A significant subgroup of resectable gallbladder cancer patients has an HER2 positive status

Abstract

Gallbladder cancer (GBC) has a poor prognosis, and new targeted therapeutic options are needed. We investigated the human epidermal growth factor receptor 2 (HER2) status and its clinicopathological significance in a large cohort of GBC patients. We assessed HER2 expression in a consecutive series of 211 GBC cases by immunohistochemistry (IHC), paying particular attention to intratumoral heterogeneity. HER2 gene amplification was analyzed by dual-color fluorescence in situ hybridization (FISH). An HER2 positive status was called when the IHC score was 3+ or when the IHC score was 2+, and FISH was positive. Correlations were analyzed between HER2 status and clinicopathological parameters including survival. The HER2 IHC score was 0 in 144 (68.2%), 1+ in 28 (13.3%), 2+ in 14 (6.6%), and 3+ in 25 cases (11.8%). In 20/39 (51%) of the IHC 2+ and 3+ cases, the staining pattern was heterogeneous. In HER2 IHC score 2+ and 3+ cases, HER2 FISH was positive in 83% (10/12) and 96% (24/25), respectively. Altogether, 35/211 cases (16.6%) were HER2 positive. There was no significant association between HER2 status and clinicopathological variables or survival. We identified a significant subgroup of HER2-positive GBC cases, for whom a clinical trial with anti-HER2 therapy might be considered.

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

“…Therefore, these findings (moderate/strong HER2 expression rates in EH-BTCs and FISH rates in IHC “selected” patients) suggest around 10–20 % of EH-BTCs can be virtually considered HER2 upregulated. In a recent case series of 211 consecutive GBC tumors, 16.6 % of tumors were globally found to be HER2 positive when IHC3+ and IHC 2+/FISH-amplified tumors were considered altogether [87]. According to international HER2 assessment criteria used for breast and gastric cancer [6, 26, 27], it may be assumed that BTCs scoring 3+ on immunohistochemistry should be interpreted as positive, while the application of in situ hybridization (fluorescence or chromogenic) could be carried out only in tumors with an ambiguous (IHC 2+) score.…”

“…Most interestingly, HER2/HER3 co-expression in BTCs ranges from 9 to 53 % [76, 83] and has been demonstrated to be frequently associated with phosphorylation (activation) of HER2 and AKT [83]. HER3 is often correlated with poorly differentiated biliary tumors [81] and appears to be a poor prognostic factor in EHCCs [76], whereas the prognostic meaning of HER2 has not been completely clarified [79, 87] . Interestingly, the combination of pertuzumab and trastuzumab has been reported to induce a synergistic inhibition of in vivo tumor growth in BTCs, likely because of a more comprehensive blockade of HER2/HER3 signaling [83].…”

“…Further data is required regarding the impact of co-expression of both HER2 and HER3. Standardization of ISH and IHC techniques, validation of scoring criteria for HER2 and HER3 immunohistochemistry, and assessment of concordance between IHC and ISH, focusing on the high intra-tumoral heterogeneity of HER2 membranous protein [87], are needed if the techniques are to be adopted to clinical practice. Assuming that an overexpression of HER2 of 5 % or less could be considered “un-interesting,” in this era of personalized medicine and spending review, our data may be particularly pertinent for the most cost-effective selection of patients with BTCs who may benefit from anti-HER2-targeted therapy.…”

Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients

“…In our preliminary investigation, the HER-2 expression profile showed relevance in higher-stage cases and significance with T-stage and nodal spread (N) of the disease, which is often seen in advanced GBC cases. In a rather recent study conducted by Yoshida et al [20], they found a significant patient population that can derive benefit from anti-HER-2 therapy by designing planned clinical trials based on preliminary immunohistochemical reports. …”

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

“…9). We also decided to evaluate the expression of human epidermal growth factor receptor 2 (HER2) because there is a subset of HER2-positive patients who might be candidates for an anti-HER2 therapy [27,28]. We did not observe HER2 expression in the tissue section of the primary tumor or in the xenograft model of PUC-GBC1.…”