Genomic analysis of germline variation associated with survival of colorectal cancer patients treated with chemotherapy plus biologics in CALGB/SWOG 80405 (Alliance).

Innocenti, Federico; Sibley, Alexander B; Patil, Sushant A; Etheridge, Amy S; Jiang, Chen; Ou, Fang-Shu; Howell, Stefanie; Plummer, Sarah J; Casey, Graham; Bertagnolli, Monica M; McLeod, Howard L; Auman, James T; Blanke, Charles D; Furukawa, Yoichi; Venook, Alan P; Kubo, Michiaki; Lenz, Heinz-Josef; Parker, Joel S; Ratain, Mark J; Owzar, Kouros

BACKGROUND Irinotecan/5-FU (FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in mCRC patients treated with these regimens in CALGB/SWOG 80405. METHODS Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for ~700,000 single-nucleotide polymorphisms (SNPs). The association between SNPs and overall survival (OS) was tested in 613 patients of genetically-estimated European ancestry using Cox proportional hazards models. RESULTS The four most significant SNPs associated with OS were three haplotypic SNPs between MGST1 and LMO3 (representative hazard ratios (HR) 1.56, p-value 1.30x10-6), and rs11644916 in AXIN1 (HR 1.39, p-value 4.26x10-6). AXIN1 is a well-established tumor suppressor gene in CRC, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 stage IV CRC patients from TCGA, rs11649255 in AXIN1 (in almost complete linkage disequilibrium (LD) with rs11644916), was associated with shorter OS (HR 2.24, p-value 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three CRC cell lines was reduced. CONCLUSIONS This is the first large GWAS ever conducted in mCRC patients treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 confers worse OS and the effect is replicated in TCGA. Further studies in CRC experimental models are required.