Clinical, Pathological and Prognostic Features of Rare BRAF Mutations in Metastatic Colorectal Cancer (mCRC): A Bi-Institutional Retrospective Analysis (REBUS Study).

Maria Alessandra Calegari,Michele Basso,Alessandra Auriemma,Lisa Salvatore,Armando Orlandi,Fiorella Lombardo,Marta Ribelli,Maurizio Martini,Brunella Di Stefano,Alessandra Cocomazzi,Emilio Bria,Ina Valeria Zurlo,Raffaella Vivolo,Maria Bensi,Floriana Camarda,Giampaolo Tortora,Alessandra Boccaccino,Michele Milella,Carmelo Pozzo

doi:10.3390/cancers13092098

Maria Alessandra Calegari, Michele Basso + Show 17 more

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https://doi.org/10.3390/cancers13092098

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Abstract

Simple SummarySomatic BRAF mutations occur in approximately 10% of metastatic colorectal cancers (mCRCs) and, according to the involved codon, are classified as V600E and in non-V600, accounting for 80% and 20%, respectively. Being the most frequent mutation, the BRAF V600E mutation has been extensively investigated and up to now its clinical, pathological and molecular phenotype and its prognostic impact have been clearly described. On the contrary, evidence concerning BRAF non-V600 is weaker. We retrospectively evaluated 537 mCRC patients treated at two Italian Institutions. This study corroborates and strengthens available evidence concerning phenotype and prognostic performance of BRAF non-V600 compared to BRAF V600E and BRAF wild-type mCRCs. This deeper insight on rare BRAF non-V600 mutated mCRC is a primary issue in the precision oncology era, since the wider application of NGS is expected to increase the identification of those aberrations.Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age < 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.

Highlights

IntroductionSomatic BRAF mutations occur in approximately 10% of metastatic colorectal cancers (mCRCs) [1,2]
Somatic BRAF mutations occur in approximately 10% of metastatic colorectal cancers [1,2].Of those, V600E missense mutation (BRAF V600E) represents the most frequent, being the most investigated
Our results provide a deeper insight on BRAF-mutated metastatic colorectal cancers (mCRCs), enlarging evidence on clinical, pathological and prognostic features of this rare entity

Summary

Introduction

Somatic BRAF mutations occur in approximately 10% of metastatic colorectal cancers (mCRCs) [1,2]. V600E missense mutation (BRAF V600E) represents the most frequent (accounting for around 80% [3]), being the most investigated. Its predictive role toward anti-EGFRs, either as monotherapy or in combination with chemotherapy, is still debated and some evidence leans toward a negative role [9,17,18]. In mCRC setting, single-agent anti-BRAF target therapy did not show efficacy, due to the ability of neoplastic cells to activate alternative pathways in response to the sole BRAF inhibition [19]. Recent evidence shows that BRAF V600E can be effectively targeted by a combination of anti-EGFR and anti-BRAF agents [20,21,22]

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