The HER3 pathway as a potential target for inhibition in patients with biliary tract cancers

Abstract

IntroductionExpression of human epidermal growth factor receptor (HER)2 and HER3 have been investigated in small BTC studies using variable scoring systems.MethodsHER2 and HER3 overexpression/amplification were explored following internationally agreed guidelines using immunohistochemistry (IHC) and fluorescent in-situ hybridisation (FISH), respectively. Logistic regression and survival analysis (Kaplan Meier, Log rank test and Cox Regression) were used for statistical analysis.ResultsSixty-seven eligible patients with Stage I/II (31.3%) or III/IV (68.7%) disease at diagnosis were included. Membrane HER2 overexpression/amplification was identified in 1 patient (1%). HER3 overexpression was predominantly cytoplasmic; the rate of overexpression/amplification of HER3 in membrane and cytoplasm was 16% [ampullary cancer (AMP) (1/13; 8%), gallbladder cancer (GBC) (1/10; 10%), intra-hepatic cholangiocarcinoma (ICC) (6/26; 23%), extra-hepatic cholangiocarcinoma (ECC) (3/18; 17%)] and 24% [AMP (1/13; 8%), GBC (1/10; 10%), ICC (10/26; 38%), ECC (4/18; 22%)], respectively.ConclusionsA significant subset of patients with BTC expressed HER3. Inhibition of HER3 warrants further investigation. A better understanding of the downstream effects of HER3 in BTC requires further mechanistic investigations to identify new biomarkers and improve patient selection for future clinical trials.

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…[74][75][76] There has been some pre-clinical and early clinical research targeting BRAF and RNF43 mutations, as well as HER2 (also known as ERBB2). [77][78][79] In addition, some tumour-agnostic targets such as NTRK may also play a role for a small proportion of patients with biliary tract tumours (3%). 15,80,81 In-depth sequencing of biliary tract cancers has shown that molecular profiles vary between iCCA, eCCA and GBC ( Fig.…”

“…One of the challenges for assessment of the HER family as a potential target in biliary tract malignancies has been the difficulty in assessing immunohistochemistry. 79 The combination of pertuzumab and trastuzumab was investigated in 11 patients with previously treated biliary tract cancer, with HER2 amplification (8 patients) or HER2 mutations (3 patients); ORRs of 7.5% and 33.3% were reported, respectively. 174 Targeting gene mutations rather than amplifications may also have potential (e.g.…”

“…175 Even though some data exist, and even though HER represents the most frequent targetable aberration for eCCA and GBC, work is still needed for this target to be ready for prime time use in clinical practice. As with IDH and FGFR, adequate patient selection may be the key for the successful development of these drugs 79 and further clinical trials are required to confirm the benefit of targeting HER in patients with biliary tract cancers.…”

“…HER3) remains unclear. 79 locations, is the access to tumour tissue. 9 Taking this into account, it is important that strategies to allow "liquid biopsies" for patient selection are developed in parallel to the development of new therapies.…”

Regarding “HER2 Overexpression as a Poor Prognostic Determinant in Resected Biliary Tract Cancer”

“…One of the strengths of this article is that the paper may open a reflection regarding the role of HER2 assessment on the "slippery slope" of adjuvant treatment in BTC, where HER2 could challenge the therapeutic decisionmaking approach to completely resected BTC [3]. Moreover, the authors performed fluorescence in situ hybridization only on immunohistochemistry (IHC) 2+ and IHC3+ patients, as being supported by current guidelines [4].…”