1. Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study
- Author
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Jeffrey S. Ross, Filippo Pederzoli, Andrea Salonia, Ewan A. Gibb, Ryan Dittamore, Maurizio Colecchia, Joep J. de Jong, Giorgio Gandaglia, Nicola Fossati, Marco Bandini, Patrizia Giannatempo, Roberta Lucianò, Laura Marandino, Andrea Gallina, Daniele Raggi, Yang Liu, Alberto Briganti, Elai Davicioni, Andrea Necchi, Francesco Montorsi, Elena Farè, Urology, Necchi, Andrea, Raggi, Daniele, Giannatempo, Patrizia, Marandino, Laura, Farè, Elena, Gallina, Andrea, Colecchia, Maurizio, Lucianò, Roberta, Salonia, Andrea, Gandaglia, Giorgio, Fossati, Nicola, Bandini, Marco, Pederzoli, Filippo, Dittamore, Ryan, Liu, Yang, Davicioni, Elai, Ross, Jeffrey S, de Jong, Joep J, Briganti, Alberto, Montorsi, Francesco, and Gibb, Ewan A
- Subjects
musculoskeletal diseases ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Cystectomy ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Hedgehog Proteins ,Radiology, Nuclear Medicine and imaging ,Fibroblast growth factor receptor-3 activity ,Fibroblast growth factor receptor-3 mutations/fusions ,Bladder cancer ,business.industry ,Muscles ,Immunotherapy ,Fibroblast growth factor receptor 3 ,Neoadjuvant pembrolizumab ,musculoskeletal system ,medicine.disease ,Neoadjuvant Therapy ,Fibroblast growth factor receptor-3 expression ,Gene expression profiling ,stomatognathic diseases ,Exact test ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Surgery ,business ,Muscle-invasive bladder cancer - Abstract
In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. Patient summary In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials.
- Published
- 2021