Advances in Endocrine and Targeted Therapy for Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer

Advances in Endocrine and Targeted Therapy for Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer

Breast cancer (BC) remains the most frequent malignancy among women worldwide and is the fifth leading cause of cancer-related deaths among females in China. Approximately 70% of breast cancers are hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, making endocrine therapy (ET) the cornerstone of treatment for this subtype. Despite the efficacy of ET, intrinsic or acquired endocrine resistance often develops, necessitating the exploration of targeted therapies to overcome this resistance. This article provides a comprehensive overview of the advancements in endocrine and targeted therapies for HR-positive, HER2-negative advanced breast cancer (ABC), focusing on the mechanisms of endocrine resistance and the role of targeted therapies.

Current Antiestrogenic Endocrine Therapies

Endocrine therapy is the mainstay of treatment for HR-positive, HER2-negative breast cancer. The primary ET options include selective estrogen receptor modulators (SERMs) like tamoxifen, aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane, and selective estrogen receptor downregulators (SERDs) like fulvestrant. Tamoxifen, approved in the 1970s, has both estrogenic and antiestrogenic effects, which can lead to side effects such as endometrial cancer and thromboembolic disease. AIs, which inhibit the aromatase enzyme, are particularly effective in postmenopausal women by reducing estrogen production. A meta-analysis of 23 randomized trials demonstrated that AIs significantly improve survival compared to tamoxifen.

Fulvestrant, a SERD, has a higher binding affinity to the estrogen receptor (ER) and exerts its effects by inhibiting ER dimerization, attenuating ER translocation to the nucleus, and accelerating ER degradation. The CONFIRM study showed that a higher dose of fulvestrant (500 mg monthly) significantly improved progression-free survival (PFS) compared to the lower dose (250 mg monthly). The FALCON trial further demonstrated that fulvestrant 500 mg improved PFS compared to anastrozole as first-line therapy for postmenopausal patients with ABC.

Mechanisms of Endocrine Resistance

Despite the effectiveness of ET, resistance remains a significant challenge. Several mechanisms contribute to endocrine resistance, including deregulation of the cell cycle, activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, and mutations in the ESR1 gene, which encodes ERα.

Deregulation of the cell cycle, particularly involving cyclin D1 and cyclin-dependent kinases (CDK) 4/6, plays a crucial role in endocrine resistance. Cyclin D1 overexpression, found in approximately 50% of primary breast tumors, promotes cell proliferation even in the presence of antiestrogens. CDK4/6 inhibitors have shown efficacy in ER-positive and endocrine-resistant breast cancers by inducing G1 cell cycle arrest.

The PI3K/AKT pathway is frequently activated in HR-positive, HER2-negative breast cancer and is associated with resistance to ET. Activation of this pathway leads to ligand-independent ER transcriptional activity, promoting tumor growth. Loss of phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/AKT signaling, is also implicated in endocrine resistance.

ESR1 mutations, particularly in metastatic breast cancer, confer constitutive activation of ERα, leading to estrogen-independent tumor growth. These mutations are enriched in patients treated with AIs but not in those treated with fulvestrant. Liquid biopsies, including circulating tumor DNA (ctDNA), have been used to detect ESR1 mutations, which are associated with more aggressive disease and worse outcomes.

Targeted Therapy Options to Overcome Endocrine Resistance

Targeted therapies have emerged as effective strategies to overcome endocrine resistance. Key targeted therapies include CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and histone deacetylase (HDAC) inhibitors.

CDK4/6 Inhibitors and Emerging Acquired Resistance

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have shown significant efficacy in HR-positive, HER2-negative breast cancer. Palbociclib, the first CDK4/6 inhibitor, demonstrated improved PFS when combined with letrozole in the PALOMA-2 trial and with fulvestrant in the PALOMA-3 trial. Ribociclib, approved based on the MONALEESA trials, showed improved PFS in combination with letrozole, fulvestrant, and tamoxifen. Abemaciclib, with greater affinity for CDK4, demonstrated improved PFS in combination with fulvestrant in the MONARCH 2 trial and with AIs in the MONARCH 3 trial.

Despite the efficacy of CDK4/6 inhibitors, resistance often develops. Mechanisms of resistance include loss of retinoblastoma protein (Rb), increased activity of CDK2 and CDK6, and upregulation of alternate pathways such as PI3K/AKT signaling. Preclinical studies have shown that loss or mutation of Rb reduces sensitivity to CDK4/6 inhibitors. Amplification of cyclin E1 and CDK6 has also been associated with resistance. Additionally, activation of the PI3K/AKT pathway can bypass CDK4/6 inhibition, highlighting the potential for combination therapies with PI3K or mTOR inhibitors.

mTOR Inhibitors

mTOR inhibitors, such as everolimus, target the PI3K/AKT/mTOR pathway, which is frequently activated in endocrine-resistant breast cancer. The BOLERO-2 trial demonstrated that everolimus combined with exemestane significantly improved PFS in patients with HR-positive, HER2-negative ABC who had progressed on nonsteroidal AIs. However, the combination did not significantly improve overall survival (OS). The MANTA trial compared fulvestrant plus everolimus with fulvestrant plus vistusertib (a dual mTORC1/2 inhibitor) and found that everolimus significantly improved PFS compared to vistusertib and fulvestrant alone.

PI3K Inhibitors

PI3K inhibitors, including pan-PI3K inhibitors like buparlisib and isoform-specific inhibitors like taselisib and alpelisib, have shown promise in overcoming endocrine resistance. The BELLE-2 trial demonstrated that buparlisib combined with fulvestrant significantly improved PFS in postmenopausal women with AI-resistant, HR-positive, HER2-negative ABC. The SANDPIPER trial showed that taselisib improved PFS in patients with PIK3CA-mutated tumors. The SOLAR-1 trial demonstrated that alpelisib combined with fulvestrant significantly improved PFS in patients with PIK3CA-mutated, HR-positive, HER2-negative ABC.

Histone Deacetylase Inhibitors

HDAC inhibitors, such as entinostat and chidamide, target epigenetic mechanisms of endocrine resistance. The ENCORE 301 trial showed that entinostat combined with exemestane improved PFS and OS in patients with HR-positive, HER2-negative ABC. The ACE trial demonstrated that chidamide combined with exemestane significantly improved PFS in Chinese patients with HR-positive, HER2-negative ABC who had failed prior ET.

Conclusions

The treatment landscape for HR-positive, HER2-negative ABC has evolved significantly with the development of targeted therapies. Endocrine therapy remains the preferred initial treatment, with AIs and fulvestrant being the mainstays. However, the emergence of targeted therapies, including CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, and HDAC inhibitors, has provided new avenues to overcome endocrine resistance. The optimal sequence of treatment remains a subject of ongoing research, with combination therapies showing promise in improving outcomes. Further studies are needed to identify predictive biomarkers, optimize treatment sequences, and explore new targeted therapies to enhance the quality of life and survival of patients with HR-positive, HER2-negative ABC.

doi.org/10.1097/CM9.0000000000000745

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