Immunotherapy in mismatch repair-deficient metastatic colorectal cancer - Outcome and novel predictive markers

EUROPEAN JOURNAL OF CANCER(2024)

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Abstract
Background: This study aims to assess predictive markers for response to immunotherapy in dMMR/MSI-H metastatic colorectal cancer (mCRC) patients. Materials and methods: A study using two prospective cohorts from MD Anderson Cancer Center and Sheba Medical Center of consecutive patients with dMMR/MSI-H mCRC that were treated with immunotherapy between 2014-2022. Primary outcome was progression-free survival (PFS) and secondary outcome was overall response rate (ORR). Evaluated predictors included ECOG-PS score, RAS/BRAF status, single-agent versus doublet immunotherapy, metastatic sites, disease burden, and CEA levels prior to treatment initiation. KaplanMeier analysis and Cox proportional hazard regression model were used to analyze the effect of exposure variables on PFS. Results: The study included 153 patients. Median follow-up time was 26 months (IQR 11-48). Median PFS was 51.6 months (95%CI 38.1-NR) and ORR was 58.1%. In a univariate analysis, male sex was associated with worse PFS with a HR of 1.67 (95% CI 1.00-2.79); Right-sided tumors were associated with improved PFS with a HR of 0.56 (95% CI 0.32-0.97); Liver or lung metastasis were associated with worse PFS with HRs of 2.35 (95%CI 1.43-3.88) and 2.30 (95%CI 1.31-4.04), respectively; ECOG-PS score >= 2, CEA levels >5 mu g/L prior to treatment initiation and >= 3 metastatic sites were associated with worse PFS with HRs of 2.09 (95%CI 0.98-4.47), 2.23 (95%CI 1.30-3.81) and 3.11 (95%CI 1.61-6.03), respectively. Liver or lung metastasis remained significant in a multivariable model. Conclusions: Extent of disease (worse PFS with high CEA, poor ECOG-PS and >= 3 metastatic sites) and disease location (worse PFS with liver or lung metastasis and left sided tumor) were associated with immunotherapy outcome in dMMR/MSI-H mCRC.
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Key words
Immunotherapy,DMMR,MSI-H,MCRC,Liver metastasis,Lung metastasis
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