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Since its introduction in the 1970s, endocrine therapy that targets the estrogen receptor alpha (ERα) signaling pathway has had tremendous success in the clinic in estrogen receptor positive (ER+) breast cancer. However, resistance to endocrine therapy eventually develops in virtually all patients with metastatic disease. Endocrine resistance is a primary unaddressed medical need for ER+ metastatic breast cancer patients. It has been shown that tumors become resistant through various mechanisms, converging on the acquisition of genetic alterations of ER, components of the MAP kinase pathway, or transcription factors (TFs). For instance, mutations in the human epidermal growth factor receptor-2 (HER2) lead to complete resistance to all current endocrine therapies including aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders, as well as cross-resistance to CDK4/6 inhibitors (CDK4/6is). Emerging evidence points to an intriguing connection between endocrine-resistant tumors and the HER2-low subtype. Specifically, recent studies and our analysis of a publicly available breast cancer dataset both indicate that metastatic ER+ breast cancer with endocrine resistance conferred through acquired genetic alterations can often be classified as HER2-low rather than HER2-0/HER2-negative. Limited data suggest that acquired endocrine resistance can also be accompanied by a subtype switch. Therefore, we suggest that there is an underappreciated association between the HER2-low subtype and endocrine resistance. In this perspective piece, we explore the evidence linking the HER2-low subtype with the various pathways to endocrine resistance and suggest that there are signaling networks in HER2-low tumors that intersect endocrine resistance and can be effectively targeted. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer subtyping is used clinically for diagnosis, prognosis, and treatment decisions. Subtypes are categorized by cell of origin, histomorphology, gene expression signatures, hormone receptor status, and/or protein levels. Categorizing breast cancer based on gene expression signatures aids in assessing a patient's recurrence risk. Protein biomarkers, on the other hand, provide functional data for selecting therapies for primary and recurrent tumors. We provide an update on protein biomarkers in breast cancer subtypes and their application in prognosis and therapy selection. Areas covered: Protein pathways in breast cancer subtypes are reviewed in the context of current protein-targeted treatment options. PubMed, Science Direct, Scopus, and Cochrane Library were searched for relevant studies between 2017 and 17 August 2024. Expert opinion: Post-translationally modified proteins and their unmodified counterparts have become clinically useful biomarkers for defining breast cancer subtypes from a therapy perspective. Tissue heterogeneity influences treatment outcomes and disease recurrence. Spatial profiling has revealed complex cellular subpopulations within the breast tumor microenvironment. Deciphering the functional relationships between and within tumor clonal cell populations will further aid in defining breast cancer subtypes and create new treatment paradigms for recurrent, drug resistant, and metastatic disease. [ABSTRACT FROM AUTHOR]

Background: In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan., Methods: Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint., Results: Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified., Conclusion: Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen., (© 2024. The Author(s).)