Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition

Andrea Necchi, Daniele Raggi, Andrea Gallina, Marco Bandini, Joep J. de Jong, Laura Marandino, Alberto Briganti, Francesco Montorsi, Elai Davicioni, Yair Lotan, Ewan A. Gibb

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Clinical high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC) represents a significant risk to patients, but these patients are not typically offered neoadjuvant therapies, including immune therapy. In this study, we determine whether patients with HG clinical T1 or T2 bladder urothelial carcinoma (UC) have profiles that predict the potential effectiveness of immune-checkpoint inhibitors (ICI). Materials and Methods: Data from transurethral resection of bladder tumor (TURBT) specimens from 2 studies was evaluated. The molecular upstaging (MOL) cohort included HG cT1N0M0 (n = 87) and cT2N0M0 (n = 119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (n = 102) was used as ICI-treated reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher). Immune-signatures scores and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of recurrence-free survival (RFS) and overall survival (OS). Results: In both the PURE-01 and MOL cohorts, the Immune190 signature, stratified by subtype, showed the highest scores in basal-type, but also in luminal-infiltrated tumors, but the lowest scores in the luminal tumors. However, in HG cT1 tumors the Immune190 scores were the lowest for luminal papillary tumors (Consensus, TCGA) and luminal tumors (GSC), with less distinct differences between other subtypes. RFS was significantly longer for luminal vs non-luminal tumors in MOL (P = 0.04) but not in PURE-01 (P = 0.8). In the MOL cohort, OS was inferior in HG cT1 tumors for Immune190-high vs low tumors (median split, P = 0.042). Conclusion: We identified a population of cT1-T2N0M0 tumors in the MOL cohort that shared molecular features with tumors included in PURE-01. These profiles suggest that treatment with ICI could be proposed to more selected HG cT1N0M0 tumors, identified with a gene expression assay.

Original languageEnglish (US)
Pages (from-to)734.e11-734.e17
JournalUrologic Oncology: Seminars and Original Investigations
Volume39
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • Immunotherapy
  • Muscle-invasive bladder cancer
  • Neoadjuvant pembrolizumab
  • Radical cystectomy
  • Tumor biomarkers

ASJC Scopus subject areas

  • Oncology
  • Urology

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