Abstract IA26: Targeting hypoxia and personalizing chemoradiation
Authors: West Catharine 
Published: August 2020

Abstract
There are multiple management options for muscle-invasive bladder cancer. Approaches include radical cystectomy and trimodality treatment with transurethral resection of bladder tumor and organ-preserving radiotherapy. Trials provided high-quality evidence for the superiority of multimodality treatments over radiotherapy alone. The BC2001 phase III trial showed adding concurrent 5-fluorouracil (5-FU) and mitomycin-C to radiotherapy increased 2-year locoregional control by 14%. The Gemtrans phase II trial, and a follow-on pooled analysis of eight trials, showed high survival outcomes (5-year overall survival rates of 59%) for gemcitabine-based chemoradiotherapy. The BCON phase III trial showed a 13% improvement in 3-year overall survival when hypoxia-targeting carbogen and nicotinamide (CON) were given with radiotherapy. Bladder-preserving trimodality treatments have equivalent survival outcomes to the previously considered gold-standard treatment of radical cystectomy for localized bladder cancer, and trials have shown it is not feasible to randomize to cystectomy or selective bladder preservation. Decisions for selecting primary cystectomy or bladder-sparing treatment are now governed largely by patient and clinician preferences. Given the poor survival outcomes for muscle-invasive bladder cancer and multiple options for its management, there is an unmet clinical need to validate predictive biomarkers to aid rational treatment selection and personalization. Personalization based on measuring tumor hypoxia is attractive. Approaches for measuring tumor hypoxia have been studied for many years. Although there are advantages and disadvantages to the different methods, gene expression signatures show promise for clinical application. The signatures can be applied using readily available pretreatment paraffin-embedded tumor samples. Signatures have been derived for multiple cancer types including bladder. A 24-gene signature was shown to have strong and independent prognostic and predictive value. The signature was validated in multiple cohorts and shown to identify patients likely to benefit from the addition of CON to radiotherapy. A key aspect for progressing personalized treatment is biomarker application, i.e., identifying a platform for clinical use. Ongoing work is taking the 24-gene signature forward and comparing platforms. Customized Taqman Low Density Array (TLDA) cards were used to take a head and neck signature forward for prospective testing in a trial, but other technologies (e.g., nanostring) are of interest. Work is also generating transcriptomic data for samples collected from patients enrolled in the BC2001 trial to test whether patients with hypoxic tumors do not benefit from having concurrent 5-FU plus mitomycin-C. A biomarker-driven trial is also being developed.
Citation Format: Catharine West. Targeting hypoxia and personalizing chemoradiation [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA26.