Enrichment of FGFR3-TACC3 Fusions in Patients With Bladder Cancer Who Are Young, Asian, or Have Never Smoked.

Abstract

<i>FGFR3-TACC3</i> (fibroblast growth factor receptor 3-transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of <i>FGFR3</i> in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with <i>FGFR3-TACC3</i> fusions and hypothesized that they are enriched in a subset of patients with bladder cancer. We correlated somatic <i>FGFR3-TACC3</i> fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one patient with <i>FGFR3-TACC3</i> bladder cancer to an FGFR3 inhibitor was investigated. Overall, 751 patients with high-grade bladder cancer without <i>FGFR3-TACC3</i> fusions and 17 with <i>FGFR3-TACC3</i> fusions were identified in the pooled analysis of the data sets from The Cancer Genome Atlas and the Dana-Farber Cancer Institute. <i>FGFR3-TACC3</i> fusions were enriched in patients age ≤ 50 years versus age 51 to 65 years versus those older than 65 years (pooled, <i>P</i> = .002), and were observed in four (12%) of 33 patients age ≤ 50 years in the pooled analysis. Similarly, <i>FGFR3-TACC3</i> fusions were significantly more common in Asians (13%) compared with African Americans (4%) and whites (2%; pooled, <i>P</i> < .001), as well as in never smokers (5.6%) compared with ever smokers (1.1%; pooled, <i>P</i> < .001). One patient with the fusion who was treated with an FGFR3 inhibitor achieved complete remission for 10 months. Clinical testing to identify <i>FGFR3</i> fusions should be prioritized for patients with bladder cancer who are younger, never smokers, and/or Asian.