Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Abstract

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.

Distant Metastasis in Colorectal Cancer Patients—Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review

“…In mCRC, the dMMR/MSI phenotype (around 5% of mCRCs) is associated with worse prognosis and chemoresistance [ 95 , 97 ]. However, recent studies have reported prolonged OS in dMMR/MSI mCRC after anti-vascular endothelial growth factor (anti-VEGF) treatment, as compared with anti-EGFR, however without change in survival conferring to chemotherapy regimen, i.e., irinotecan-based chemotherapy, in contrast to oxaliplatin-based chemotherapy [ 98 ]. Finally, recent nonrandomized trials point to the high efficacy of the immune checkpoint inhibitor in dMMR/MSI chemo-resistant mCRC as a reason for the high tumor mutational burden.…”

“…Both immunological and molecular markers seem to provide promising prognostic and predictive information in distant metastasis, but this topic warrants further research [ 93 , 94 , 98 ].…”

Molecular Targets for the Treatment of Metastatic Colorectal Cancer

“…Data are more controversial in metastatic setting. Still, the available literature suggests MSI/dMMR mCRC are less responsive to conventional chemotherapy, compared to microsatellite stable/MMR-proficient (MSS/pMMR) tumors [ 43 , 81 , 82 , 83 ].…”

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

“…Furthermore, BRAF mutations are significantly more common in MSI rather than in MSS CRC (34% vs. 6% of cases) [ 28 ]. MSI metastatic CRC are characterized by poorer prognosis, and they are usually resistant to common cytotoxic and targeted agents [ 24 , 29 , 30 ]. Interestingly, while MSS mCRCs exhibit primary resistance to CPIs, MSI mCRC are greatly sensitive to CPIs [ 16 , 31 , 32 ].…”