LRRC8A as a candidate biomarker of cisplatin sensitivity in muscle-invasive bladder cancer: an exploratory immunohistochemical study

BACKGROUND: Despite recent therapeutic advances, platinum-based chemotherapy still remains a cornerstone in the treatment of muscle invasive bladder cancer (MIBC). We investigated the association between leucine-rich-repeat-containing 8A (LRRC8A) expression, a protein with a potential mechanistic role in platinum-sensitivity, and clinical outcomes following neoadjuvant chemotherapy in MIBC. METHODS: We histologically characterized transurethral resection of bladder tumor (TUR-B) and cystectomy MIBC samples. We analyzed membranous and cytoplasmic tumor expression levels of LRRC8A, correlating results with clinical outcomes. RESULTS: We analyzed clinical data from 35 MIBC patients treated at the University Hospital of Bern between September 2017 and March 2023. Immunohistochemistry (IHC) expression was assessed for 17 patients with paired TUR-B and cystectomy samples. High membranous LRRC8A expression was observed more frequently in patients achieving a complete pathologic response (tumor regression grade [TRG] 1) than in those with TRG2 or TRG3 (3/5 [60%] vs. 2/12 [16.7%]); however, this difference did not reach statistical significance. Kaplan-Meier survival analysis showed no statistically significant difference in overall survival (OS) between patients with negative/low versus high membranous LRRC8A. CONCLUSIONS: Our data suggest a potential association of LRRC8A expression levels with cisplatin sensitivity in MIBC. Given the limited sample size and retrospective nature of the study, these findings should be considered preliminary, exploratory and hypothesis-generating. Further validation in larger, independent cohorts, as well as functional studies, will be needed.