The genomic landscape and its prognostic significance for stage III colorectal cancer in Japan: An ancillary study of JCOG0910 trial—JCOG1506A1.

Abstract

3607 Background: To date, large-scale genomic sequencings of colorectal cancers (CRC) have been reported mainly from Western countries. However, ethnic diversities, differences by stage, and the prognostic impact of the genomic landscape in CRC remain poorly identified. Methods: The subjects were 534 patients (pts) with stage III CRC from the JCOG0910 study—a randomized phase-III trial conducted in Japan on 1564 pts to assess the efficacy of S-1 versus capecitabine as adjuvant chemotherapy. Targeted-capture sequencing of 171 potentially CRC-associated genes was performed on both normal tissue and tumor samples, and somatic single-nucleotide variants and insertion/deletions were determined. Tumors with MSIsensor scores > 7 and ultra-mutated tumors with POLE mutations were grouped as hypermutated tumors. Genes whose alterations were associated with recurrence-free survival (RFS) were evaluated using multivariable Cox regression models. Results: Of the 534 pts (right-sided: 184, left-sided: 350), 109 pts had recurrences or died during the study. Mutation frequencies were as follows: TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%) (right: 14.1%, left: 1.4%). None of the 49 genes with mutation frequencies > 3% showed a significant association with RFS based on Bonferroni’s adjustment for multiple testing. The following modest associations were observed: mutant KRAS [HR, 1.66; p=0.011] and mutant RNF43 [HR, 2.17; p=0.055] had poorer RFS, whereas mutant COL6A3 [HR, 0.35; p=0.040] and mutant NOTCH3 [HR, 0.18; p=0.093] had better RFS. RFS tended to be better for hypermutated than for non-hypermutated tumors [HR, 0.53; p=0.229]. Conclusions: The overall mutation spectrum of our stage III CRC cohort was generally similar to that of the Cancer Genome Atlas (TCGA). However, the mutation frequencies of TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations seemed to impact RFS, indicating that tumor genomic profiling has a high potential to support precision medicine for pts with CRC.