Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases

We were interested in this recent article by Gardmark et al.[1], in which they describe their analysis of 90 patients with metastatic TCC of the urinary bladder to evaluate “the suitability of HER2 as a target in preparation for planned systemic therapies of HER2-positive urinary bladder carcinoma”. The authors examined HER2 expression using two different immunohistochemical stains (the HerceptTest and modified HerceptTest, MH). According to these authors, HER2 staining was positive in 79% of the primary tumours and 62% of the metastases when the MH staining and target-score criteria were applied. Moreover, in their conclusions section, they underlined that the primary goal of the study was to analyse over-expressed receptors for possible treatment with HER2 targeting agents. To that end, in our opinion, essential requisites are those of evaluating not only HER2 expression, but also gene amplification and chromosome 17 aneusomy. Many studies have evaluated HER2 protein expression and gene amplification rates; they report HER2 expression rates of 2–74%[2]. This variation is partly a result of differences in the methods used to assess HER2 and variability in the reporting of data. Both overexpression with no gene amplification and heterogeneity in HER2 expression are more common in bladder cancer than in breast cancer [3,4]. This is mainly explained by a high level of chromosome 17 polysomy in TCC. Latif et al.[5], in 75 TCC classified as G3pT2, showed polysomy 17 in 97%, increased HER2 copy number in 92% and HER2 gene amplification in 7% of cases examined. In our previous investigation, we reported that chromosome 17 aneusomy is present in 84% of examined superficial bladder cancer, but also in 47% and 21% of normal-appearing adjacent proximal and distal mucosa, respectively [6]. Moreover, in our recent article, we found, in 48 advanced bladder cancers, chromosome 17 polysomy in 42% and HER2 gene amplification in 15% of specimens. Our study strongly confirmed the importance of chromosome 17 polysomy in detecting HER2 amplification [7]. Evidence from breast cancer suggests that only tumours with HER2 gene amplification respond to the anti-HER2 therapy ( Herceptin) [8]. If this were true for bladder cancer, only a low proportion of patients would be suitable for treatment. In conclusion, Gardmark et al. should be more careful in stating that immunohistochemical staining is sufficient to select HER2-targeting in patients. We suggest that it would be useful to re-evaluate these results using fluorescence in situ hybridisation, which permits the simultaneous assessment of the chromosome 17 aneusomy and HER2 gene status.