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Class 1, 2, and 3 BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular

Marta Schirripa1, Paola Biason1, Sara Lonardi1

  • 1Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 11, 2019
PubMed
Abstract

Insights

This study classifies BRAF mutations in metastatic colorectal cancer (mCRC) into three distinct classes. Class 3 BRAF mutations show unique clinical features and improved survival compared to BRAF wild-type mCRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRAF mutations are key drivers in various cancers, including metastatic colorectal cancer (mCRC).
  • BRAF mutations are categorized into three classes based on RAS-independent or dependent signaling and kinase activity.
  • While Class 1 BRAF mutations (e.g., V600E) are well-characterized in mCRC, data on Class 2 and Class 3 mutations remain limited.

Purpose of the Study:

  • To investigate and compare the clinical, pathological, and molecular features of mCRC patients across the three distinct BRAF mutation classes.
  • To evaluate the impact of different BRAF mutation classes on overall survival (OS) and progression-free survival (PFS) in mCRC.
  • To provide a comprehensive analysis of BRAF mutation subclasses in mCRC, addressing a gap in current knowledge.

Main Methods:

  • Retrospective analysis of 117 patients with BRAF-mutated mCRC (Class 1: 92, Class 2: 12, Class 3: 13) and 540 BRAF wild-type (wt) mCRC controls.
  • Immunohistochemistry (IHC) profiling to determine Consensus Molecular Subtypes (CMS), cytokeratin profiles, and tumor-infiltrating lymphocyte (TIL) infiltration.
  • Kaplan-Meier analysis and log-rank tests to assess OS and PFS differences between BRAF mutation classes and BRAF wt mCRC.

Main Results:

  • Class 3 BRAF-mutated mCRC exhibited a higher frequency of left-sided tumors, pN0 status, and absence of peritoneal metastases compared to Class 1.
  • Overall survival hazard ratios relative to BRAF wt were: Class 1: 2.38, Class 2: 1.90, and Class 3: 0.93, indicating significantly worse survival for Class 1.
  • All Class 2 and Class 3 tumors were classified as CMS2-3, with Class 2 showing higher CD3/CD8+ TIL infiltration than Class 3.

Conclusions:

  • This study provides the first detailed comparison of clinical, pathological, and outcome data across the three BRAF mutation classes in mCRC.
  • Class 3 BRAF mutations are associated with distinct clinicopathological features and a more favorable prognostic profile than Class 1.
  • Future research should focus on developing specific targeted treatment strategies tailored to the unique characteristics of each BRAF mutation class in mCRC.

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