A randomized phase II study of coexpression extrapolation (COXEN) with neoadjuvant chemotherapy for bladder cancer (SWOG S1314; NCT02177695).

Dose-dense Methotrexate-Vinblastine-Adriamycin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). The aim of this study was to validate the score from a Coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy.

Eligibility included cT2-T4a N0 M0, urothelial BC, {greater than or equal to} 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective assessed pre-specified dichotomous treatment specific COXEN score as predictive of pT0 rate or {less than or equal to} pT1 (downstaging) at surgery.

Among 167 evaluable patients, the odds ratio for pT0 with the GC GEM score in GC-treated patients was 2.63 (p=0.10; 95% CI [0.82,8.36]); for the ddMVAC COXEN GEM score with ddMVAC treatment, the OR was 1.12 (p=0.82, 95% CI [0.42, 2.95]). The GC GEM score was applied to pooled arms (GC and ddMVAC) for downstaging with an OR of 2.33 (p=0.02; 95% CI [1.11, 4.89]). In an intention to treat analysis of eligible patients (n=227), pT0 rates for ddMVAC and GC were 28% and 30% (p = 0.75); downstaging was 47% and 40% (p = 0.27), respectively.

Treatment-specific COXEN scores were not significantly predictive for response to individual chemotherapy treatment. The COXEN GEM GC score was significantly associated with downstaging in the pooled arms. Additional biomarker development is planned.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Feb 10 [Epub ahead of print]

Thomas W Flaig, Catherine M Tangen, Siamak Daneshmand, Ajjai S Alva, Seth P Lerner, M Scott Lucia, David J McConkey, Dan Theodorescu, Amir Goldkorn, Matthew I Milowsky, Rick Bangs, Gary R MacVicar, Bruno R Bastos, Jared S Fowles, Daniel L Gustafson, Melissa Plets, Ian M Thompson

Department of Medicine, University of Colorado Denver School of Medicine ., SWOG Statistical Center, Fred Hutchinson Cancer Research Center., Department of Urology, USC/Norris Comprehensive Cancer Center., Internal Medicine, Division of Hematology/Oncology, University of Michigan–Ann Arbor., Urology, Baylor College of Medicine., Department of Pathology, University of Colorado School of Medicine., The Greenberg Bladder Cancer Institute, Johns Hopkins School of Medicine., Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center., Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA., Medicine, University of North Carolina at Chapel Hill., Patient Advocate Committee, SWOG., Illinois CancerCare PC, Peoria, IL., Miami Cancer Institute - Hematology/Oncology, Baptist Health South Florida., Clinical Sciences, Colorado State University., Animal Cancer Center, Clinical Sciences, Colorado State University., Public Health Sciences Division, Fred Hutchinson Cancer Research Center., Administration, CHRISTUS Santa Rosa Hospital - Medical Center.