A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

Autor: Élez E; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Mulet-Margalef N; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Colorectal Cancer Unit, Medical Oncology Department, Catalan Institute of Oncology, L'Hospitalet de Llobregat, 08908 Barcelona, Spain., Sanso M; Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Genomics for Precision Oncology Laboratory, Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), 07120 Palma de Mallorca, Spain., Ruiz-Pace F; Oncology Data Science Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Mancuso FM; Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Research and Development Department, Universal Diagnostics S.L., 41013 Sevilla, Spain., Comas R; Oncology Data Science Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Ros J; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Departament of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 81100 Naples, Italy., Argilés G; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Martini G; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Departament of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, 81100 Naples, Italy., Sanz-Garcia E; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Baraibar I; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Salvà F; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Noguerido A; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Cuadra-Urteaga JL; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.; Medical Oncology, IOB-Hospital Quirón, 08023 Barcelona, Spain., Fasani R; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Garcia A; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Jimenez J; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Aguilar S; Molecular Prescreening Program, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Landolfi S; Department of Pathology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain., Hernández-Losa J; Department of Pathology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain., Braña I; Medical Oncology Department, Research Unit for Molecular Therapy of Cancer, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Nuciforo P; Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Dienstmann R; Oncology Data Science Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Tabernero J; Colorectal Cancer Program, Medical Oncology Department, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain., Salazar R; Colorectal Cancer Unit, Medical Oncology Department, Catalan Institute of Oncology, L'Hospitalet de Llobregat, 08908 Barcelona, Spain.; Medical Oncology Department, Catalan Institute of Oncology, Oncobell Program (IDIBELL), CIBERONC, L'Hospitalet de Llobregat, 08908 Barcelona, Spain., Vivancos A; Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Dec 21; Vol. 24 (1). Date of Electronic Publication: 2022 Dec 21.
DOI: 10.3390/ijms24010118
Abstrakt: The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group ( n : 9 patients) or IT-resistant group ( n : 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.
Databáze: MEDLINE
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