Variability in genomic alterations between right- and left-sided microsatellite stable (MSS) metastatic colorectal cancer and impact on survival.

Abstract

3534 Background: Metastatic colorectal cancers (mCRCs) with a right-sided primary site are associated with shorter survival and insensitivity to EGFR inhibitors compared to those originating in the left side of the colon or rectum. Methods: We performed targeted gene sequencing of 928 consecutive MSS mCRCs. Primary tumor site was divided into right-sided for cecum to distal transverse colon (n = 242), left-sided for splenic flexure to rectum (n = 673), or unknown colonic location (n = 13). Histologic subtypes were conventional (adenocarcinoma not otherwise specified), conventional with mucinous features ( < 50% mucinous), mucinous, signet ring, and poorly differentiated. To evaluate receptor tyrosine kinase (RTK) signaling, we analyzed ligand mRNA expression in TCGA. Results: Overall survival from time of metastasis was shorter for right-sided than left-sided primary site (survival at 5 years: 45% v 67%, p < 0.001). Right-sided tumors had more mutations (5.60 v 4.62 per MB, p < 0.001) but fewer copy-number changes (0.18 v 0.22 fraction genome altered, p = 0.001) compared to left-sided tumors. Alterations of KRAS, BRAF, PIK3CA, PTEN, AKT1, RNF43, and SMAD4 were significantly enriched in right-sided tumors, and of APC and TP53 in left-sided tumors. In a multivariate model, APC (HR = 0.7, p = 0.03), BRAF (HR = 3.7, p < 0.001), and KRAS (HR = 1.7, p < 0.01) alterations predicted for survival, but primary site did not (HR = 0.74, p = 0.07). Amphiregulin, epiregulin, neuregulin, and HGF expression was significantly higher in left-sided tumors. We found a higher proportion of conventional histology (83% v 63%) and moderate differentiation (82% v 69%) for left versus right-sided cases. Conclusions: We find that within MSS mCRC there are significantly more oncogenic mutations in right-sided tumors, and the difference in survival between right- and left-sided mCRC is primarily driven by differences in mutations. Left-sided tumors more commonly exhibit a “simpler” conventional histology that is lower grade and may rely on native RTK signaling, such as EGFR, for growth, providing a potential mechanism for the differential sensitivity to EGFR inhibitors seen by primary tumor site.