Clinical Challenges in the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: A Literature Review

Adv Ther. 2021 Jan;38(1):109-136. doi: 10.1007/s12325-020-01552-2. Epub 2020 Nov 15.


Endocrine therapy (ET) is integral to the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Aromatase inhibitors (AIs; e.g., anastrozole, letrozole, exemestane), selective estrogen receptor modulators (e.g., tamoxifen), and the selective estrogen receptor degrader, fulvestrant, inhibit tumor cell proliferation by targeting ER signaling. However, the efficacy of ET could be limited by intrinsic and acquired resistance mechanisms, which has prompted the development of targeted agents and combination strategies. In recent years, the treatment landscape for HR+, HER2- MBC has evolved rapidly. AIs, historically the first-line treatment for postmenopausal patients with HR+, HER2- MBC, have been challenged by more effective ET, such as fulvestrant alone or in combination with an AI, and the cyclin-dependent kinase (CDK)4/6 inhibitors, which have increasingly become the new standard of care. For endocrine-resistant disease (≥ second-line), clinical trials demonstrated that the mammalian target of rapamycin inhibitor, everolimus, enhanced the efficacy of exemestane or fulvestrant after progression on an AI. CDK4/6 inhibitors in combination with fulvestrant have demonstrated superior progression-free survival and overall survival versus fulvestrant alone. Recently, the combination of fulvestrant with alpelisib in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2- MBC following progression on or after ET was approved, based on the SOLAR-1 study. However, the optimal sequencing of treatments is unknown, especially following disease progression on a CDK4/6 inhibitor. This review aims to provide practical guidance for the management of HR+, HER2- MBC based on available data and the utility of genomic biomarkers, including germline breast cancer genes 1 and 2 (BRCA1/2) mutations, and somatic estrogen receptor alpha gene (ESR1), HER2, and PIK3CA mutations.

Keywords: Aromatase inhibitors; Cyclin-dependent kinase 4/6 inhibitors; Endocrine therapy; Fulvestrant; Hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer; Mammalian target of rapamycin inhibitors; Phosphoinositide 3-kinase pathway inhibitors; Selective estrogen receptor degrader.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Humans
  • Receptor, ErbB-2 / therapeutic use
  • Receptors, Estrogen*


  • Receptors, Estrogen
  • ERBB2 protein, human
  • Receptor, ErbB-2