Colorectal cancer molecular markers and subtypes in relation to disease survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. Such biological heterogeneity reflects diversity in tumor etiology and has implications for survival. Previous studies have demonstrated a strong association between the presence of microsatellite instability (MSI) in CRC and longer disease-specific survival. The influence of other tumor markers, including the CpG island methylator phenotype (CIMP) and BRAF and KRAS mutation status, on survival is less clear. However, these four markers are correlated. Thus, consideration for these markers in combination, with recognition for the distinct etiologies those combinations may reflect, is important to further our understanding of CRC survival. We pooled data from 7 observational studies of CRC: the multisite Colon Cancer Family Registry (CCFR), the Cancer Prevention Study-II (CPS-II), the Diet Activity and Lifestyle Study (DALS), the Health Professionals Follow-Up Study (HPFS), the Nurses9 Health Study (NHS), the Melbourne Collaborative Cohort Study (MCCS), and The Cancer Genome Atlas (TCGA). All studies collected data on MSI, CIMP, and somatic mutation status for BRAF and KRAS. Participants with complete tumor marker data were classified into five subtypes based on tumor marker combinations previously proposed to reflect different etiologic pathways: Type 1 (MSI-high, CIMP+, BRAF-mutated, KRAS-wildtype); Type 2 (microsatellite-stable/low-instability (MSS/MSI-low), CIMP+, BRAF-mutated, KRAS-wildtype); Type 3 (MSS/MSI-low, non-CIMP, BRAF-wildtype, KRAS-mutated); Type 4 (MSS/MSI-low, non-CIMP, BRAF-wildtype, KRAS-wildtype); and Type 5 (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with disease-specific (DSS) and overall survival (OS) for each tumor marker individually (N=4727 to 5105) and for the above tumor marker combinations (N=118 to 2109); analyses were adjusted for age, sex, and study population. When considered individually, MSI-high status was associated with significantly longer (HR OS =0.74, HR DSS =0.39, p OS =1.11, HR DSS =1.31, p=0.04 and Type2 =1.73, p=0.002; HR Type3 =1.28, p=0.002) and those with Type 1 and 5 CRC had longer DSS (HR Type1 =0.30, p Type5 =0.46, p=0.003). Associations were similar for OS. In this large, collaborative study, CRC subtype classified by proposed etiologic pathways were associated with marked differences in survival. These findings highlight the clinical importance of molecular heterogeneity in CRC. Citation Format: Amanda I. Phipps, Peter T. Campbell, Barbara Banbury, Daniel Buchanan, Andrew T. Chan, Dallas English, Alton B. Farris, Graham G. Giles, Tabitha Harrison, Roger Milne, Polly A. Newcomb, Martha L. Slattery, Melissa Southey, Shuji Ogino, Ulrike Peters. Colorectal cancer molecular markers and subtypes in relation to disease survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4205.