Amplification of HER-2/neu (erbB2) gene expression in gallbladder (GBC) and in bile duct cancer (BDC) (biliary tract cancer, BTC)

Abstract

4011 Background: GBC and BDC (BTC) are uncommon in the United States, but are endemic in parts of South America and Asia. BTC are aggressive tumors with poor survival rates. Chemotherapy RR is <30%, and no survival benefit has been demonstrated. Improved understanding of the molecular carcinogenic mechanisms of BTC may lead to improved therapeutic regimens. Activation of HER-2/neu play a prominent role in the development of breast cancer. In this study, BTC patient (pt) specimens from the U.S., Chile, and Japan were examined the HER-2/neu immunohistochemical (IHC) expression and its gene amplification by fluorescence in situ hybridization (FISH). Methods: Specimens from 26 GBC patients (Chile, US), 12 BDC (USA), 6 cholecystitis (Chole.) (Japan) and 7 normal GB (Chile) were examined. pStage (AJCC) of the pt was: IA: 2, IB: 9, IIA: 7, IIB: 9, III: 3, IV: 4, unknown: 4. Histologic grade was G1 and G2 adenocarcinoma (adca): 22, G3 adca: 13, squamous cell carcinoma: 1, unknown: 2. All cases were screened for HER-2/neu by IHC (0–3+). HER-2/neu gene amplification (FISH (+)) (defined as a HER-2/CEP17 ratio of 2.0 or greater) was performed by double color Her-2/neu gene/chromosome 17 centromere (CEP17) FISH assays using PathVysion HER-2/neu DNA probe kit. Results: In BTC, HER-2/neu IHC 0, 1+, 2+ and 3+ scores were found in 0 (0%), 20 (53%), 11 (29%) and 7 (18%), respectively. In Chole., 3 of 6 (50%) showed 1+ while the remaining and normal GB were all negative for IHC. FISH on paraffin sections was considered successful on 36 (95%) of the 38 cases. HER-2/neu FISH (+) was detected in 7 of 36 (19%) (6 from 3+ cases and 1 from 2+ case) and none in Chole. and normal GB. There was a significant correlation between overexpression by IHC (2+ and 3+) and FISH (+) (Fisher’s exact test; P=0.0123), but no significant correlation between pStage, histologic grade and FISH (+). Conclusions: The HER-2/neu amplification was identified in 19% of BTC in comparison with the other organ cancer (breast cancer:20–25%, lung cancer: 4.5%, colorectal cancer; 2.4%, prostate cancer: 9.3%). There was a strong correlation between IHC overexpression and FISH (+). These data support therapeutic approaches using HER-2/neu targeted agents in BTC pt. HER-2/neu IHC may be a useful surrogate for its gene amplification. No significant financial relationships to disclose.