Outcomes of Chemotherapy for Microsatellite Instable-High Metastatic Colorectal Cancers

Abstract

Purpose: Microsatellite instable-high (MSI-H) colorectal cancers (CRCs) are known to carry better survival in the local disease stage even without treatment. The influence of types of treatment on survival of MSI-H metastatic CRCs (mCRCs) is still unclear and is evaluated in this study.

Materials and methods: Patients with MSI-H mCRC treated with first-line chemotherapy, with or without bevacizumab, identified in the Israeli population-based Molecular Epidemiology of Colorectal Cancer (MECC) study, were diagnosed between 1998 and 2013 and followed up until May 2017; MSI status was determined by comparing 10 markers in tumor and normal tissue. Dates of metastases and death and treatment details were extracted from oncology records.

Results: Among 590 patients treated for mCRC, 106 (18%) had MSI-H tumors. Patients with MSI-H had a median overall survival (OS, from start of first-line treatment) of 1.6 years. The presence of a somatic B-Raf proto-oncogene (BRAF) mutation was a significant adverse prognostic factor in the MSI-H group (hazard ratio [HR], 1.8; 95% CI, 1.1 to 3.0; P = .026). MSI-H tumors without BRAF mutation (n = 87) had similar OS benefit from fluorouracil (FU) only as from any combination protocols (HR, 0.93; P = .78), whereas microsatellite-stable (MSS) tumors without BRAF mutation (n = 456) showed improved OS over FU-only regimens when combination chemotherapy with or without bevacizumab was used (HR, 0.58; P < .01; P value for interaction = .07). Patients with MSI-H/BRAF wild type (WT) had survival advantage over patients with MSS disease (adjusted HR, 0.58; 95% CI, 0.35 to 0.98) when treated with FU-only protocols.

Conclusion: Clinical outcomes differ substantially between patients with MSS/BRAF-WT mCRC and MSI-H/BRAF-WT mCRC, with measurable differences between chemotherapy regimens. MSI-H mCRCs are a clinically distinct subset of colorectal cancers. Their current poor outcome suggests that new clinical trials are needed to identify therapeutic options, potentially taking advantage of the new developments in the field of immunotherapy.

Fig 1.

Year of treatment onset by treatment protocol group in patients with metastatic colorectal cancer (n = 590). FU, fluorouracil.

Fig 2.

Overall survival according to tumor BRAF mutation status in treated patients with microsatellite-instable metastatic colorectal cancer in the Molecular Epidemiology of Colorectal Cancer study, northern Israel (n = 106).

Fig 3.

Overall survival of patients with microsatellite-instable, BRAF–wild type metastatic colorectal cancer by treatment groups in the in the Molecular Epidemiology of Colorectal Cancer study, northern Israel (n = 87). FU, fluorouracil.

Fig 4.

Effect of combination treatment on overall survival of patients with metastatic, BRAF–wild type colorectal cancer by microsatellite instability status in the Molecular Epidemiology of Colorectal Cancer study, northern Israel. (A) Microsatellite stable (n = 456). (B) Microsatellite instable (n = 87).