BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer

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 colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer 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 median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas 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.

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…In addition, a recent study showed that the BM1 subtype was more sensitive to the triplet therapy with dabrafenib, trametinib, and panitumumab, and had better clinical outcomes compared to the treatment of the BM2 subtype. The BM subtype was an independent predictive factor in the multivariate analysis that includes other immune-related signatures [191]. Whether the BM subtyping is a robust biomarker, it requires future validation to be determined.…”

Mutational profiles associated with resistance in patients with BRAFV600E mutant colorectal cancer treated with cetuximab and encorafenib +/− binimetinib or alpelisib

“…A total of six prior published clinical trials report molecular results of tumour tissue and circulating free DNA (cfDNA) in patients with BRAF V600E mutated metastatic CRC receiving therapies consisting of a backbone of BRAF and EGFR inhibition or BRAF inhibition monotherapy. 7 , 10 , 13 , 18 , 23 , 24 No difference in outcome was described between microsatellite stable and instable tumours in this cohort nor in literature. 7 , 12 , 13 The genetic alterations identified for acquired resistance arose in genes directly or indirectly activating signalling via the MAPK pathway or cross-linked pathways.…”

“… 17 A higher sensitivity for BRAF, MEK and EGFR inhibition with dabrafenib, trametinib and panitumumab was found in BM1. 18 These results suggest that BRAF V600E mutated CRC is indeed a heterogeneous disease with different molecular patterns, responses to and targets for therapy.…”

Paradox breaker BRAF inhibitors have comparable potency and MAPK pathway reactivation to encorafenib in BRAF mutant colorectal cancer

“…These data suggest that other reasons beyond pathway reactivation might limit the efficacy of BRAF inhibition in BRAF mutant CRC. We have recently reported that response rate, progression free survival and overall survival is significantly greater in BRAF mutant CRC patients with the BM1 transcriptional sub-type than the BM2 sub-type when treated with combined BRAF/MEK/EGFR inhibition [17]. BM1 is immunologically enriched compared with BM2 and this is likely to be pertinent to this differential efficacy [18,19].…”

“…As with the continued clinical development of BRAF inhibition in BRAF mutant cancers, the activity of PLX8394 should be investigated as part of a combination with other drugs that limit pathway reactivation such as MEK and EGFR inhibitors. However, the general strategy of targeting RAF dimerization in RAS/RAF mutant colorectal cancers is unlikely to qualitatively transform the outcomes with targeted therapies without appropriate attention to the unique biology of BRAF and KRAS mutant CRC [17,24,25]. The lack of confirmed objective responses in BRAF mutant CRC, in contradistinction to melanoma, to the RAF dimer inhibitor lifirafenib which inhibits all RAF isoforms as well as EGFR and KRAS supports this hypothesis [26].…”