Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients

Abstract

Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

Keywords: B-raf; KRAS protein; colorectal neoplasm; microsatellite instability; neoplasm metastasis; prognosis; proto-oncogene proteins.

Figure 1

Mutation status in a population‐based Scandinavian cohort of metastatic colorectal cancer: (A) Venn diagram illustrating KRAS, BRAF and MSI status in primary tumors of patients in the TMA cohort with analysis available (n = 428), (B) Distribution of BRAF/MSI subgroups in patients with sufficient material for these analyses (n = 569), (C) Incidence (%) of BRAF mutations in MSI‐H tumors in the Scandinavian prospective colorectal cancer cohort (SPCRC) (n = 40) compared to recently published immunotherapy trials by Le et al 2015 (n = 21), Overman et al 2017 (n = 74) and Overman et al 2018 (n = 119)

Figure 2

Survival in a population‐based Scandinavian cohort of patients with metastatic colorectal cancer according to MSI status. Kaplan‐Meier curves was calculated with log‐rank test for p‐value and univariate Cox regression for HR and 95% CI. A, Median overall survival for all patients with MSI status was 6 mo for patients with MSI‐H tumors and 11 mo for patients with MSS tumors. B, Median overall survival in patients given first‐line chemotherapy was 9 mo for patients with MSI‐H tumors and 18 mo for patients with MSS tumors. C, Median progression free survival in patients given first‐line chemotherapy was 4 mo for patients with MSI‐H tumors and 8 mo for patients with MSS tumors. n, number of patients; e, number of events, HR, Hazard Ratio, CI, confidence interval

Figure 3

Frequency of molecular alterations and survival data after first‐line chemotherapy in a Scandinavian population‐based cohort of metastatic colorectal cancer (SPCRC) with suggestions on choice of treatment for the specific patient groups. Double wildtype, BRAF and KRAS wildtype; mutBRAF, BRAF mutation; mutKRAS, KRAS mutation; MSI‐H, microsatellite instability‐high; OS, median overall survival; PFS, median progression‐free survival; CI, confidence interval; †) after first‐line chemotherapy

Figure 4

Survival in a population‐based Scandinavian cohort of metastatic colorectal cancer patients according to MSI and BRAF status. Kaplan‐Meier curves was calculated with log‐rank test for p‐value and univariate Cox regression for HR and 95% CI. A, Median overall survival for patients with MSS tumors was 8 mo if mutBRAF and 12 mo if wtBRAF. B, Median overall survival for patients with MSI‐H tumors was 6 mo if mutBRAF and 2 mo if wtBRAF. C, Median overall survival for patients with BRAF‐wildtype tumors was 2 mo if MSI‐H and 12 mo if MSS. D, Median overall survival for patients with BRAF‐mutated tumors was 6 mo if MSI‐H and 8 mo if MSS. E, Median overall survival for all patients in subgroups of MSI and BRAF status. F, Median overall survival for patients given first‐line chemotherapy. G, Median progression free survival for patients given first‐line chemotherapy. n, number of patients; e, number of events