Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level

Atallah, N. M.; Alsaleem, M.; Toss, M. S.; Mongan, N. P.; Rakha, E.

Abstract

Background: Increasing data indicate that HER2-positive (HER2 +) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. Methods: A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. Results: Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. Conclusion: In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.

Citation

Atallah, N. M., Alsaleem, M., Toss, M. S., Mongan, N. P., & Rakha, E. (2023). Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level. British Journal of Cancer, https://doi.org/10.1038/s41416-023-02426-4

• Journal Article Type: Article
• Acceptance Date: Sep 5, 2023
• Online Publication Date: Sep 22, 2023
• Publication Date: 2023
• Deposit Date: Sep 21, 2023
• Publicly Available Date: Sep 27, 2023
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Springer Science and Business Media LLC
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s41416-023-02426-4
• Keywords: Breast cancer; HER2 positive; differential response; clinical outcome; Therapy; molecular profiling 1
• Public URL: https://nottingham-repository.worktribe.com/output/25365905
• Publisher URL: https://www.nature.com/articles/s41416-023-02426-4
• PMID: 37740038
• Additional Information: Received: 27 December 2022; Revised: 25 August 2023; Accepted: 5 September 2023; First Online: 22 September 2023; : The authors declare no competing interests.; : This study was approved by the Yorkshire & the Humber—Leeds East Research Ethics Committee (REC Reference: 19/YH/0293) under the IRAS Project ID: 266925. Data collected were fully anonymised.; : Not applicable.