Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression

Atallah, Nehal M.; Haque, Maria; Quinn, Cecily; Toss, Michael S.; Makhlouf, Shorouk; Ibrahim, Asmaa; Green, Andrew R.; Alsaleem, Mansour; Rutland, Catrin S.; Allegrucci, Cinzia; Mongan, Nigel P.; Rakha, Emad

Abstract

Background: Breast cancer (BC) expressing low levels of human epidermal growth factor receptor 2 (HER2 Low) is an emerging category that needs further refining. This study aims to provide a comprehensive clinico-pathological and molecular profile of HER2 Low BC including response to therapy and patient outcome in the adjuvant and neoadjuvant settings. Methods: Two different independent and well-characterised BC cohorts were included. Nottingham cohort (A) (n = 5744) and The Cancer Genome Atlas (TCGA) BC cohort (B) (n = 854). The clinical, molecular, biological and immunological profile of HER2 Low BC was investigated. Transcriptomic and pathway enrichment analyses were performed on the TCGA BC cohort and validated through next-generation sequencing in a subset of Nottingham cases. Results: Ninety percent of HER2 Low tumours were hormone receptor (HR) positive (HR+), enriched with luminal intrinsic molecular subtype, lacking significant expression of HER2 oncogenic signalling genes and of favourable clinical behaviour compared to HER2 negative (HER2-) BC. In HR+ BC, no significant prognostic differences were detected between HER2 Low and HER2- tumours. However, in HR- BC, HER2 Low tumours were less aggressive with longer patient survival. Transcriptomic data showed that the majority of HR- /HER2 Low tumours were of luminal androgen receptor (LAR) intrinsic subtype, enriched with T-helper lymphocytes, activated dendritic cells and tumour associated neutrophils, while most HR-/HER2- tumours were basal-like, enriched with tumour associated macrophages. Conclusion: HER2 Low BC is mainly driven by HR signalling in HR+ tumours. HR-/HER2 Low tumours tend to be enriched with LAR genes with a unique immune profile.

Citation

Atallah, N. M., Haque, M., Quinn, C., Toss, M. S., Makhlouf, S., Ibrahim, A., Green, A. R., Alsaleem, M., Rutland, C. S., Allegrucci, C., Mongan, N. P., & Rakha, E. (2023). Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression. European Journal of Cancer, 195, Article 113371. https://doi.org/10.1016/j.ejca.2023.113371

• Journal Article Type: Article
• Acceptance Date: Sep 29, 2023
• Online Publication Date: Oct 27, 2023
• Publication Date: Dec 1, 2023
• Deposit Date: Oct 12, 2023
• Publicly Available Date: Oct 28, 2024
• Journal: European Journal of Cancer
• Print ISSN: 0959-8049
• Electronic ISSN: 1879-0852
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 195
• Article Number: 113371
• DOI: https://doi.org/10.1016/j.ejca.2023.113371
• Keywords: HER2 Low; breast cancer; intrinsic molecular subtype; transcriptomic analysis; CIBERSORT 1
• Public URL: https://nottingham-repository.worktribe.com/output/25811264
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0959804923006731
• PMID: 37897865
• Additional Information: This article is maintained by: Elsevier; Article Title: Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression; Journal Title: European Journal of Cancer; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejca.2023.113371; Content Type: article; Copyright: © 2023 The Authors. Published by Elsevier Ltd.