# Pattern of HER2 and HER3 Overexpression in Patients with Pancreatic Ductal Adenocarcinoma

## TL;DR

The study examines HER2 and HER3 overexpression in pancreatic cancer patients, linking these protein markers to tumor aggression and suggesting their potential for targeted therapies.

## Contribution

The study identifies HER2 and HER3 overexpression patterns in pancreatic ductal adenocarcinoma and their association with tumor invasion features.

## Key findings

- HER2 positivity was associated with high rates of lymphatic and perineural invasion.
- Combined HER2 and HER3 positivity was linked to significant perineural invasion.
- HER2 and HER3 overexpression correlates with aggressive tumor features in pancreatic cancer.

## Abstract

The new era of targeted treatment is continuously developing to include protein receptors in the standard protocols before and after surgical treatment in the endeavor of finding a cure for pancreatic cancer. Pancreatic cancer presents high heterogeneity and mortality rates. Epidermal growth factor family receptors (ErbBs) represent a common carcinogenic pathway, in particular, HER2 and HER3. Their overexpression increases tumor burden. This molecular profiling enhances the development of new-generation therapies dependent on ErbBs.

Background and Objectives: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive, heterogeneous, and lethal human malignancies, underscoring the urgent need for novel, targeted therapeutic strategies for neo(adjuvant) individualized treatment. The epidermal growth factor receptor family (ErbB) is directly involved in abnormal cell proliferation and tumor growth. The overexpression and amplification of HER2 and HER3 have emerged as key molecular events in pancreatic ductal adenocarcinoma. The aim of this study was to evaluate these membrane receptors’ overexpression in relation to pTNM staging, perineural and lymphovascular invasion, and tumor volume in order to obtain the immunohistochemical profile and enhance the development of a targeted and personalized therapy. Materials and Methods: An observational analytical cohort study included patients with histopathologically naïve, confirmed PDAC who underwent cephalic pancreatoduodenectomy at a national high-volume referral center between 2017 and 2022. Archived surgical specimens were retrieved and examined using a tissue microarray technique in two separate pathology departments by two independent pathologists. Results: HER2 positivity was found in 25 cases, of which 84% had lymphatic invasion, 50% had vascular invasion, and 84% had perineural invasion. Patients with HER3 positivity had lymphatic invasion (82.5%), perineural invasion (79.4%), and vascular invasion (38.1%). Combined HER2 and HER3 positivity was present in 19 cases, and these patients had 84.2% perineural invasion. Conclusions: HER2 and HER3 overexpression often coexisted with pathological features, such as perineural invasion, in cases of combined HER2 and HER3 positivity. These findings support the involvement of the ErbB receptor family in pancreatic carcinogenesis and suggest their potential as targets for future (neo)adjuvant therapeutic strategies.