Endocrine and Targeted Therapy for Hormone-Receptor-Positive, HER2-Negative Advanced Breast Cancer: Insights to Sequencing Treatment and Overcoming Resistance Based on Clinical Trials

Abstract

Background: Advanced hormone-receptor positive HER2 negative breast cancer is a common and a very heterogeneous disease. Hormone therapy is the main first line treatment of choice, given alone or in combination with other agents that have shown to improve patient outcomes, Nevertheless, treatment remains generally palliative rather than curative. Sequencing of such treatment remains challenging, especially with resurgence of variable resistance patterns. Multiple attempts have been made to overcome resistance and improve patient survival, yet resistance remains not very well understood and metastatic cancer remains a disease with dismal prognosis. Methods: In this paper, we searched pubmed database as well as local and international meetings for all studies discussing advanced and metastatic hormone-receptor-positive, her2-negative breast cancer, hormonal treatment, resistance to hormonal treatment, mechanism of resistance, and means to overcome such resistance. Conclusion: There does not exist an optimal treatment sequence for hormone-receptor-positive, her2-negative advanced breast cancer. However, after review of literature, a reasonable approach may be starting with tamoxifen, aromatase inhibitors, or fulvestrant in absence of visceral crisis, in addition to ensuring adequate ovarian function suppression in pre/peri-menopausal women. Aromatase inhibitors and fulvestrant seem to be superior. Resistance to such agents is increasing, mostly attributed to genetic and molecular changes. Multiple modalities are addressed to overcome such resistance including use of CKD4/6 inhibitors, mTOR inhibitors and PI3K inhibitors in addition to other agents under study, all with promising results. CDK4/6 inhibitors work best when used in frontline setting. Finally, treatment of breast cancer remains a growing field, and more studies are to be awaited.

Clinical implications of prospective genomic profiling of metastatic breast cancer patients

“…Breast cancer remains the most common malignancy and cause of cancer-associated death amongst women worldwide [1,2]. For patients with metastatic breast cancer (MBC) the disease is almost always fatal, with 5-year survival rates of approximately 26% [3,4]. In early-stage breast cancer, treatment decisions are guided by the clinical subtypes of oestrogen receptor positive (ER+ HER2−), human epidermal growth factor receptor 2 amplified (HER2+) and triple-negative breast cancer (TNBC), which are defined by the presence or absence of the oestrogen receptor and progesterone receptor and HER2 overexpression or gene amplification.…”

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…Moreover, the agonist effect of tamoxifen may induce a risk of endometrial cancer after long-term use in postmenopausal women [71]. Generally, AIs and fulvestrant are used to follow or replace when patients are resistant to tamoxifen [71,72]. However, resistance to AIs and fulvestrant eventually occurs [73][74][75].…”

“…Recently, multiple targeted agents are used to overcome endocrine resistance, including the use of inhibitors for cyclin-dependent kinases 4 and 6 (CDK4/6), mammalian target of rapamycin (mTOR), PI3K/AKT and histone deacetylase, as well as investigation of new SERDs/SERMs [70,72,80]. In addition, it has been shown that HER2 inhibitors combined with endocrine therapies contain clinical benefit [79].…”

Optimizing care for younger women with hormone receptor‐positive, HER2‐negative metastatic breast cancer

“…2,6,22,23 Adding a targeted therapy to ET has been shown to improve efficacy and delay the development of endocrine resistance. 6,22,23 Targeted therapies include CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib), the mTOR inhibitor everolimus and the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib (approved for use in combination with fulvestrant as a treatment for postmenopausal women and men with HR + /HER2 -, PIK3CAmutated metastatic breast cancer, after progression on or after an endocrine-based regimen). 6,23,24 The development of potent, selective, orally bioavailable CDK4/6 inhibitors has transformed the care of patients with advanced HR + /HER2breast cancer.…”

“…6,22,23 Targeted therapies include CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib), the mTOR inhibitor everolimus and the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib (approved for use in combination with fulvestrant as a treatment for postmenopausal women and men with HR + /HER2 -, PIK3CAmutated metastatic breast cancer, after progression on or after an endocrine-based regimen). 6,23,24 The development of potent, selective, orally bioavailable CDK4/6 inhibitors has transformed the care of patients with advanced HR + /HER2breast cancer. 6,25,26 Each of the available CDK4/6 inhibitors -ribociclib, palbociclib and abemaciclib -has been shown to be effective and generally well tolerated when used in combination with ET in both the first-line [25][26][27][28][29][30][31][32][33][34] and second-line settings.…”