Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 May 31;9(1):45.
doi: 10.1038/s41523-023-00533-2.

Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer

Mark Pegram  1 , Christian Jackisch  2 , Stephen R D Johnston  3
Affiliations
Review

Estrogen/HER2 receptor crosstalk in breast cancer: combination therapies to improve outcomes for patients with hormone receptor-positive/HER2-positive breast cancer

Mark Pegram et al. NPJ Breast Cancer. .

Abstract

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 13-22% of breast cancers (BC). Approximately 60-70% of HER2+ BC co-express hormone receptors (HRs). HR/HER2 co-expression modulates response to both anti-HER2-directed and endocrine therapy due to "crosstalk" between the estrogen receptor (ER) and HER2 pathways. Combined HER2/ER blockade may be an effective treatment strategy for patients with HR+/HER2+ BC in the appropriate clinical setting(s). In this review, we provide an overview of crosstalk between the ER and HER2 pathways, summarize data from recently published and ongoing clinical trials, and discuss clinical implications for targeted treatment of HR+/HER2+ BC.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing interests: MP has served as a consultant for Roche/Genentech, AstraZeneca, Novartis, Pfizer, Seattle Genetics. CJ has served as a consultant for Roche, AstraZeneca, Pfizer, Celgene, Exact Sciences, Lilly, Pierre Fabre, and Sanofi Genzyme; has presented on behalf of Roche, AstraZeneca, Pfizer, Celgene, Exact Sciences, Novartis, Lilly, and medupdate GmbH; and has received research funding from Exact Sciences and Roche. SRDJ has served as a consultant for Lilly, Puma Biotechnology, Pfizer, Novartis, and Sanofi Genzyme; has presented on behalf of Pfizer, Novartis, Eisai, Lilly, AstraZeneca, Roche/Genentech, and Sanofi Genzyme; and has received research funding from Lilly, Pfizer, AstraZeneca, Novartis, Roche/Genentech, and Puma Biotechnology.

Figures

Fig. 1
Fig. 1. Overview of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) signaling crosstalk.
a HER2 overactivation results in downregulation of ER-regulated transcription and resistance to endocrine therapy. b Blockade of HER2 leads to activation of ER gene transcription via signaling crosstalk pathways as a compensatory mechanism for tumor growth and survival. c Inhibition of HER2 and ER pathways are both required to achieve effective HER2+/HR+ antitumor activity. Gray shading of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK signaling pathways in panels a and b indicate downregulation of these pathways. AI aromatase inhibitor, ER estrogen receptor, ERK extracellular signal-regulated kinase, HER2 human epidermal growth factor receptor 2, HR hormone receptor, MEK mitrogen-activated protein kinase kinase, mTOR mammalian target of rapamycin, P13K phosphatidylinositol 3-kinase, RAF rapidly accelerated fibrosarcoma, SERD selective estrogen receptor degrader, SERM selective estrogen receptor modulator, TKI tyrosine kinase inhibitor.
Fig. 2
Fig. 2. PFS and DFS benefits of dual ER/HER2 blockade in key phase 2 and 3 clinical trials.
Error bars indicate 95% CI. AI aromatase inhibitor; CI confidence interval; DFS disease-free survival; ER estrogen receptor; HER2 human epidermal growth factor receptor 2; HR hormone receptor; PFS progression-free survival; TTP time to progression.
See this image and copyright information in PMC

References

    1. Caldarella A, et al. Female breast cancer status according to ER, PR and HER2 expression: a population based analysis. Pathol. Oncol. Res. 2011;17:753–758. doi: 10.1007/s12253-011-9381-z. - DOI - PubMed
    1. Howlader, N. et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J. Natl Cancer Inst.10.1093/jnci/dju055 (2014). - PMC - PubMed
    1. Purdie CA, et al. Increased mortality in HER2 positive, oestrogen receptor positive invasive breast cancer: a population-based study. Brit. J. Cancer. 2010;103:475–481. doi: 10.1038/sj.bjc.6605799. - DOI - PMC - PubMed
    1. Gong Y, Liu YR, Ji P, Hu X, Shao ZM. Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study. Sci. Rep. 2017;7:45411. doi: 10.1038/srep45411. - DOI - PMC - PubMed
    1. Noone, A. M. et al. SEER Cancer Statistics Review 1975–2015 (National Cancer Institute, 2018).