Consensus molecular subtypes and CRCassigner classifications in metastatic colorectal cancer (mCRC): Prognostic and predictive impact in the TRIBE2 study.

4016 Background: The TRIBE2 study (NCT02339116) recently demonstrated the superiority of upfront FOLFOXIRI/bevacizumab (bev) when compared to a pre-planned strategy of doublets/bev in molecularly unselected but mostly (74%) RAS/ BRAF mutant mCRC patients. The Consensus Molecular Subtypes (CMS) and CRCAssigner (CRCA) demonstrated prognostic value in multiple studies, but their predictive role has not been established so far. Given the poor prognosis associated with early stage mesenchymal/stem-like subtypes, we hypothesized that the CMS/CRCA classifiers could predict benefit from the upfront intensified strategy in patients included in the TRIBE2 study. Methods: Untreated formalin-fixed paraffin-embedded samples were classified into CMS/CRCA subtypes using a custom nCounter assay (NanoString Technologies). The impact of subtypes on progression free survival (PFS), progression free survival 2 (PFS2, defined as the time from randomization until the second evidence of disease progression) or overall survival (OS) was evaluated in the profiled population. Results: 426 and 428 (63%) patients enrolled in the TRIBE2 study were profiled according to CMS and CRCA classifications, respectively. The distribution of CMS/CRCA subtypes differed according to primary tumour site (both p < 0.001 for CMS/CRCA) and RAS/ BRAF mutational status (both p < 0.001 for CMS/CRCA). Significant associations of both CMS/CRCA classifiers with PFS, PFS2 and OS were demonstrated (Table). The effect of treatment intensification was independent of CMS subtypes (p for interaction for PFS/PFS2/OS: ns). Significant interaction effect between CRCA subtypes and treatment arm was reported in terms of PFS (p = 0.017), PFS2 (p = 0.010) and OS (p = 0.008). The benefit from the intensification of the upfront chemotherapy seemed more relevant in the stem-like (PFS, HR = 0.60; p = 0.03) and mixed subtypes (HR = 0.44; p = 0.002). Conclusions: CMS subtypes have a prognostic role in mCRC independently of RAS/ BRAF status. CRCA classification may help identifying subgroups of patients who may derive a more substantial benefit from upfront FOLFOXIRI/bev. [Table: see text]