Prognostic Value and Clinical Significance of FGFR Genomic Alterations (GAs) in Metastatic Urothelial Cancer Patients

Abstract

Fibroblast growth factor receptor (FGFR) genomic alterations (GAs) represent an actionable target, key to the pathogenesis of some urothelial cancers (UCs). Though FGFR GAs are common in noninvasive UC, little is known about their role in the metastatic(m) setting and response to therapy. This study aimed to assess the impact of FGFR alterations on sensitivity to systemic treatments and survival and to validate Bajorin’s and Bellmunt’s prognostic scores in mUC patients according to their FGFR status. We retrospectively analyzed data from 98 patients with tumor-sequenced UC who received treatment between January 2010 and December 2020. Up to 77 developed metastatic disease and were deemed the study population. Twenty-six showed FGFR GAs. A trend toward a better response to cisplatin and checkpoint inhibitors was suggested favoring FGFR GA tumors. FGFR GA patients who received an FGFR inhibitor as first-line had poorer responses compared with other options (20% vs. 68.4%, p = 0.0065). Median PFS was 6 vs. 5 months in the FGFR GA vs. FGFR WT cohort (p = 0.71). Median OS was significantly worse in the FGFR GA vs. FGFR WT cohort (16.2 vs. 31.9 months, p = 0.045). Multivariate analyses deemed FGFR GAs as a factor independently associated with the outcome (HR 2.59 (95% CI 1.21–5.55)). Bajorin’s model correctly predicted clinical outcomes in the whole study population but not in FGFR GA cases. FGFR GAs are a relevant biomarker in mUC that could condition the response to systemic therapy. New prognostic models, including this molecular determination, should be designed and validated.

Stellettin B Induces Cell Death in Bladder Cancer Via Activating the Autophagy/DAPK2/Apoptosis Signaling Cascade

“…Meanwhile, FGFR3 genetic alterations are frequently associated with the luminal papillary subtype in MIBC patients, and these tumors are reportedly lymphocyte-exclusionary and are less immunogenic [ 6 , 18 ]. Santiago-Walker et al evaluated anti-PD-L1 therapy outcomes in advanced BC patients with and without FGFR alternations, and the results revealed that the median overall survival in FGFR-altered patients was lower than that in FGFR-wildtype patients [ 61 ]. Therefore, SP-2 may help to overcome resistance to immunotherapy by releasing neoantigens and by priming the immune system in the future.…”

Correlation between fibroblast growth factor receptor mutation, programmed death ligand-1 expression and survival in urinary bladder cancer based on real-world data

“…Compared to the literature (26), our findings suggest an oncogenic relationship, as FGFR3 mutation is mostly seen in non-invasive tumors, and less frequently at more advanced stages. Fernandez et al found FGFR genomic alterations as an independent factor associated with the survival and as a relevant biomarker of mUC that may influence response to systemic therapy (28).…”

Development and deployment of a histopathology-based deep learning algorithm for patient prescreening in a clinical trial

“…Currently, Fibroblast Growth Factor Receptor (FGFR) alteration testing is used to identify patients who could benefit from FGFR-targeted therapies such as BALVER-SA™(erdafitinib), the first targeted therapy approved by the FDA to treat patients with metastatic or locally advanced bladder cancer who have previously received platinum-based chemotherapy 2,3 . For instance, the QIAGEN Therascreen FGFR RT-PCR kit 4,5 is the companion diagnostic approved by the FDA to screen patients for the presence of specific alterations in FGFR2 and FGFR3 genes that determine eligibility for treatment with erdafitinib and is also used to identify which patients are eligible to enroll in clinical trials using erdafitinib to treat urothelial cancer [6][7][8] .While FGFR-targeted treatments improved clinical care 9 , the wide adoption of molecular testing as standard of care remains slow due, in part, to its high cost and slow turn around, with an average 7 day turnaround time for test results [10][11][12][13][14] . Furthermore, molecular tests require substantial amounts of tissue with up to six, 4-5 µm sections of tumor tissue 15 and can fail to detect the target due to poor DNA/RNA quality…”

“…While FGFR-targeted treatments improved clinical care 9 , the wide adoption of molecular testing as standard of care remains slow due, in part, to its high cost and slow turn around, with an average 7 day turnaround time for test results [10][11][12][13][14] . Furthermore, molecular tests require substantial amounts of tissue with up to six, 4-5 µm sections of tumor tissue 15 and can fail to detect the target due to poor DNA/RNA quality…”