Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors
Background Immune 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...
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2025-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| author | Michael Hoffmeister Hermann Brenner Chiara Cremolini Sara Lonardi Filippo Pietrantonio Julien Taieb David Tougeron Robyn L Ward Marco Vitellaro Thierry André Pierre Laurent-Puig Jitendra Jonnagaddala Francesca Bergamo Raghav Sundar Claire Gallois Michael J Overman Jakob Nikolas Kather Lisa Salvatore Romain Cohen Rossana Intini Priya Jayachandran Miriam Koopman Javier Ros Marwan Fakih Vincenzo Nasca Giacomo Mazzoli Jeanine M L Roodhart Filippo Ghelardi Elena Elez Durgesh Wankhede Marta Ligero Joseph Zhao Koen Zwart Jeroen Derksen Nicholas Hawkins Javier Carmona |
| author_facet | Michael Hoffmeister Hermann Brenner Chiara Cremolini Sara Lonardi Filippo Pietrantonio Julien Taieb David Tougeron Robyn L Ward Marco Vitellaro Thierry André Pierre Laurent-Puig Jitendra Jonnagaddala Francesca Bergamo Raghav Sundar Claire Gallois Michael J Overman Jakob Nikolas Kather Lisa Salvatore Romain Cohen Rossana Intini Priya Jayachandran Miriam Koopman Javier Ros Marwan Fakih Vincenzo Nasca Giacomo Mazzoli Jeanine M L Roodhart Filippo Ghelardi Elena Elez Durgesh Wankhede Marta Ligero Joseph Zhao Koen Zwart Jeroen Derksen Nicholas Hawkins Javier Carmona |
| author_sort | Michael Hoffmeister |
| collection | DOAJ |
| description | Background Immune 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.Methods 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.Results 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.Conclusions 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. |
| format | Article |
| id | doaj-art-58791d4fc73e47818e0735506b45d00c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-58791d4fc73e47818e0735506b45d00c2025-02-11T10:35:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-02-0113210.1136/jitc-2024-010598Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitorsMichael Hoffmeister0Hermann Brenner1Chiara Cremolini2Sara Lonardi3Filippo Pietrantonio4Julien Taieb5David Tougeron6Robyn L Ward7Marco Vitellaro8Thierry André9Pierre Laurent-Puig10Jitendra Jonnagaddala11Francesca Bergamo12Raghav Sundar13Claire Gallois14Michael J Overman15Jakob Nikolas Kather16Lisa Salvatore17Romain Cohen18Rossana Intini19Priya Jayachandran20Miriam Koopman21Javier Ros22Marwan Fakih23Vincenzo Nasca24Giacomo Mazzoli25Jeanine M L Roodhart26Filippo Ghelardi27Elena Elez28Durgesh Wankhede29Marta Ligero30Joseph Zhao31Koen Zwart32Jeroen Derksen33Nicholas Hawkins34Javier Carmona35Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, GermanyDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, GermanyUnit of Medical Oncology 2, Azienda Ospedaliero Universitaria Pisana, Pisa, ItalyMedical Oncology 1, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico, Padua, ItalyMedical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyDepartment of Digestive Oncology, Georges Pompidou European Hospital, Paris, FranceGastroenterology and Hepatology Department, University Hospital Centre Poitiers, Poitiers, FranceFaculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, AustraliaUnit of Hereditary Digestive Tract Tumours, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyDepartment of Medical Oncology, Saint-Antoine hospital, APHP, Sorbonne University, Paris, FranceCentre de Recherche des Cordeliers, INSERM, Sorbonne Université, Paris, Île-de-France, FranceSchool of Population Health, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, AustraliaMedical Oncology 1, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico, Padua, ItalyDepartment of Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USACARPEM, SIRIC, Université Paris Cité, Georges Pompidou European Hospital, Paris, FranceDepartment of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USAElse Kroener Fresenius Center for Digital Health, Technical University of Dresden, Dresden, GermanyCancer Comprehensive Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, ItalyDepartment of Medical Oncology, Saint-Antoine hospital, APHP, Sorbonne University, Paris, FranceMedical Oncology 1, Istituto Oncologico Veneto Istituto di Ricovero e Cura a Carattere Scientifico, Padua, ItalyOncology, University of Southern California, Los Angeles, California, USADepartment of Medical Oncology, Utrecht University, Utrecht, The NetherlandsMedical Oncology Department, Vall d’Hebron University Hospital, Barcelona, SpainMedical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center Duarte, Duarte, California, USAMedical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyMedical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyDepartment of Medical Oncology, Utrecht University, Utrecht, The NetherlandsMedical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyMedical Oncology Department, Vall d’Hebron University Hospital, Barcelona, SpainDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, GermanyElse Kroener Fresenius Center for Digital Health, Technical University of Dresden, Dresden, GermanyDepartment of Medicine, National University Hospital, SingaporeDepartment of Medical Oncology, Utrecht University, Utrecht, The NetherlandsDepartment of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSchool of Medical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, AustraliaVall d’Hebron Barcelona Hospital Campus, Barcelona, SpainBackground Immune 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.Methods 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.Results 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.Conclusions 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.https://jitc.bmj.com/content/13/2/e010598.full |
| spellingShingle | Michael Hoffmeister Hermann Brenner Chiara Cremolini Sara Lonardi Filippo Pietrantonio Julien Taieb David Tougeron Robyn L Ward Marco Vitellaro Thierry André Pierre Laurent-Puig Jitendra Jonnagaddala Francesca Bergamo Raghav Sundar Claire Gallois Michael J Overman Jakob Nikolas Kather Lisa Salvatore Romain Cohen Rossana Intini Priya Jayachandran Miriam Koopman Javier Ros Marwan Fakih Vincenzo Nasca Giacomo Mazzoli Jeanine M L Roodhart Filippo Ghelardi Elena Elez Durgesh Wankhede Marta Ligero Joseph Zhao Koen Zwart Jeroen Derksen Nicholas Hawkins Javier Carmona Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors Journal for ImmunoTherapy of Cancer |
| title | Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| title_full | Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| title_fullStr | Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| title_full_unstemmed | Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| title_short | Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| title_sort | sex and outcomes of patients with microsatellite instability high and braf v600e mutated metastatic colorectal cancer receiving immune checkpoint inhibitors |
| url | https://jitc.bmj.com/content/13/2/e010598.full |
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