High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort

Abstract

RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy-treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies.

Fig 1. Collection of tumor blocks and tissue micro array (TMA) availability in a population-base cohort of 798 cases with metastatic colorectal cancer (mCRC).

Fig 2

Overall survival in a population-based cohort of 798 metastatic colorectal cancer patients comparing patients with and without available cancer tissue for tissue microarray (TMA) analyses (Kaplan-Meier curves with log-rank test): A. Survival for all patients according to TMA availability (n = 798). Median survival for patients with no TMA was 7m vs 11m for patients with TMA available, p<0.001. B. Survival for patients treated with 1-line chemotherapy according to TMA availability (n = 457). Median survival for patients with no TMA was 12m vs 17m for patients with TMA available, p<0.001.

Fig 3. Survival in a population-based cohort of metastatic colorectal cancer patients with available tumor material for analyses of mutation status (mutBRAF, mutKRAS, wtKRAS/BRAF) (Kaplan-Meier curves with log-rank test).

A. Overall survival for all patients according to mutational status (n = 442). Median survival was 7 m for patients with mutBRAF, 12 m if mutKRAS and 14 m if wtKRAS/BRAF. *mutBRAF significantly different from wtKRAS/BRAF and mutKRAS. B. Overall survival in patients receiving chemotherapy according to mutational status (n = 275). Median survival was 12 m for mutBRAF, 18 m for mutKRAS and 21 m for wtKRAS/BRAF. *mutBRAF significantly different from wtKRAS/BRAF and mutKRAS. C. Progression free survival in patients receiving chemotherapy according to mutational status (n = 275), Median progression-free survival was 6.9 m for patients with mutBRAF, 7.1 m if mutKRAS and 8.9 m if wtKRAS/BRAF. D. Overall survival patients in good performance status (PS 0–1) and age< 75, comparing patients with wtKRAS/BRAF vs mutKRAS tumors (n = 178). Median survival was 18 m for patients with mutKRAS and 26 m for patients with wtKRAS/BRAF. Two patients with BRAF mutation status given chemotherapy were missing KRAS analyses.