSI-H CRC to gain translational insights on the association between sex,BRAFstatus and immune contextures/ICI efficacy.ResultsAlthough no differences were observed between females and males either overall or in theBRAFwild-type cohort, male sex was associated with inferior progression-free survival (PFS) and overall survival (OS) in theBRAFmutated cohort (in multivariable models, HR for PFS: 1.79, 95% CI: 1.13 to 2.83, p=0.014, and for OS: 2.33, 95% CI: 1.36 to 3.98, p=0.002). Males receiving anti-PD-(L)1 monotherapy had the worst outcomes, with a 3-year PFS and 3-year OS of 23.9% and 41.8%, respectively, while the addition of anti-CTLA-4 agents rescued such a worse outcome. We also observed that females experienced a higher frequency of any-grade immune-related adverse events. Conversely, sex was not prognostic in the independent cohorts of patients with MSI-H CRCs not treated with ICIs. Exploratory transcriptomic analyses suggest that tumors of males withBRAFmutated MSI-H metastatic CRC are characterized by an enrichment of androgen receptor signature and an immune-depleted microenvironment, with a reduction in memory B cells, activated natural killer cells, and activated myeloid dendritic cells.ConclusionsOverall, our findings suggest a complex interplay between sex andBRAFmutational status that may modulate the activity of ICIs in patients with MSI-H mCRC and pave the way to novel tailored strategies.