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Abraham JP , Magee D , Cremolini C , Antoniotti C , Halbert DD , Xiu J , Stafford P , Berry DA , Oberley MJ , Shields AF , Marshall JL , Salem ME , Falcone A , Grothey A , Hall MJ , Venook AP , Lenz HJ , Helmstetter A , Korn WM , Spetzler DB
Clinical validation of a machine-learning derived signature predictive of outcomes from first-line oxaliplatin-based chemotherapy in advanced colorectal cancer
Clin Cancer Res. 2021 Feb 15;27(4) :1174-1183
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PURPOSE: FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab (BV) are considered standard 1(st) line treatment options for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with BV in patients with mCRC. EXPERIMENTAL DESIGN: A machine-learning approach was applied and tested on clinical and NGS data from a real-world evidence (RWE) data set and samples from the prospective TRIBE2 study resulting in identification of a molecular signature - FOLFOXai Algorithm training considered time-to-next-treatment (TTNT). Validation studies used TTNT, PFS and overall survival (OS) as the primary endpoints. RESULTS: A 67 gene signature was cross-validated in a training cohort (N=105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated mCRC patients with increased benefit (IB) from those with decreased benefit (DB). The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/BV in 1(st) line and inversely predictive of survival in RWE data from 55 patients who had received 1(st) line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR=0.629, p=0.04 and FOLFOXIRI HR=0.483, p=0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers (EC/GEJC) as well as pancreatic ductal adenocarcinoma (PDAC). CONCLUSIONS: Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers since patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.
1557-3265 Abraham, Jim P Magee, Daniel Cremolini, Chiara Antoniotti, Carlotta Halbert, David D Xiu, Joanne Stafford, Phillip Berry, Donald A Oberley, Matthew J Orcid: 0000-0001-6419-2513 Shields, Anthony F Orcid: 0000-0002-9122-1014 Marshall, John L Orcid: 0000-0002-3449-2344 Salem, Mohamed E Falcone, Alfredo Orcid: 0000-0001-5840-2529 Grothey, Axel Hall, Michael J Venook, Alan P Orcid: 0000-0001-9749-6548 Lenz, Heinz-Josef Orcid: 0000-0003-2178-9568 Helmstetter, Anthony Korn, W Michael Orcid: 0000-0002-0124-6841 Spetzler, David B Journal Article United States Clin Cancer Res. 2020 Dec 8:clincanres.3286.2020. doi: 10.1158/1078-0432.CCR-20-3286.