Abstract IA24: Predictive biomarkers of response to neoadjuvant therapy
Authors: Kent W. Mouw
Journal: Clinical Cancer Research (2020)

Abstract The addition of cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy provides a modest overall survival benefit for patients with muscle-invasive bladder cancer (MIBC). Moreover, the extent of pathologic response at cystectomy correlates with survival, and patients who achieve a complete pathologic response following neoadjuvant chemotherapy have significantly improved survival compared to patients with residual MIBC. Clinical features alone are unable to predict which patients will respond to neoadjuvant chemotherapy, and there is an urgent clinical need to identify genomic biomarkers to guide neoadjuvant therapy for MIBC. The Cancer Genome Atlas (TCGA) and related efforts have defined the genomic landscape of MIBC and have identified recurrent genomic alterations including mutations, chromosomal translocations, and copy number alterations. Additionally, gene expression profiling has defined molecular subtypes of MIBC that have distinct clinical and genomic features. These genomic data are being harnessed to understand the association among genomic features, response to neoadjuvant therapy, and clinical outcomes. Alterations in DNA damage and repair (DDR) genes have emerged as a biomarker of response to neoadjuvant cisplatin-based chemotherapy in several studies. Loss-of-function mutations in the nucleotide excision repair gene ERCC2 as well as in related DDR genes including ATM, FANCC, and RB1 have been associated with complete pathologic response to cisplatin-based chemotherapy and improved survival in MIBC patients receiving cisplatin-based chemotherapy. Functional studies have confirmed that many of the clinically identified DDR gene mutations confer loss of DNA repair capacity and drive cisplatin sensitivity in preclinical bladder systems. These data have informed the design of several ongoing biomarker-driven clinical trials that seek to identify a subset of patients with DDR-altered tumors who may be cured with cisplatin-based chemotherapy alone. In addition to driving response to DNA damaging-based chemotherapy, DDR gene alterations have also recently been associated with improved response to immune checkpoint inhibition in patients with metastatic urothelial cancer. The mechanism underlying this association remains incompletely understood; however, DDR pathway alterations can lead to increased tumor mutational burden and neoantigen load, which have each been associated with improved response to anti-PD1/PD-L1 agents. Immune checkpoint inhibitors have transformed the management of metastatic bladder cancer, and these agents are now being investigated in numerous clinical trials for patients with localized bladder cancer. However, only a subset of patients benefit from anti-PD1/PD-L1 therapy; therefore, identifying reliable predictive biomarkers of immunotherapy response in bladder cancer remains a critical need. Gene expression-based analyses have defined molecular subtypes that exhibit distinct clinical properties and therapeutic vulnerabilities. Tumors with basal-like gene expression properties appear to respond more robustly to neoadjuvant chemotherapy than luminal-like tumors. However, the specific genetic/epigenetic drivers of chemotherapy response among basal tumors are incompletely understood. Recently, gene expression subtypes were also found to correlate with response to immune checkpoint inhibition, including robust responses among a small but unique subset of patients with a neuronal tumor subtype. It is likely that applying similar genomic approaches to additional cohorts may provide further insights into the genomic drivers of therapeutic response and resistance to neoadjuvant therapies. Citation Format: Kent W. Mouw. Predictive biomarkers of response to neoadjuvant therapy [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA24.