Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The oncologist			2021 Feb 25	668-675	Oncologist

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