Genomic profiling of urothelial cancers finds many with actionable alterations

Comprehensive genomic profiling shows that more than one-third of patients with upper tract and bladder urothelial cancer have tier 1-2 genomic alterations, defined as those that potentially can benefit from approved or investigational targeted therapies.¹

Using a modified European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets, of 2463 patients with urothelial cancer who underwent comprehensive genomic profiling, 39% harbored ≥1 tier 1-2 genomic alterations, and 29% had a tier 3 genomic alteration “that provides a strong rationale for clinical trial consideration,” according to researchers led by Andrea Necchi, from Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy.

For their study, which appears in European Urology, tumor tissue samples for comprehensive genomic profiling were obtained from 479 patients with upper tract urothelial cancer and 1984 with bladder urothelial cancer. The distribution of genomic alterations was as follows:

• The most frequently altered genes in both groups were TERT (promoter region), TP53, and CDKN2A.
• TERT (68% vs 47%; P <.001) and TP53 (58% vs 49%; P = .04) alterations were significantly more common in bladder cancer, while CDKN2A (35% vs 40%; P = .4) was more common in upper tract urothelial cancer.
• RB1 alterations were more significantly frequent in bladder cancer versus upper tract (21% vs 8%; P <.001).
• FGFR3 (26% vs 19%; P = .02) and HRAS (6.9% vs 2.8%; P = .006) alterations were more common in upper tract urothelial cancer versus bladder cancer. FGFR3 mutations were more common in upper tract urothelial cancer (21% vs 14%; P = .002) while FGFR3 amplifications (0.4% vs 0.5%), rearrangements (3.3% vs 3.9%), and cases with multiple FGFR3 alterations (1.3% vs 1.0%), occurred at similar rates between patients with upper tract urothelial and bladder cancer.
• The enrichment of HRAS alterations in upper tract urothelial cancer arose from a greater frequency of alteration in renal pelvis tumors versus urothelial tumors (9.5% vs 1.8%; P = .002).
• Non-FGFR3 kinase fusions were observed in only 1% of patients, including BRAF/RAF1 fusions in 0.5%.
• BRAF mutations and/or fusions were found in 2% of cases and were mutually exclusive with FGFR3 alterations (P = .002).
• No significant differences in genomic alterations were observed between samples from the primary tumor and metastatic sites, except for the enrichment in primary site tumors of RB1 in bladder urothelial cancer.

There were no differences in tumor mutational burden–high (≥20 mut/Mb) or microsatellite instability–high (MSI-H) status between primary tumor and metastatic sites, but upper tract urothelial cancer was enriched for MSI-H relative to bladder urothelial cancer (3.4% vs 0.8%; P <.001).

Genomic profiling of cell-free circulating tumor (ct)-DNA was performed for 126 patients. Overall, there was a 69% positive percent agreement between ctDNA and tumor tissue, and 71% of cases shared at least 1 mutation. This concordance decreased with greater time lapse between acquisition of the 2 specimens.

According to the authors, “This study provides an additional rationale for the routine incorporation of ctDNA assays in clinical trials and possibly in clinical practice, especially when a recently obtained tumor tissue sample is not available and/or to complement tumor tissue analysis.”

They continued, “Outside of clinical trials, our study findings have potential implications for the selection of erdafitinib [Balversa], a pan-FGFR inhibitor, which currently has accelerated approval by the US Food and Drug Administration for the treatment of platinum-treated advanced urothelial carcinoma. The potential roles of ctDNA as a putative prognostic biomarker and its ability to detect actionable genomic alterations in patients with and without available tumor tissue are experiencing growing interest among investigators.”

Reference

1. Necchi A, Madison R, Pal SK, et al. Comprehensive genomic profiling of upper-tract and bladder urothelial carcinoma [published online August 26, 2020]. Eur Urol Focus. doi: 10.1016/j.euf.2020.08.001