Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions

Objective: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. Materials and Methods: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180–395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. Results: In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFR_exon20ins) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2_exon20ins occurred in 3.6% (20/552) of cases. EGFR_exon20ins and ERBB2_exon20ins occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. Conclusion: EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFR_exon20ins and ERBB2_exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.