PMID- 33293373 OWN - NLM STAT- MEDLINE DCOM- 20220120 LR - 20220120 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 27 IP - 4 DP - 2021 Feb 15 TI - Clinical Validation of a Machine-learning-derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer. PG - 1174-1183 LID - 10.1158/1078-0432.CCR-20-3286 [doi] AB - PURPOSE: FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC. EXPERIMENTAL DESIGN: A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset 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, progression-free survival, 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 patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-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, as well as pancreatic ductal adenocarcinoma. CONCLUSIONS: Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens. CI - (c)2020 American Association for Cancer Research. FAU - Abraham, Jim P AU - Abraham JP AD - Caris Life Sciences, Phoenix, Arizona. FAU - Magee, Daniel AU - Magee D AD - Caris Life Sciences, Phoenix, Arizona. FAU - Cremolini, Chiara AU - Cremolini C AD - Departments of Oncology and Translational Research and New Technologies in Medicine, University Hospital Pisa, Pisa, Tuscany, Italy. FAU - Antoniotti, Carlotta AU - Antoniotti C AD - Departments of Oncology and Translational Research and New Technologies in Medicine, University Hospital Pisa, Pisa, Tuscany, Italy. FAU - Halbert, David D AU - Halbert DD AD - Caris Life Sciences, Phoenix, Arizona. FAU - Xiu, Joanne AU - Xiu J AD - Caris Life Sciences, Phoenix, Arizona. FAU - Stafford, Phillip AU - Stafford P AD - Caris Life Sciences, Phoenix, Arizona. FAU - Berry, Donald A AU - Berry DA AD - Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Oberley, Matthew J AU - Oberley MJ AUID- ORCID: 0000-0001-6419-2513 AD - Caris Life Sciences, Phoenix, Arizona. FAU - Shields, Anthony F AU - Shields AF AUID- ORCID: 0000-0002-9122-1014 AD - Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. FAU - Marshall, John L AU - Marshall JL AUID- ORCID: 0000-0002-3449-2344 AD - Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. FAU - Salem, Mohamed E AU - Salem ME AD - Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina. FAU - Falcone, Alfredo AU - Falcone A AUID- ORCID: 0000-0001-5840-2529 AD - Departments of Oncology and Translational Research and New Technologies in Medicine, University Hospital Pisa, Pisa, Tuscany, Italy. FAU - Grothey, Axel AU - Grothey A AD - Medical Oncology, West Cancer Center, Germantown, Tennessee. FAU - Hall, Michael J AU - Hall MJ AD - Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. FAU - Venook, Alan P AU - Venook AP AUID- ORCID: 0000-0001-9749-6548 AD - Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California. FAU - Lenz, Heinz-Josef AU - Lenz HJ AUID- ORCID: 0000-0003-2178-9568 AD - University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California. FAU - Helmstetter, Anthony AU - Helmstetter A AD - Caris Life Sciences, Phoenix, Arizona. FAU - Korn, W Michael AU - Korn WM AUID- ORCID: 0000-0002-0124-6841 AD - Caris Life Sciences, Phoenix, Arizona. dspetzler@carisls.com wmkorn@carisls.com. FAU - Spetzler, David B AU - Spetzler DB AD - Caris Life Sciences, Phoenix, Arizona. dspetzler@carisls.com wmkorn@carisls.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Validation Study DEP - 20201208 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Biomarkers, Tumor) RN - 04ZR38536J (Oxaliplatin) RN - 2S9ZZM9Q9V (Bevacizumab) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use MH - Bevacizumab/pharmacology/*therapeutic use MH - Biomarkers, Tumor/*genetics MH - Clinical Trials as Topic MH - Colorectal Neoplasms/*drug therapy/genetics/mortality/pathology MH - Datasets as Topic MH - Drug Resistance, Neoplasm/genetics MH - Female MH - Follow-Up Studies MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Machine Learning MH - Male MH - Middle Aged MH - Models, Genetic MH - Oxaliplatin/pharmacology/*therapeutic use MH - Prognosis MH - Progression-Free Survival MH - Prospective Studies MH - Risk Assessment/methods MH - Young Adult EDAT- 2020/12/10 06:00 MHDA- 2022/01/21 06:00 CRDT- 2020/12/09 06:05 PHST- 2020/08/19 00:00 [received] PHST- 2020/10/30 00:00 [revised] PHST- 2020/12/03 00:00 [accepted] PHST- 2020/12/10 06:00 [pubmed] PHST- 2022/01/21 06:00 [medline] PHST- 2020/12/09 06:05 [entrez] AID - 1078-0432.CCR-20-3286 [pii] AID - 10.1158/1078-0432.CCR-20-3286 [doi] PST - ppublish SO - Clin Cancer Res. 2021 Feb 15;27(4):1174-1183. doi: 10.1158/1078-0432.CCR-20-3286. Epub 2020 Dec 8.