Background: Recent clinical trials suggest an emerging role for HER2-targeted therapy in locally advanced and metastatic UC (LA/mUC). The prevalence of HER2 expression and gene amplification (encoded by ERBB2) in LA/mUC has not been well defined, as testing for HER2 expression in LA/mUC is not part of current routine practice and is not standardized. We report (1) findings of a systematic literature review (SLR) of HER2 status in LA/mUC and (2) preliminary results of an ongoing evaluation of HER2 status in UC assaying HER2 protein expression by immunohistochemistry (IHC) and gene amplification by in situ hybridization (ISH). Methods: (1) The SLR used databases PubMed and EMBASE to identify English-language studies of LA/mUC HER2 status published Jan2000 – Oct2021. We used the following definitions: HER2-positive (HER2+) was defined as IHC 3+, or IHC 2+ with HER2 gene amplification (Amp+). HER2-low was defined as IHC 2+/Amp–, or as IHC 1+. HER2-zero was defined as IHC 0. Weighted averages were calculated to estimate population prevalence. (2) Commercially sourced, formalin-fixed paraffin-embedded surgical resections of primary UC were evaluated by trained readers for HER2 protein expression using the VENTANA HER2/neu (4B5) Rabbit Monoclonal Primary Antibody IHC assay and for HER2 gene amplification using the VENTANA HER2 Dual ISH DNA Probe Cocktail that detects both ERBB2 and its residing chromosome, chromosome 17 (Chr17), using a two-color chromogenic stain. HER2 IHC staining was scored based on an established scoring algorithm for gastric cancer. HER2 gene amplification was defined by a HER2/Chr17 ratio ≥2.0. Results: (1) Of 744 records screened for the SLR, 45 studies reported HER2 status, including 10,602 patients (pts) with LA/mUC. A variety of assays and scoring guidelines were used. In the 4 studies (862 pts) reporting data applicable to our predefined criteria for HER2 status, the percentage of HER2+ ranged from 6.7% to 37.5% (weighted average, 13.1%; 95% CI, 7.3%–18.8%). (2) Of 252 UC samples evaluated, 38 were HER2+ (15.1%; 95% CI, 11.2%–20.0%), 74 were HER2-low (29.4%; 95% CI, 24.1%–35.3%), and 140 were HER2-zero (55.5%; 95% CI: 49.4%–61.6%; Table). The HER2 gene was amplified in 31 (12.3%), among them 24 (77.4%) at stage III or IV muscle-invasive UC (MIUC). Conclusions: The SLR revealed wide variability of HER2 status in LA/mUC, highlighting a lack of standardized methods for assessing and defining HER2 status. In our large study using standardized laboratory methods, 44% of UC samples were HER2+ or HER2-low, and HER2 status distribution was consistent with that reported for pts with LA/mUC. Results suggest a potentially important role for HER2-targeted therapy for UC.

^aStages II–IV were MIUC.