Assessing HER2 gene amplification as a potential target for therapy in invasive urothelial bladder cancer with a standardized methodology: results in 1005 patients

Abstract

Background: This study assessed the human epidermal growth factor receptor-2 (HER2) protein expression and its relationship with gene amplification in invasive bladder carcinoma, using the same criteria than for breast cancer.Patients and methods: In 1005 patients, paraffin-embedded tissues of transurethral resection or cystectomy were evaluated by immunohistochemistry (IHC), using antibodies against HER2. All samples with a 2+ or 3+ HER2 overexpression were evaluated by FISH.Results: HER2 overexpression was observed in 93 (9.2%) tumors (2+: 42 tumors and 3+: 51 tumors). Using FISH, all HER2 3+ tumors had a gene amplification, whereas no amplification was found in 2+ tumors. Intratumoral heterogeneity was observed in 35% of cases. These tumors showed the same heterogeneous pattern, with adjacent 3+ positive and negative areas by both IHC and FISH.Conclusions: This study showed that 5.1% of invasive bladder carcinomas had a HER2 gene amplification. These findings may have clinical implications for the management of patients with HER2-positive locally advanced or metastatic bladder cancer, as they could be potential candidates for targeted therapy.

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

“…29 The HER2 protein is considered to have a significant role in bladder cancer outcomes, with HER2 protein expression reported in up to 31-65.5% of samples. 12,16,30 Furthermore, HER2 protein expression seems to correlate with tumor stage, tumor grade, [30][31][32] and poor prognosis. [30][31][32][33][34] One study found that the 5-year disease-free survival rate decreased from 48.5% in HER2-negative patients to 9.7% in those who were HER2 positive.…”

“…Overall, there does not seem to be a strong association between HER2 protein expression and gene amplification in conventional urothelial carcinoma, 12 which is perhaps explained by the relative paucity of gene amplification found in conventional urothelial carcinoma specimens, ranging from only 5.1 to 22.2%. 12,[16][17][18] Sauter et al 35 found that even when urothelial carcinomas show HER2 amplification, there is extreme heterogeneity in the amount of amplification per cell, with areas of amplification 'clustering' together and the fraction of amplified cells ranging from 18-94% within tumors.…”

“…In a phase II study of a dual inhibitor of HER-1 and HER2 kinase, only 1.7% of locally advanced or metastatic UCC patients had an objective response. 16,42 A separate phase II trial that combined trastuzumab (monoclonal antibody to HER2) with carboplatin, paclitaxel, and gemcitabine showed a complete response in 5 of 44 (11.4%) HER2-positive patients and a partial response in 26 of 44 (59.1%) patients (defined as a reduction of Z50% in the size of the lesion). 43 Although many of these studies used HER2 protein expression as a marker for potential therapeutic response, the lack of close correlation between protein levels and gene amplification and the low number of conventional UCCs that show HER2 gene amplification may explain these results.…”

“…15 On the basis of these findings, there has been interest in the possible efficacy of HER2-targeted therapy in other cancers. Previous investigation into HER2 expression in conventional urothelial carcinoma has identified an inconsistent and often low frequency of gene amplification in this disease (0-32% of cases [16][17][18] ),which made HER2-targeted therapy less feasible. However, there is a paucity of literature on HER2 expression in micropapillary carcinoma.…”

Outcome of patients with micropapillary urothelial carcinoma following radical cystectomy: ERBB2 (HER2) amplification identifies patients with poor outcome

“…12,13 ERBB2 amplification has been identified in other tumor types, although its role in treatment for these malignancies is yet to be defined. 10,[14][15][16] Although ERBB2 amplification has been identified in micropapillary urothelial carcinoma, its frequency and association with outcome has not been established in patients undergoing curative surgery. The objective of this study was to examine ERBB2 amplification and protein expression in a consecutive series of patients with micropapillary urothelial carcinoma undergoing radical cystectomy to determine the frequency of amplification and protein expression, and their association with outcome.…”