In a comprehensive transcriptional analysis of 460 patients with early-stage urothelial carcinoma, Hedegaard et al.1 found that non-muscle invasive bladder cancer can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. In this study, there were 31 progression events that occurred of which 80% occurred in subtype UROMOL class 2, which included several mutational signatures (APOBEC, CIS & Progression, and TP53 & ERCC2 mutations). Thus, the identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
Specific to T1 tumors in the TCGA dataset, patients that progress to secondary muscle-invasive bladder cancer are not enriched for any molecular subtype compared to primary muscle-invasive bladder cancer. Studies assessing genomic subtypes of non-invasive Ta tumors demonstrate unsupervised clustering defined by two genomic subtypes:
- Genomic subtype 1: mostly low-grade Ta, Lund UroA, UROMOL Class 1, very few alterations
- Genomic subtype 2: mostly high-grade Ta, Lund UroA, UROMOL Class 2, DNA damage/tumor mutational burden, APOBEC signature
Of note, within genomic subtype 2, it is common to have a loss of chromosome 9, as well as loss of TSC1.
Work from Dr. Pietzak’s group previously assessed pretreatment index tumors and matched germline DNA from 105 patients with NMIBC.2 TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. Furthermore, ERBB2 or FGFR3 alterations were also present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. FGFR alterations included 60% of high-grade Ta tumors without CIS compared to 70-80% of patients with low-grade Ta tumors. As follows is an overview of the genomic landscape of NMIBC by grade and stage with a comparison to muscle-invasive bladder cancer:
Based on the actionable targets of mutations in NMIBC, clinical trials are now taking advantage of these opportunities. For example, the phase 2 WOO study of pemigatinib in NMIBC patients with recurrent low- or intermediate-risk tumors has 43 patients with recurrent low grade Ta with no prior treatment required.
DNA damage repair genes have also been identified in patients with NMIBC. In Dr. Pietzak’s work, DNA damage repair gene alterations were seen in 30% of high-grade NMIBC tumors, a rate similar to muscle invasive bladder cancer, and were associated with a higher mutational burden compared with tumors with intact DNA damage repair genes (p<0.001). Also, ERCC2 mutations have been identified in NMIBC. Bellmunt et al.3 performed exome sequencing on 62 high-grade T1 and 15 matched normal tissue samples, finding that DNA damage response gene mutations were associated with higher tumor mutational burden (p < 0.0001) and good outcomes (p = 0.003). ERCC2 and BRCA2 mutations were also associated with good outcomes, whereas TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequently associated with progressive disease in this cohort. Additionally, Dr. Pietzak found that ARID1A mutations were associated with an increased risk of recurrence after BCG (HR 3.14, 95% CI 1.51-6.51, p=0.002):2
Dr. Pietzak concluded his presentation with the following summary points:
- NMIBC molecular subtypes may uncover interesting and novel biology
- Over 75% of high-grade NMIBC tumors have an actionable alteration
- There is emerging data for tumor mutational burden and DNA damage repair mutations suggesting that tumor-specific T-cells may be a mechanism of action for BCG response
- There is an increasing role of multi-disciplinary care for patients with NMIBC as urologists will need to become familiar with managing patients on systemic therapies, and medical oncologist will need to become familiar with the nuances of NMIBC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
- Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell. 2016 Jul 11;30(1):27-42.
- Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur Urol. 2017 Dec;72(6):952-959.
- Bellmunt J, Kim J, Reardon B, et al. Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer. Cancer Res. 2020 Oct 15;80(20):4476-4486.