Association of colon cancer (CC) molecular signatures with prognosis and oxaliplatin prediction-benefit in the MOSAIC Trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer).

Abstract

3503 Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA (Colorectal Cancer Assigner) stem-like subtype were associated with a poor prognosis and no OX-benefit, but stage III patients with an enterocyte subtype did. We tested the association of CRCA and CMS molecular subtypes with prognosis and OX-benefit in stage III MOSAIC patients. Also, recombination proficiency scores (RPS) were tested for the same associations. RPS scores quantify the efficiency of DNA-damage repair. Low RPS have been associated with inferior overall survival (OS) in non-small cell lung carcinoma patients treated with surgery alone but better OS for patients who received surgery plus chemotherapy. Methods: Gene expression profiles from 590 stage III pts with follow up were successfully profiled by a custom designed nCounter code set. CRCA subtypes were determined by a locked down algorithm based on a re-estimated centroid using 72 genes (Song et al 2016). CMS subtypes were determined by modified single sample predictor (SSP) using 84 genes. RPS scores were determined as previously described by Pitroda et al (2014). Signature predictions were made while blinded to clinical outcome and signature performance was evaluated while blinded to gene expression. Results: The stem-like subtype was associated with a very poor prognosis (Stem-like vs others HR=1.56, p<0.01) and no OX-benefit. CRCA and CMS subtypes did not associate with OX-benefit. Using a median cut point, stage III patients with low RPS scores received significant OX-benefit (HR=0.67, p=0.033, N=290) and patients with high RPS scores did not (HR=1.2, p=0.32, N=300) with significant interaction p=0.025. Conclusions: The observation in C-07, that the stem-like subtype has the poorest prognosis and did not receive OX-benefit, was validated in MOSAIC, identifying patients who need new therapies. RPS scores may help to identify the subset of patients with OX-benefit in stage III CC, confirmation of this observation is currently being investigated in C-07. Support: PA DoH; NSABP; Sanofi.

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer

“…However, the results were not significant in terms of benefit with oxaliplatin in the CMS2 population. 57 …”

“…However, the results were not significant in terms of benefit with oxaliplatin in the CMS2 population. 57 In the metastatic setting, retrospective analyses of large clinical trials have been conducted to investigate an association between CMS groups and activity of cetuximab or bevacizumab. Both the CALGB-80405 and FIRE3 trials reported poor survival for patients with CMS1 tumors, intermediate survival for CMS4, and good outcomes associated with CMS2 across the two treatment arms.…”

Prognostic and predictive impact of consensus molecular subtypes and CRCAssigner classifications in metastatic colorectal cancer: a translational analysis of the TRIBE2 study

“…Oppositely, prognostic associations in the early and/or metastatic setting were found for both CMS and pre-consensus classifications including CRCA subtypes. [12][13][14]20 We therefore investigated whether gene expression subtypes could predict the benefit from two treatment strategies, rather than from individual targeted agents, with the hypothesis that an intensified upfront treatment could be especially useful for subtypes with poor prognosis. In order to focus on a homogeneous series, we selected only chemotherapy-naive primary tumors for our analysis.…”

Predictive modeling in colorectal cancer: time to move beyond consensus molecular subtypes

“…oxaliplatin, used in the vast majority of patients included in the CALGB study, is limited to tumors with a fibroblast-low microenvironment (CMS2/3). In this context, it is important to note inconsistent results in studies assessing CMS groups as predictors of benefit with oxaliplatin and irinotecan in the early-stage and metastatic settings, respectively [11,12]. In practice, the independent versus combinatorial effect of different chemotherapy agents and targeted drugs in the CMS framework is difficult to disentangle.…”

“…In order to better exploit CMS for therapy selection, we should exit the paradigm of CMS as a 'one marker fits all' tool to optimize the use of existing drugs. Different research groups are actively working to refine the transcriptomic analysis of CRC from the viewpoint of treatment efficacy prediction, such as the combination of CMS classification with a signature of DNA damage repair efficiency to model oxaliplatin benefit in the adjuvant setting [11]. The CMS classification should be a starting point to deepen our knowledge about CRC biology and the 'drivers' of metastatic progression that could support drug discovery and rational combination therapies.…”