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

Abstract

Purpose: BRAF mutations are grouped in activating RASindependent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and RAS-dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of V600E BRAFmutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design: Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test. Results: Class 3 BRAF-mutated mCRC was more frequently left sided (P ¼ 0.0028), pN0 (P ¼ 0.0159), and without peritoneal metastases (P ¼ 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61-3.54] for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P ¼ 0.033) compared with class 3 cases. Conclusions: For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity

“…We detected a rare class 3 BRAF D594G mutation in both the CRLM and PDO from patient 1. This mutation leads to RAS-dependent kinase inactivation and has been reported to associate with a different histopathology and a markedly longer overall patient survival than class 1 BRAF V600E mutations (55). The mutation is not a target for approved BRAF inhibitors, and accordingly the PDO did not show any response to encorafenib.…”

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

“…Different BRAF point mutations can affect the encoded protein function in many ways; most of them cluster to the conserved P loop and DFG motif of the kinase, destabilizing the inactive protein structure and thereby promoting an active conformation [34,36].…”

“…Hence, CRCs bearing non-V600 BRAF mutations constitute a distinct clinico-pathological subset, different from other BRAF mutations classes; indeed, class 2 and class 3 CRCs usually are non-mucinous, MSS, arise on the left side of younger male patients, have no peritoneal spread, lower grade at presentation and are related to a more favorable overall survival (OS) rates compared to both V600E BRAF mutants and wild-type CRCs [23,34,74].…”

“…Of note, many studies have demonstrated that the BRAF negative prognostic impact is often independent of the other considered clinico-pathological features [33]. This could be related to several factors: different BRAF mutations have different prognostic value [34]; CRC intratumor heterogeneity and the complex interactions with other molecular alterations can influence the therapeutic response; BRAF mutation in CRC is difficult to target and several resistance mechanisms have been discovered, but some of them still remain unknown; tumor stage can influence the prognostic value of BRAF mutations.…”

Colorectal cancer genomic biomarkers in the clinical management of patients with metastatic colorectal carcinoma

“…Alterations in class II or III are less frequent as compared to class I and account for 2.2% of all patients tested or 21.6% of all BRAF mutations in CRC [54]. Recent data suggest that class III BRAF mutations are associated with a favorable prognosis in patients with mCRC, while class II mutant cases seem to have an outcome similar to patients with class I BRAF mutations [54][55][56]. However, the limited number of cases included in these studies suggests that additional experimentation should be performed in this field.…”