Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer

Mark Pegram; Richard Pietras; Chau T Dang; Rashmi Murthy; Thomas Bachelot; Wolfgang Janni; Priyanka Sharma; Erika Hamilton; Cristina Saura

doi:10.1177/17588359231187201

Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer

Ther Adv Med Oncol. 2023 Aug 11:15:17588359231187201. doi: 10.1177/17588359231187201. eCollection 2023.

Authors

Mark Pegram¹, Richard Pietras^{2

3}, Chau T Dang^{4

5}, Rashmi Murthy⁶, Thomas Bachelot⁷, Wolfgang Janni⁸, Priyanka Sharma⁹, Erika Hamilton¹⁰, Cristina Saura¹¹

Affiliations

¹ Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building/SIM 1, 265 Campus Drive, Ste G2103, Stanford, CA 94305-5456, USA.
² Division of Hematology-Oncology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
³ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
⁴ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁵ Weill Cornell Medical College, New York, NY, USA.
⁶ Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
⁸ Department of Gynecology and Obstetrics, University Hospital Ulm, University of Ulm, Ulm, Germany.
⁹ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Kansas City, KS, USA.
¹⁰ Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
¹¹ Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Medical Oncology Service, Barcelona, Spain.

Abstract

Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR-/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.

Keywords: CDK4/6 inhibitors; HR+/HER2+ breast cancer; metastatic breast cancer; resistance; triple-positive breast cancer.

Publication types

Review

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States