Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability, and CIMP status: Prognostic implications and response to chemotherapy.

Oscar Murcia,Miriam Juárez,Cecilia Egoavil,Miren Alustiza,Maria Rodriguez-Soler,Xavier Llor,Eva Hernández-Illán,Cristina Alenda,Adela Castillejo,Joan Clofent,Antoni Castells,Mar Giner-Calabuig,Luís Bujanda,Ana Yuste,Carolina Mangas,Rodrigo Jover,Victor Barberá,Montserrat Andreu,Pedro Zapater

doi:10.1200/jco.2018.36.4_suppl.668

Abstract

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

Highlights

Colorectal cancer (CRC) is one of the most prevalent neoplasms and an important cause of death in Western countries [1]
Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CpG island methylator phenotype (CIMP) positive exhibited the worst prognosis in univariate and multivariate
We confirmed the prognostic value of stratifying CRC according to molecular subtypes using microsatellite instability (MSI), CIMP status, and somatic KRAS and BRAF mutation

Summary

Introduction

Colorectal cancer (CRC) is one of the most prevalent neoplasms and an important cause of death in Western countries [1]. Studies demonstrating the role of immunotherapy in MSI tumours highlighted the importance of adequately classifying CRC patients in order to effectively provide the best molecular-based treatment [2]. We can classify CRC into five subtypes according to the described pathways of colorectal carcinogenesis [5] Studies have shown clinical and pathological differences between the subtypes, as well as relevant differences in prognosis [3,4,5,6,7]. As the molecular classification based on MSI, CIMP, BRAF, and KRAS [3] is simple and easy to apply, the aim of our study was to reproduce and validate this classification and investigate the response of each of subtypes to chemotherapy

Methods

Results

Conclusion