# Characterisation of HER2‐Driven Morphometric Signature in Breast Cancer and Prediction of Risk of Recurrence

## TL;DR

This study identifies a morphological signature in HER2-positive breast cancer that predicts response to anti-HER2 therapy and recurrence risk.

## Contribution

A novel HER2-driven morphometric signature is developed to predict prognosis and treatment response in HER2-positive breast cancer.

## Key findings

- 22 morphometric features were significantly associated with HER2 positivity.
- HER2 IHC 3+/ER-negative tumors showed the least intra-tumor heterogeneity and strongest HER2-related features.
- The morphometric signature predicted recurrence risk with 87% accuracy and improved metastasis-free survival.

## Abstract

Human epidermal growth factor receptor 2‐positive (HER2‐positive) breast cancer (BC) is a heterogeneous disease. In this study, we hypothesised that the degree of HER2 oncogenic activity, and hence response to anti‐HER2 therapy is translated into a morphological signature that can be of prognostic/predictive value.

We developed a HER2‐driven signature based on a set of morphometric features identified through digital image analysis and visual assessment in a sizable cohort of BC patients. HER2‐enriched molecular sub‐type (HER2‐E) was used for validation, and pathway enrichment analysis was performed to assess HER2 pathway activity in the signature‐positive cases. The predictive utility of this signature was evaluated in post‐adjuvant HER2‐positive BC patients.

A total of 57 morphometric features were evaluated; of them, 22 features were significantly associated with HER2 positivity. HER2 IHC score 3+/oestrogen receptor‐negative tumours were significantly associated with HER2‐related morphometric features compared to other HER2 classes including HER2 IHC 2+ with gene amplification, and they showed the least intra‐tumour morphological heterogeneity. Tumours displaying HER2‐driven morphometric signature showed the strongest association with PAM50 HER2‐E sub‐type and were enriched with ERBB signalling pathway compared to signature‐negative cases. BC patients with positive HER2 morphometric signature showed prolonged distant metastasis‐free survival post‐adjuvant anti‐HER2 therapy (p = 0.007). The clinico‐morphometric prognostic index demonstrated an 87% accuracy in predicting recurrence risk.

Our findings underscore the strong prognostic and predictive correlation between HER2 histo‐morphometric features and response to targeted anti‐HER2 therapy.