A composite biomarker approach to withhold neoadjuvant chemotherapy in select muscle-invasive bladder cancer patients.

Abstract

841 Background: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is recommended for muscle-invasive bladder cancer (MIBC). However, we propose a composite biomarker approach of circulating tumor cell status and gene expression to select patients in whom NAC may be omitted. Methods: Transurethral resection of bladder tumor (TURBT) samples were collected from patients with cT2-T4aN0-N1M0 MIBC who were included in the prospective CirGuidance study (NL3954), in which circulating tumor cells (CTC) were enumerated using the CELLSEARCH system. Expression profiling was performed using the validated Decipher Bladder genomic subtyping classifier to determine luminal and non-luminal molecular subtypes (Veracyte, Inc.). The luminal favorable subtype was determined using a lncRNA-based classifier (de Jong et al. 2019 & 2024). The primary endpoint was cancer-specific mortality (CSM), calculated from the date of study inclusion to the date of bladder cancer related death. Results: In the CirGuidance study (n = 231), most patients (n = 213; 92%) underwent RC without NAC, while (n = 18) received NAC plus RC. Among RC-only patients, CTCneg status (n = 172) was associated with a two-year CSM of 21% versus 41% in CTCpos patients (Gray’s test, p = 0.01). No significant differences were observed in the distribution of molecular subtypes between CTCpos or CTCneg patient subgroups. Within CTCneg patients treated with RC alone, 2-year CSM was 14% in luminal (n = 77, 36%) versus 25% in non-luminal (n = 136, 64%) whereas in CTCpos patients it was 38% and 44%, respectively. Among 18 NAC plus RC treated patients, non-luminal subtype (n = 10) had a two-year CSM of 11%, whereas in luminal subtype it was 27%, similar to outcomes when treated with RC alone. Importantly, the lncRNA-based luminal favorable classifier identified 26 patients with luminal favorable subtype among CTCneg patients with 0% CSM at two years (MVA p = 0.02) when treated with RC alone. Conclusions: We identified a biomarker-defined subgroup of MIBC with more favorable outcomes after RC alone. These findings support the future prospective validation of CTC and molecular subtyping as a tool to guide NAC selection.