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Mol Cancer Ther. 2017 Sep;16(9):1999-2007. doi: 10.1158/1535-7163.MCT-17-0153. Epub 2017 Jun 16.

Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer.

Author information

1
Department of Medical Oncology, Catalan Institute of Oncology (ICO), Translational Research Laboratory, ICO-Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain.
2
Traslational Research Laboratory, ICO-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
3
Department of Medical Oncology, Hospital Doce de Octubre, CIBERONC, Madrid, Spain.
4
Department of Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain.
5
Department of Medical Oncology, Hospital Ramón y Cajal, IRYCIS, CIBERONC, Alcala University, Madrid, Spain.
6
Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
7
Department of Medical Oncology IMIBIC, Reina Sofía Hospital, University of Córdoba, Red Temática de Investigación Cooperativa en Cáncer (RTICC). Instituto de Salud Carlos III, Spain.
8
Department of Medical Oncology, Catalan Institute of Oncology, San Joan Despí, Barcelona, Spain.
9
Department of Medical Oncology, Del Mar University Hospital, Barcelona, Spain.
10
Department of Medical Oncology, Hospital General Universitario, Alicante, Spain.
11
Clinical Research Unit, ICO, L'Hospitalet, Barcelona, Spain.
12
Department of Pathology, Bellvitge University Hospital, L'Hospitalet, Barcelona, Spain.
13
Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, ICO - IDIBELL and CIBERESP, L'Hospitalet, Barcelona, Spain.
14
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Spain.
15
Department of Medical Oncology, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain.
16
Department of Medical Oncology, ICO, Badalona, Barcelona, Spain.
17
Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain.
18
Department of Medical Oncology IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC Instituto de Salud Carlos III, Spain.
19
CIBERONC Instituto de Salud Carlos III, Spain.
20
Department of Medical Oncology, Catalan Institute of Oncology (ICO), Translational Research Laboratory, ICO-Bellvitge Biomedical Research Institute (IDIBELL)-CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain. ramonsalazar@iconcologia.net.

Abstract

In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR- (n = 255) or bevacizumab- (n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen, and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti-EGFR cohort (P < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in RAS/BRAF wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario (HR = 1.53; CI 95%, 1.12-2.09 for PFS, and HR = 1.9; CI 95%, 1.33-2.72 for OS). Although the rate of mutations observed among techniques is different, RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. Mol Cancer Ther; 16(9); 1999-2007. ©2017 AACR.

PMID:
28626084
DOI:
10.1158/1535-7163.MCT-17-0153
[Indexed for MEDLINE]
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