Abstract 337P
Background
Colorectal cancer (CRC) is usually treated with oxaliplatin-based regimens in stages II, III and IV as standard of care. However, no predictive oxaliplatin biomarker has ever been fully validated despite intensive research. Here we aimed to discover a biomarker of early progression on oxaliplatin based chemotherapy with potential use in the clinic to guide therapy selection.
Methods
The COIN clinical trial was used as a discovery set selecting patients either on continuous or intermittent fluoropyrimidine chemotherapy combined with oxaliplatin. 3’RNAseq was successfully applied to primary CRCs from patients either progressing within the first 12 weeks (progressors, n=47) or progressing after 18 weeks (non-progressors, n=112). Validation was performed on two clinical trials profiled with Almac XCel microarray by the S:CORT consortium: FOCUS (N=359) and FOxTROT (N=93). The former is composed of stage IV CRCs randomised for 5FU/FA with or without oxaliplatin and the latter of high risk stage II and III CRCs treated with neoadjuvant FOLFOX.
Results
Analysis on COIN identified 29 differentially expressed genes comprising the new RNA signature. In the randomized FOCUS trial, this signature used as a continuous score in patients treated with single agent 5FU/FA (76 poor responders/211 good responders) did not show any signal (OR=1.09 (0.51-2.35), P=0.82). The FOLFOX arm was statistically underpowered (7 poor responders/67 good responders) but did show a trend in the expected direction (OR=3.25 (0.38-27.72), P=0.28) where the interaction with the 5FU/FA arm was not significant (OR=2.84 (0.14-57.07), P=0.49). In FOxTROT, using the endpoint pathological response post-treatment (69 progressors/24 non-progressors), the signature was significantly associated with poor response (OR=3.31 (1.03-10.60), P=0.04).
Conclusions
A new RNA signature has been generated and validated in high quality clinical trial CRC data identifying patients with early progression on oxaliplatin + 5FU/FA. Despite heterogeneity in the clinical settings used, this signature has the potential to provide useful information for oxaliplatin stratification in future clinical trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
S:CORT: Stratification for Colorectal Cancer Consortium.
Funding
S:CORT Consortium/ Cancer Research UK.
Disclosure
All authors have declared no conflicts of interest.