Investigating the clinical and molecular characteristics of class II and III BRAF mutations and their response to anti-EGFR therapy in MSS CRC: A comprehensive analysis.
Authors: Sahin Ibrahim Halil , Xiu Joanne , Khushman Moh'd M. , Palumbo Emily , Weinberg Benjamin Adam , Goel Sanjay , Akce Mehmet , Singhi Aatur D. , Gorantla Vikram , Lou Emil , Kasi Anup , Shields Anthony F. , Oberley Matthew James , Sledge George W. , Shen John Paul Y.C. , Saeed Anwaar , Tejani Mohamedtaki Abdulaziz 
Published: January 2025

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Background:
BRAF
mutations (mts) are a heterogeneous group of molecular alterations seen in colorectal cancer (CRC). Class I
BRAF
mts (V600) are known to be associated with aggressive biology to CRC, but the knowledge of clinical characteristics of class II and III
BRAF
mts is limited. In this large cohort analysis, we evaluated the clinical and molecular features of class II and III
BRAF
mts and performed comparative analyses for their impact on survival outcomes.
Methods:
A total of 24402 MSS CRC samples were profiled by NGS (592-gene, NextSeq; WES, WTS NovaSeq) (Caris Life Sciences, Phoenix, AZ).
BRAF
mts were detected by NGS and classified using published literature (1). MAPK pathway activity score (MPAS) was calculated using RNA expression data. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact, while post-treatment survival from first treatment to last contact. KM estimates were calculated for defined patient cohorts. Significance was determined as P<0.05.
Results:
A total of 1270, 134, and 327 patients with class I, II, and III
BRAF
mts were identified.
BRAF
mts overall and class I
BRAF
mts were significantly less common among younger pts (age<50) compared to patients ≥ 50 (4.7% vs. 7.4 %; P< 0.001 and 3.2% vs. 5.7%, respectively, P<0.001). Class I
BRAF
mts were enriched with consensus molecular subtype 1 (CMS1) (class I, II, and III: 46% vs. 14% vs. 18% respectively) while class II and III mts had more CMS2 subtype compared to class I (2%, 30% and 29%, p<0.05). Higher MPAS scores were noted among patients with class I
BRAF
mts than those with class II and III mts (1.73 versus 0.38 vs 0.79). Class I
BRAF
mts and KRAS mts were nearly mutually exclusive (0.5%), while KRAS mts were relatively common among class II and III mts (12.8% and 27.4%, respectively). Median OS for patients with wild-type
BRAF
, class I, II, and III
BRAF
mts were significantly different (29.8, 17.3, 21.8, and 24.6 months, respectively, p<0.01). Similar OS was seen among patients who did not receive anti-EGFR therapy (28.3, 15.2, 20.7- and 21.9 months P<0.001). Patients with class III mts had significantly better OS compared to patients with class I mts (HR=1.28 CI: 1.09-1.48 p=0.002), and while no significant difference was noted for patients with class II vs class I mts, numerically more favorable outcomes were noted (mOS 21.8 vs 17.3 months P=0.133). Among treated with anti-EGFR, patients with class II and III
BRAF
mts had numerically better post-anti-EGFR survival compared to class I mts; however, this was not statistically significant (21.2 vs 14.2 vs. 10.4 respectively P=0.3).
Conclusions:
Class II and III
BRAF
mts represent a distinct biological subgroup of MSS CRC with distinct prognoses. Class II and III
BRAF
mts are associated with improved survival outcomes compared to patients with class I mts. 1. Sahin et al. JCO OP 2021.