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Background <p>Fibroblast growth factor receptor 3 (FGFR3) alterations and ERBB2 (HER2) amplification are clinically actionable genomic events in metastatic urothelial carcinoma (mUC). However, their prevalence and overlap in metastatic-specific cohorts remain incompletely defined. We evaluated their nationwide distribution and co-occurrence using the Japanese C-CAT registry.</p> Methods <p>This retrospective study included patients with histologically confirmed mUC who underwent comprehensive genomic profiling with tissue-based FoundationOne assays between January 2019 and June 2025. FGFR3 positivity was defined as pathogenic mutations or fusions meeting companion diagnostic criteria, and HER2 positivity as ERBB2 amplification. Associations with clinicopathological variables were assessed using logistic regression. Co-occurrence was analyzed with Fisher’s exact test.</p> Results <p>Among 1014 patients, FGFR3 alterations were identified in 157 (15.5%) and HER2 amplification in 150 (14.8%). Concurrent alterations occurred in 13 patients (1.3%). Under statistical independence, the expected co-occurrence rate was 2.3%; the observed frequency was significantly lower (<i>P</i> = 0.010; crude OR 0.47). In multivariable analysis, female sex (OR 0.58, 95% CI 0.36–0.93; <i>P</i> = 0.024) and upper tract origin (OR 0.57, 95% CI 0.39–0.84; <i>P</i> = 0.005) were independently associated with lower odds of HER2 amplification. HER2 amplification was independently associated with reduced odds of FGFR3 alterations (adjusted OR 0.49, 95% CI 0.27–0.88; <i>P</i> = 0.018).</p> Conclusions <p>In this nationwide metastatic cohort, FGFR3 alterations and ERBB2 amplification were each detected in approximately 15% of cases and showed a significant but partial negative association. These findings clarify the molecular epidemiology of mUC and support comprehensive genomic profiling to guide biomarker-driven therapy.</p>

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Prevalence and complementary distribution of FGFR3 alterations and ERBB2 amplification in metastatic urothelial carcinoma: a nationwide registry analysis

  • 期刊论文

  • 发表日期：

    2026年6月27日

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  • Takuto Hara,
  • Taisuke Tobe,
  • Hideto Ueki,
  • Naoto Wakita,
  • Yasuyoshi Okamura,
  • Yukari Bando,
  • Kotaro Suzuki,
  • Tomoaki Terakawa,
  • Yoji Hyodo,
  • Akihisa Yao,
  • Koji Chiba,
  • Jun Teishima,
  • Hideaki Miyake

摘要

Background

Fibroblast growth factor receptor 3 (FGFR3) alterations and ERBB2 (HER2) amplification are clinically actionable genomic events in metastatic urothelial carcinoma (mUC). However, their prevalence and overlap in metastatic-specific cohorts remain incompletely defined. We evaluated their nationwide distribution and co-occurrence using the Japanese C-CAT registry.

Methods

This retrospective study included patients with histologically confirmed mUC who underwent comprehensive genomic profiling with tissue-based FoundationOne assays between January 2019 and June 2025. FGFR3 positivity was defined as pathogenic mutations or fusions meeting companion diagnostic criteria, and HER2 positivity as ERBB2 amplification. Associations with clinicopathological variables were assessed using logistic regression. Co-occurrence was analyzed with Fisher’s exact test.

Results

Among 1014 patients, FGFR3 alterations were identified in 157 (15.5%) and HER2 amplification in 150 (14.8%). Concurrent alterations occurred in 13 patients (1.3%). Under statistical independence, the expected co-occurrence rate was 2.3%; the observed frequency was significantly lower (P = 0.010; crude OR 0.47). In multivariable analysis, female sex (OR 0.58, 95% CI 0.36–0.93; P = 0.024) and upper tract origin (OR 0.57, 95% CI 0.39–0.84; P = 0.005) were independently associated with lower odds of HER2 amplification. HER2 amplification was independently associated with reduced odds of FGFR3 alterations (adjusted OR 0.49, 95% CI 0.27–0.88; P = 0.018).

Conclusions

In this nationwide metastatic cohort, FGFR3 alterations and ERBB2 amplification were each detected in approximately 15% of cases and showed a significant but partial negative association. These findings clarify the molecular epidemiology of mUC and support comprehensive genomic profiling to guide biomarker-driven therapy.