BRAF-mutant transcriptional subtypes predict outcome of combined BRAF, MEK, and EGFR blockade with dabrafenib, trametinib, and panitumumab in patients with colorectal cancer

Research output: Contribution to journalArticle

Authors

  • Yiqun Yang
  • Catarina D Campbell
  • Thierry André
  • Chloe E Atreya
  • Jan H M Schellens
  • Takayuki Yoshino
  • Johanna C Bendell
  • Antoine Hollebecque
  • Autumn J McRee
  • Salvatore Siena
  • Michael S Gordon
  • Josep Tabernero
  • Rona Yaeger
  • Peter J O'Dwyer
  • Filip De Vos
  • Eric Van Cutsem
  • John M Millholland
  • Jan C Brase
  • Fatima Rangwala
  • Eduard Gasal
  • Ryan B Corcoran

Colleges, School and Institutes

Abstract

PURPOSE: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E-mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with CRC.

EXPERIMENTAL DESIGN: Paired fresh tumour biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM CRC enrolled in a Phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).

RESULTS: Confirmed response rates, median PFS, and overall survival (OS) were higher in BM1 subtype patients compared to BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, while cell cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell cycle signatures revealed that BM subtype encompasses the majority of the effect.

CONCLUSIONS: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.

Details

Original languageEnglish
JournalClinical Cancer Research
Early online date11 Feb 2020
Publication statusE-pub ahead of print - 11 Feb 2020