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 4.1154) 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 15552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50; ERBB2(exon20ins) occurred in 3.620/552) 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 (3.73 P = 4.3E-14 and 208 P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. CONCLUSION: EGFR and ERBB2 alterations occur in 45 respectively. EGFR(exon20ins) and ERBB2(exon20ins) were present in 0.7.5 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.
|Publication status||Published - May 1 2020|