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000298888 041__ $$aEnglish
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000298888 1001_ $$aNasca, Vincenzo$$b0
000298888 245__ $$aSex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors.
000298888 260__ $$aLondon$$bBioMed Central$$c2025
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000298888 520__ $$aImmune 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.In 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 to RAS-BRAF mutational 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, BRAF status and immune contextures/ICI efficacy.Although no differences were observed between females and males either overall or in the BRAF wild-type cohort, male sex was associated with inferior progression-free survival (PFS) and overall survival (OS) in the BRAF mutated 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 with BRAF mutated 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.Overall, our findings suggest a complex interplay between sex and BRAF mutational status that may modulate the activity of ICIs in patients with MSI-H mCRC and pave the way to novel tailored strategies.
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000298888 650_7 $$2Other$$aColorectal Cancer
000298888 650_7 $$2Other$$aImmune Checkpoint Inhibitor
000298888 650_7 $$2Other$$aMicrosatellite
000298888 650_7 $$2Other$$aMismatch repair - MMR
000298888 650_7 $$2NLM Chemicals$$aImmune Checkpoint Inhibitors
000298888 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProto-Oncogene Proteins B-raf
000298888 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aBRAF protein, human
000298888 650_2 $$2MeSH$$aHumans
000298888 650_2 $$2MeSH$$aColorectal Neoplasms: drug therapy
000298888 650_2 $$2MeSH$$aColorectal Neoplasms: genetics
000298888 650_2 $$2MeSH$$aColorectal Neoplasms: pathology
000298888 650_2 $$2MeSH$$aMicrosatellite Instability
000298888 650_2 $$2MeSH$$aImmune Checkpoint Inhibitors: therapeutic use
000298888 650_2 $$2MeSH$$aImmune Checkpoint Inhibitors: pharmacology
000298888 650_2 $$2MeSH$$aMale
000298888 650_2 $$2MeSH$$aProto-Oncogene Proteins B-raf: genetics
000298888 650_2 $$2MeSH$$aFemale
000298888 650_2 $$2MeSH$$aMiddle Aged
000298888 650_2 $$2MeSH$$aAged
000298888 650_2 $$2MeSH$$aMutation
000298888 650_2 $$2MeSH$$aSex Factors
000298888 650_2 $$2MeSH$$aNeoplasm Metastasis
000298888 650_2 $$2MeSH$$aAdult
000298888 7001_ $$aZhao, Joseph$$b1
000298888 7001_ $$aRos, Javier$$b2
000298888 7001_ $$00000-0002-7593-8138$$aLonardi, Sara$$b3
000298888 7001_ $$aZwart, Koen$$b4
000298888 7001_ $$00000-0001-9602-5162$$aCohen, Romain$$b5
000298888 7001_ $$00000-0002-6554-5488$$aFakih, Marwan$$b6
000298888 7001_ $$aJayachandran, Priya$$b7
000298888 7001_ $$aRoodhart, Jeanine M L$$b8
000298888 7001_ $$aDerksen, Jeroen$$b9
000298888 7001_ $$aIntini, Rossana$$b10
000298888 7001_ $$aBergamo, Francesca$$b11
000298888 7001_ $$aMazzoli, Giacomo$$b12
000298888 7001_ $$aGhelardi, Filippo$$b13
000298888 7001_ $$aLigero, Marta$$b14
000298888 7001_ $$aJonnagaddala, Jitendra$$b15
000298888 7001_ $$aHawkins, Nicholas$$b16
000298888 7001_ $$aWard, Robyn L$$b17
000298888 7001_ $$0P:(DE-He78)b1b2f6c878545eac4cbd9729d8c10b7d$$aWankhede, Durgesh$$b18$$udkfz
000298888 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b19$$udkfz
000298888 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b20$$udkfz
000298888 7001_ $$aVitellaro, Marco$$b21
000298888 7001_ $$aSalvatore, Lisa$$b22
000298888 7001_ $$aGallois, Claire$$b23
000298888 7001_ $$aLaurent-Puig, Pierre$$b24
000298888 7001_ $$aCremolini, Chiara$$b25
000298888 7001_ $$00000-0001-5377-135X$$aOverman, Michael J$$b26
000298888 7001_ $$00000-0002-9955-4753$$aTaieb, Julien$$b27
000298888 7001_ $$00000-0002-8065-9635$$aTougeron, David$$b28
000298888 7001_ $$00000-0002-5103-7095$$aAndre, Thierry$$b29
000298888 7001_ $$aKather, Jakob Nikolas$$b30
000298888 7001_ $$00000-0001-9423-1368$$aSundar, Raghav$$b31
000298888 7001_ $$aCarmona, Javier$$b32
000298888 7001_ $$00000-0002-4653-6324$$aElez, Elena$$b33
000298888 7001_ $$aKoopman, Miriam$$b34
000298888 7001_ $$00000-0002-8530-8420$$aPietrantonio, Filippo$$b35
000298888 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2024-010598$$gVol. 13, no. 2, p. e010598 -$$n2$$pe010598$$tJournal for ImmunoTherapy of Cancer$$v13$$x2051-1426$$y2025
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