Overcoming Endocrine Resistance in Hormone Receptor–Positive Breast Cancer

Abstract

Endocrine therapy, a major modality in the treatment of hormone receptor (hr)-positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)-targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways-most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.

A data driven approach to identify ZM-447439 as a potential repurposed drug to overcome tamoxifen-resistance in breast cancer

“…We had 190 drugs and 376 genetic perturbants that have connectivity score < -90 (Table S7 and Table S8) in the MCF7 cell line. From Table S7, palbociclib, an CDK inhibitor, had the best connectivity score (Cs=-99.96) which is consistent with reports of the potential of CDK inhibitors to significantly reduce tamoxifen resistance (5,19,20).…”

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

“…20), capivasertib in combination with fulvestrant significantly improved PFS in patients with advanced ER þ HER2 À breast cancer previously treated with aromatase inhibitors, with an observed OS improvement of approximately 6 months, although this was not statistically significant (37% OS data maturity). The successful development of a targeted AKT inhibitor such as capivasertib, either as monotherapy or in combination, may provide a new treatment option in breast cancer that helps circumvent endocrine therapy resistance from aberrant activation of the pathway (21). In a separate phase II trial (BEECH: NCT01625286), adding capivasertib to weekly paclitaxel did not prolong PFS in a population of patients with advanced ER þ /HER2 À breast cancer or in a subpopulation whose tumors harbored a PIK3CA mutation (22).…”

Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer

“…Of note, two ESR1 ORFs conferred resistance specifically to GDC-0810 but not fulvestrant, possibly due to GDC-0810 having a less potent effect on ER degradation than fulvestrant [21, 39]. Among the resistance mechanisms shared by fulvestrant and GDC-0810, many are frequently altered in ER+ MBC, such as CCNDs/CDK6, KRAS/MAPK, EGFR/ERBB2 and PIK3CA/AKTs/PIMs , and agents targeting those alterations are under clinical development to be combined with endocrine therapy [14, 40]. We also identified potential resistance mechanisms that are not characterized to the same extent, such as G protein-coupled receptors, Wnt pathway ( FZD10, RSPO1, RSPO3 ) and Src family kinases ( YES1, FYN, FGR ), providing clues as to the potential crosstalk between these pathways and ER signaling [41–43] and suggesting that breast cancer patients harboring functional alterations in these pathways may develop resistance to SERDs.…”