The significance of low-frequent RAS pathway mutated alleles and the optimal sensitivity cut-off in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of RAS panel using two commercial assays (Roche Cobas® and Qiagen Therascreen® pyrosequencing kit) and a highly-sensitive and quantitative digital PCR (dPCR).
Analysis of hotspots including RAS (KRAS/NRAS ex 2/3/4) and BRAF (ex 15) was analyzed in tumor FFPE samples from 585 mCRC patients treated with anti-EGFR (n = 252) or bevacizumab (n = 333) from trials and retrospective series from the TTD/RTICC Spanish network. Response rate (RR), progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutated allele fraction.
In patients treated with anti-EGFR 33% and 36% were positive for one mutation with the Cobas® and Therascreen® assays respectively. Analysis by dPCR increased to 45%. An inverse correlation between the fraction of mutated alleles and radiological response was observed (p
RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms in first-line setting.
Clinical trial identification
Legal entity responsible for the study
Spanish Cooperative Group for Digestive Tumour Therapy
F. Hoffmann-La Roche LTD
P. García Alfonso: Advisory role: Roche, Merck, Amgen, Sanofi, Lilly and Bayer. M. Valladares-Ayerbes: Consultant or advisory role: Amgen. Honoraria: Roche, Merck, Sanofi. E. Aranda: Advisory role from Amgen, Bayer, Celgene, Merck, Roche and Sanofi. R. Salazar: Research funding: Roche Pharma, Roche Diagnostics. All other authors have declared no conflicts of interest.