Current Landscape of Targeted Therapy in Hormone Receptor-Positive and HER2-Negative Breast Cancer

Abstract

Background: Hormone receptor-positive and HER2-negative breast cancer (HR + BC) is the most prevalent breast cancer. Endocrine therapy is the mainstay of treatment, however, due to the heterogeneous nature of the disease, resistance to endocrine therapy is not uncommon. Over the past decades, the emergence of novel targeted therapy in combination with endocrine therapy has shown improvement in outcomes of HR + BC. This paper reviews available data of targeted therapy and the results of pivotal clinical trials in the management of HR + BC. Methods: A literature search in PubMed and Google Scholar was performed using keywords related to HR + BC and targeted therapy. Major relevant studies that were presented in international cancer research conferences were also included. Results: Endocrine therapy with tamoxifen and aromatase inhibitors are backbone treatments for women with early-stage HR + BC leading to a significant reduction in mortality. They can also be used for primary prevention in women with a high risk of breast cancer. Preliminary data has shown the efficacy of adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor, abemaciclib, in high-risk disease in combination with aromatase inhibitors. For most women with advanced HR + BC, endocrine therapy is the primary treatment. Recent evidence has shown that the use of CKD 4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors in combination with endocrine therapy has been associated with better outcomes and delays initiation of chemotherapy. Several novel agents are under study for HR + BC. Discussion: Targeted treatment options for HR + BC have evolved. The future of overcoming resistance to targeted therapy, novel compounds, and predictive markers are key to improving HR + BC outcomes.

Efficacy of Fulvestrant in Women with Hormone-Resistant Metastatic Breast Cancer (mBC): A Canadian Province Experience

“…Although our study participants were primarily using fulvestrant monotherapy, based on promising new data on CDK 4/6 inhibitors, it is recommended that CDK 4/6 inhibitors be added in combination with patients who have not previously received them. The benefit of CDK 4/6 inhibitors to fulvestrant treatment has been well established by significant increases in both PFS and OS [6,14]. In our study cohort, women treated with fulvestrant in combination with a CDK 4/6 inhibitor had better TTP and OS.…”

“…Fulvestrant and exemestane are equally active and well-tolerated in women with advanced breast cancer who have experienced progression or recurrence on a non-steroidal aromatase inhibitor [13]. More recently, fulvestrant in combination with targeted therapy in the first and subsequent line settings has shown better outcomes compared to fulvestrant alone [14]. For example, the phase III MONALESSA-3 trial involving 726 postmenopausal women showed that a combination of fulvestrant and ribociclib (a CDK 4/6 inhibitor) in the firstor second-line setting was associated with a median PFS of 20.5 months compared to 12.8 months with fulvestrant alone (HR: 0.59, 95% CI 0.48-0.73).…”

“…Likewise, the PALOMA-3 trial showed that fulvestrant in combination with palbociclib (another CDK 4/6 inhibitor) in the second or later line therapy was associated with a significantly superior median PFS of 9.5 months compared to 4.6 months with fulvestrant alone (HR: 0.46, 95% CI 0.36-0.59). Fulvestrant in combination with the PI3K3CA inhibitor, alpelisib, in the second or later line treatment has also shown better outcomes with a median PFS of 11.0 months compared to 5.7 months with fulvestrant alone (HR: 0.65, 95% CI 0.50-0.85) [14].…”

SARS-CoV-2 neutralizing antibodies after first vaccination dose in breast cancer patients receiving CDK4/6 inhibitors

“…Breast cancer represents a common malignancy of significant epidemiologic relevance among women. While, endocrine therapy (ET) has been historically the backbone of hormone receptor (HR)-positive disease, the recent advent of CDK4/6 inhibitors has transformed the therapeutic landscape of HR-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer [ 7 ]. Thus, these novel targeted therapies in combination with ET or fulvestrant are nowadays considered the standard of care for this subgroup of patients [ 8 ].…”

Histone Variant H2A.J Is Enriched in Luminal Epithelial Gland Cells

“…Breast cancers with a high expression of H2AFJ had a slightly higher survival rate compared to breast cancers that expressed low levels of H2AFJ (Figure 8). Since luminal breast cancer cells express H2AFJ at higher levels than basal breast cancer cells, this survival difference may reflect the more aggressive nature of basal versus luminal breast cancer [35]. Separating the breast cancer survival data according to PAM50 intrinsic molecular subtypes, high H2AFJ expression was correlated with a slightly elevated survival for all subtypes except luminal A breast cancer for which it showed significant negative correlation with survival (Supplementary Figure S7).…”