Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically Additional Supporting Information may be found in the online version of this article. ratio; ICI: immune checkpoint inhibitors; IHC: immunohistochemistry; IPTW: inverse of probability of treatment weighting; mCRC: metastatic CRC; MSI: microsatellite instability; OS: overall survival; PFS: progression-free survival; pMMR: proficient mismatch repair; RR: response rate Tumor Markers and Signatures significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00-3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.What's new? Some reports suggest short overall survival (OS) and chemoresistance of mismatch repair-deficient and/or microsatellite instability-high metastatic colorectal cancers (dMMR/MSI mCRC). In a large multicenter series of dMMR/MSI mCRC we observed a relatively long OS but short progression-free survival. Irinotecan-based chemotherapy was not associated with better OS than oxaliplatin-based chemotherapy but anti-VEGF, as compared to anti-EGFR, was associated with a trend to longer OS. These results could help clinicians to choose treatment in patients with dMMR/MSI mCRC.

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3536 Background: Deficient Mismatch Repair (dMMR) in colorectal cancers (CRC) represent 12% of all tumors. In non-metastatic CRC setting, dMMR are associated with good prognosis but also with resistance to adjuvant 5-FU chemotherapy. In metastatic CRC (mCRC) setting, dMMR is found in less than 5% and its influence on prognosis and treatment response is little known. Methods: This multicenter retrospective study included all consecutive patients with dMMR mCRC treated between 2005 and 2015 in 17 centers. The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Prognostic variables were evaluated in univariate analysis using the Log rank test and in multivariate analysis using the Cox regression model. Results: A total of 198 patients with dMMR mCRC were included (median age 64.6 years). dMMR mCRC were mostly diagnosed with synchronous metastases (59%) and frequent peritoneal carcinosis (43%). Lynch syndrome was found in 34% of cases and 36% of tumors had a BRAFV600E mutation. Median OS was 20.6 months. A low risk Kohne's prognostic index (HR = 0.40 [0.22-0.72], p = 0.02) and absence of peritoneal carcinosis (HR = 0.51 [0.29-0.90], p = 0.02) were associated with better OS in multivariate analysis. Main first-line regimens were 5FU-based (n = 20), oxaliplatin-based (n = 75) or irinotecan-based (n = 46) chemotherapy. Median PFS on first-line treatment was 5.9 months. The objective response rate (ORR) was 0%, 19% and 36% for 5FU-based, oxaliplatin-based and irinotecan-based chemotherapies, respectively (p = 0.02). A trend for a longer PFS (3.3, 5.5 and 10.2 months, respectively, p = 0.06) and OS (17.7, 21.1 and 34.2 months, respectively, p = 0.05) was also observed for irinotecan-based chemotherapy. The addition of bevacizumab to chemotherapy was associated with a significant increase of ORR (p = 0.01) and PFS (p = 0.04) as compared to the addition of an anti-EGFR therapy. Conclusions: This study suggests that dMMR mCRC are associated with poor prognosis and chemoresistance, especially to 5FU-based chemotherapy. Efficacy of irinotecan and bevacizumab should be evaluated in a prospective trial in combination with immune checkpoint inhibitors.