Phenotypic subtypes as a novel validated prognostic classification system for patients with colorectal cancer.

Abstract

625 Background: There has been enormous effort to develop a prognostic genomic classification of colorectal cancer (CRC). As a result, mismatch repair (MMR) status was established as a prognostic marker in addition to TNM-staging. Phenotypic subtypes were recently proposed that stratified patient survival, however their clinical utility had not been compared to other proposed classification systems including consensus molecular subtypes (CMS) or current prognostic markers including MMR status. Methods: Three patient cohorts, a pilot cohort of 237 stage I-III CRC patients, a validation cohort of 879 stage I-III CRC patients, and the AMC-AJCCII-90 cohort with 81 stage II colon cancer patients were utilised to investigate associations between phenotypic subtypes, MMR status, CMS and patient survival. Results: In the pilot cohort, phenotypic subtype stratified cancer-specific survival (P < 0.001). In the validation cohort, phenotypic subtype stratified overall (p = 0.003) and cancer-specific survival (CSS, p < 0.001) independent of tumour location. MMR status associated with right-sided colon cancer (p < 0.001), therefore further analysis was restricted to this subset of patient (n = 380). The immune subtype had the highest MMR deficiency (p = 0.001). Phenotypic subtype (p < 0.001) more effectively stratified CSS than MMR status (p = 0.023). Furthermore, in left-sided colon cancer (p = 0.007) and rectal cancer (p < 0.001) only phenotypic subtype stratified CSS. Phenotypic subtype and not MMR status was independently prognostic in the full cohort (p < 0.001) and right-sided colon cancer (p < 0.001). In the AMC-AJCCII-90 cohort phenotypic subtypes aligned with CMS (p < 0.001) and stratified overall survival better than CMS (p = 0.125 v p = 0.487 respectively). Conclusions: Phenotypic subtype is a more effective prognostic classification than CMS and MMR status. Phenotypic subtypes should be incorporated alongside MMR status as a clinical aid for the prognosis of patients with CRC.