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Ref Type Journal Article
PMID (33631043)
Authors Sahin IH, Goyal S, Pumpalova Y, Sonbol MB, Das S, Haraldsdottir S, Ahn D, Ciombor KK, Chen Z, Draper A, Berlin J, Bekaii-Saab T, Lesinski GB, El-Rayes BF, Wu C
Title Mismatch Repair (MMR) gene alteration and BRAF V600E mutation are potential predictive biomarkers of immune checkpoint inhibitors in MMR-deficient colorectal cancer.
Journal The oncologist
Vol
Issue
Date 2021 Feb 25
URL
Abstract Text Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC.Patient databases at 4 cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test.A total of 60 CRC patients with MMR-D/MSI-H who previously received ICI were identified. Patients with liver metastasis had a lower overall response rate (ORR) as compared to other sites of metastasis (36.4% vs 68.7%; P=0.081). Patients with MLH1/ PMS2 loss had worse 1-year and 2-year PFS rates compared to patients with MSH2/MSH6 loss (84.2% vs 57.8% and 78.2% vs 54.2%, respectively; p<0.001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared to patients with BRAF V600E mutation (73.3% vs 40%, and 73.3% vs 26.7%; respectively [P<0.001]). Patients aged >65 had significantly worse PFS rates as compared to patients aged ≤ 65 (P<0.001).BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis may be predictive of duration of ICI response in MMR-deficient CRC patients. Larger cohorts are needed to confirm our findings.This results of this original research article reveals clinically important biomarkers that potentially predict immune checkpoint inhibitor response in mismatch repair deficient colorectal cancer patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MSH6 loss colorectal cancer predicted - sensitive unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, treatment with Keytruda (pembrolizumab), Opdivo (nivolumab), or the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) in patients with mismatch repair-deficient colorectal cancer harboring MSH6 loss or MSH2 and MSH6 loss versus patients with PMS2 loss or MLH1 and PMS2 loss resulted in a similar objective response rate (60.0% vs. 70.6% ), but led to greater progression-free survival (PFS) rates (1-year PFS 84.2% vs. 57.8%, 2-year PFS 78.2% vs. 54.2%) (PMID: 33631043). 33631043
BRAF V600E colorectal cancer decreased response unspecified immune checkpoint inhibitor Clinical Study - Cohort Actionable In a retrospective analysis, treatment with Keytruda (pembrolizumab), Opdivo (nivolumab), or combination treatment with Opdivo (nivolumab) and Yervoy (ipilimumab) in patients with mismatch repair-deficient colorectal cancer harboring BRAF V600E vs. patients with wild-type BRAF resulted in a lower objective response rate (44.4% vs. 74.2%, p = 0.12) and shorter progression-free survival (PFS) rates (1-year PFS 40% vs. 73.3%, 2-year PFS 26.7% vs. 73.3%) (PMID: 33631043). 33631043