Investigation of prognostic biomarkers in patients with urothelial carcinoma treated with platinum-based regimens

• Published in: Urologic oncology 2022-12, Vol.40 (12), p.538.e15-538.e24
• Main Authors: Papadopoulou, Kyriaki, Koliou, Georgia-Angeliki, Tsimiliotis, Dimitrios, Kotoula, Vassiliki, Foukas, Periklis, Goussia, Anna, Tsiatas, Marinos, Visvikis, Anastasios, Chatzopoulos, Kyriakos, Nifora, Martha, Charchanti, Antonia, Koumarianou, Anna, Christodoulou, Christos, Pectasides, Dimitrios, Psyrri, Amanda, Fostira, Florentia, Fountzilas, George, Samantas, Epaminontas
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Bladder cancer; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - pathology; CD8-Positive T-Lymphocytes - metabolism; DNA damage response and repair; Humans; Lymphocytes, Tumor-Infiltrating - metabolism; Platinum - pharmacology; Platinum - therapeutic use; Platinum sensitivity, PD-L1; Prognosis; Subtype; Urinary Bladder Neoplasms - pathology; Xeroderma Pigmentosum Group D Protein
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2022.07.007

•DNA damage response and repair (DDR) alterations confer cisplatin sensitivity in muscle invasive bladder cancer (MIBC) patients.•Immune markers PD-L1, TILs or CD8+ are also potential biomarkers for cisplatin response in MIBC.•TP53, ARID1A, ERCC2 and BRCA2 were the top mutated genes among our study's tumors from 66 BC patients administered platinum regimens.•Immune markers positively correlated with each other and PD-L1 with the basal subtype.•DDR mutations, immune markers or subtypes were not associated with overall survival. Bladder cancer (BC) is a heterogeneous malignancy with dismal outcome. Mutations in genes, altered or linked to platinum sensitivity in BC, were examined in 66 patients’ tumors along with tumor infiltrating lymphocytes (TILs) density and MMR, PD-L1 and CD8 protein expression, as well as basal and luminal subtypes, defined by protein expression of markers, including CK5/6 and GATA3 or CK20, respectively. 41 tumors harbored mutations, mainly in TP53 (38%), ARID1A (17%) and the DNA damage response and repair (DDR) genes ERCC2 (17%) and BRCA2 (15%). Mutations in other DDR relevant genes were also present. Age showed unfavorable prognosis for overall survival (HR=1.07, P = 0.026); no benefit was seen for patients with TP53, ARID1A, ERCC2 or BRCA2 mutations or mutations in 1 or more DDR genes. PD-L1 status positively correlated with stromal (rho=0.46, P < 0.001) and intratumoral (rho=0.53, P < 0.001) CD8 expression or TILs (rho=0.29, P = 0.018); none associated with overall survival (OS). A statistically significant difference was observed between PD-L1 status and immunohistochemistry (IHC)‑based subtypes, with tumors classified as luminal (GATA3+ and/or CK20+ and CK5/6−) showing lower PD-L1 expression relative to basal (CK5/6+ and GATA3- and/or CK20-) (median value 0 vs. 2.5, P = 0.029). Concerning OS, no statistically significant difference was seen among patients with basal or luminal tumors. No association was seen herein between DDR mutations, TILs, PD-L1, CD8 expression or IHC-based subtypes and patient survival; these observations warrant validation within a larger cohort.