A large multicenter study evaluating prognosis and chemosensitivity of metastatic colorectal cancers with microsatellite instability.

Abstract

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.

LRP1 expression in colon cancer predicts clinical outcome

“…Indeed, stage II-III MSI CRC had a better prognosis than stage II-III MSS CRC. However, stage IV MSI CRC are associated with poor prognosis and chemoresistance, especially to 5FU-based chemotherapy [ 51 ]. Thus, the association of low LRP1 expression with MSI might explain the pejorative prognosis impact of low LRP1 expression on metastatic patients only.…”

Pharmacogenomics in colorectal cancer: current role in clinical practice and future perspectives

“…The role of MSI as a predictive marker with modern combination regimens, such as FOLFOX and FOLFIRI, has less evidence [ 87 – 89 ] , and although an MSI-H status was retrospectively shown to predict improved DFS with adjuvant irinotecan and 5-FU (IFL regimen) in the CALGB (Alliance) 89803 trial, these results were inconsistently demonstrated in other exploratory analyses [ 90 , 91 ] . In the metastatic setting, recent data suggest a greater activity of irinotecan in MSI-H mCRC and better outcomes in favor of bevacizumab treatment compared to anti-EGFRs [ 92 ] . Indeed, vascular endothelial growth factor (VEGF) is known to play a crucial role in tumor microenvironment immuno-modulation and anti-angiogenic treatment has been proposed as an effective modality to potentiate immunotherapy [ 93 ] .…”

Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer

“…In metastatic CRCs (mCRC), dMMR/MSI represents only around 3% to 5% of mCRCs and has been associated with poor prognosis and chemoresistance to standard treatment [9,10]. Nevertheless, recent series have reported prolonged overall survival in dMMR/MSI mCRC and a trend toward better outcomes of anti-vascular endothelial growth factor (anti-VEGF) as compared with anti-epidermal growth factor receptor (anti-EGFR), but no difference according to chemotherapy regimen, i.e., irinotecan-based chemotherapy as compared with oxaliplatin-based chemotherapy has been reported [11]. Finally, recent nonrandomized trials suggest high efficacy of immune checkpoint inhibitor (ICI) in chemoresistant dMMR/MSI metastatic tumors due to the high tumor mutational burden in these tumors, while the other predictor of response to ICI is the IHC labeling of the PD-L1 protein (programmed death-ligand 1) [12,13].…”