Potential Role of HER2/Neu as a Molecular Target in the Treatment of High Grade Urothelial Cancer. Determination of Gene Amplification by FISH, CISH and IHC.
Phyu P Aung, Beatriz A Walter, Carmen Garcia, Gennady Bratslavsky, Maria J Merino. National Cancer Institute, Bethesda, MD; University of Salamanca, Spain
Background: Bladder cancer is the fourth most common malignancy in men with more than 16,000 patients dying of the disease. Currently, the treatment of patients with advanced urothelial tumors is surgery and standard chemotherapy. Promising new targeted therapies as anti-Her2 drugs are currently under study in a variety of cancers. This study investigates the potential role of HER2/neu gene as a possible molecular target in bladder cancer.
Design: Forty-seven cases of urothelial carcinoma were analyzed. HER2/neu gene and chromosome 17 alterations were studied by FISH and chromogenic in situ hybridization (CISH) and protein expression by IHC. Correlation was done with tumor stage, grade and clinical behavior. Her2/neu IHC was evaluated following the CAP/ASCO guidelines and gene amplification by guidelines from the FDA-approved Her2 CISH kit (Invitrogen, CA). Polysomy of chromosome 17 was defined as 3 or more individual signals within a nucleus.
Results: Thirty tumor samples were high grade and 14 cases were low grade TCC. One case of mucinous adenocarcinoma and 2 cases of epithelial atypia were also evaluated. Superficial or locally invasion (pTa/PT1) was reported in 28 cases and muscle invasion (pT2+) in 17 cases. Patient's mean age was 47 years. In high grade tumors, Her2/neu protein expression by IHC was observed in 13 cases score 3+, indeterminate in 4 (2+) and no staining or weak in 2 cases (0-1). All 3+ cases also had Her2/neu gene amplification by CISH and FISH. Most of 2+ and all 0-1+ cases did not show gene amplification. The mucinous adenocarcinoma case was negative for Her2/neu expression and gene amplification. Eight low grade TCC cases did not show Her2/neu protein expression. Only 1 case was 3+ and 5 cases were 2+. None of the cases showed Her2/neu gene amplification. Polysomy of chromosome 17 was found in 96% of high grade tumors associated with Her2/neu gene amplification (22/23). Most of the low grade tumors had disomy of chromosome 17 (10/12).
Conclusions: Our study shows that high-grade urothelial carcinomas have Her2/neu protein overexpression and gene amplification in association with polysomy of chromosome 17. Low-grade cases were disomic with low expression and no amplification of the Her2/neu gene. These findings support the role that Her2/neu may have in the clinical management and treatment of patients with high-grade urothelial carcinoma that over express Her2/neu gene.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 119, Monday Morning