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

Cancer Med. 2019 Jul;8(7):3623-3635. doi: 10.1002/cam4.2205. Epub 2019 May 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / epidemiology*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Male
  • Microsatellite Instability*
  • Middle Aged
  • Mutation*
  • Neoplasm Staging
  • Population Surveillance
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Scandinavian and Nordic Countries / epidemiology

Substances

  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf