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., …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.