Endocrine therapy and strategies to overcome therapeutic resistance in breast cancer
Introduction
Breast cancer is a major health problem worldwide with more than 1 million new cases diagnosed each year and approximately 400,000 deaths annually.1 Approximately 70%-80% of all breast cancers express the estrogen receptors (ER) and progesterone receptors (PgR),2 at times referred to collectively as hormone receptor-positive breast cancer. The presence of hormone receptors is associated with certain predictable tumor characteristics and a biologic behavior that is more indolent when compared with hormone receptor-negative tumors. Importantly, ER and its ligand estrogen play a key role in the development and progression of breast cancer, and disruption of the ER signaling pathway using a variety of endocrine strategies has been a mainstay in the treatment of this disease (Fig).
More than 120 years ago, and long before we knew about the existence of ER in breast cancer, Beatson3 described the benefit of estrogen deprivation by oophorectomy in treatment of premenopausal women with advanced breast cancer. Although this estrogen deprivation strategy was the original endocrine therapy described, and the first targeted therapy approach, endocrine strategies evolved to include agents that target ER itself, with the selective estrogen receptor modulator tamoxifen as the prototype endocrine therapy modality for decades.4, 5, 6, 7 Although effective, tamoxifen was limited by the problem of therapeutic resistance2 and additional treatment modalities were needed. With time, therapeutic options for treatment of ER-positive breast cancer evolved further with the addition of several new and more powerful anti-ER strategies, including third-generation aromatase inhibitors (AIs), which cause estrogen deprivation in postmenopausal women,8 and fulvestrant, which leads to the degradation of ER.9
Despite the addition of these expanded endocrine therapy options with more effective inhibition of ER signaling,10 therapeutic resistance remained a major problem limiting the benefit of all forms of endocrine therapy, but also created more opportunity to study mechanisms of resistance and to target new resistance pathways to improve endocrine therapy action and modulate resistance. This has become possible with significant advances in our understanding of ER biology and the unraveling of an intricate interplay between ER and other survival and growth factor signaling pathways in a breast cancer cell (Fig).2, 11 Consequently, we have witnessed a progressive shift away from viewing ER as an isolated and static pathway in breast cancer, and increasingly view it as an interactive partner with other signaling pathways, as well as a dynamic target in response to the effect of treatment.
In this article, we highlight 2 key strategies that can be used to modulate endocrine response and resistance in patients. The first strategy involves inhibition of the PI3K/AKT/mTOR pathway, which is a key driver of endocrine resistance in patients with progressive disease on endocrine therapy. The second strategy involves cell cycle inhibition using agents that target cyclin dependent kinases (CDK) 4 and 6, and this strategy is increasingly taking center stage as a reliable approach to enhance endocrine effect, for both second and first-line metastatic disease. We will also highlight the evolving role of fulvestrant and ER degradation as a unique endocrine therapy approach to use in combination with resistance pathway inhibitors and future strategies. Finally, we will discuss the subset of ER-positive breast cancer that expresses the human epidermal growth factor receptor-2 (HER2) and potential implications for endocrine resistance. There are of course many facets and dimensions involved in endocrine resistance, and through continued understanding of ER biology and dynamicity we will continue to refine our therapeutic options in individual patients with ER-positive breast cancer and the timing of when to most effectively use the different available strategies to modulate endocrine therapy.
Section snippets
Role of PI3K/AKT/mTOR pathway in endocrine resistance
One of the most critical signaling pathways that emerge after prolonged estrogen deprivation in ER-positive breast cancer is the PI3K/AKT/mTOR survival pathway12, 13 and has, therefore, been an important feature of progressive disease biology after AI failure.14 Preclinical models of ER-positive breast cancer have consistently shown that inhibition of PI3K/AKT/mTOR signaling can restore endocrine sensitivity and halt tumor regrowth.15, 16, 17 Clinical data also support the role of this pathway
Role of CDK4/6 inhibition to modulate endocrine response
CDK 4/6 inhibition has recently emerged as an effective and feasible strategy to prevent as well as to overcome endocrine resistance in metastatic ER-positive breast cancer. Palbociclib, an oral inhibitor of CDK 4 and CDK 6, has shown activity in both the first-line and second-line metastatic disease settings when combined with endocrine therapy. PALOMA-1 was a phase II randomized clinical trial in patients with newly metastatic ER-positive breast cancer, which compared the combination of
Is ER degradation a more effective endocrine strategy to use with targeted therapy?
Theoretically, a strategy of completely or nearly completely destroying the ER, may lead to a more effective inhibition of highly ER-dependent tumors. Fulvestrant, which degrades ER, has emerged as a valuable endocrine modality for patients with metastatic ER-positive breast cancer, but there were questions on how best to use it in patients, with earlier issues related to timing of its use, proper dosing, and whether it should be combined with other agents for optimal effect.33, 34, 35 Despite
The interplay between ER and HER2
HER2 is amplified or overexpressed in 20%-30% of all invasive breast cancers, with approximately 10% of breast tumors expressing both ER and HER2.57, 58 HER2 is a critical driver of cancer cell survival that is associated with decreased benefit from endocrine therapy when present.59, 60 Preclinical studies show that functional “crosstalk” between HER2 and ER can be a mechanism of resistance to endocrine therapy and inhibition of HER2 improves endocrine sensitivity in these studies.61, 62
There
Future directions
Endocrine therapy has come a long way since it was initially described and continues to play a central role in the management of patients with ER-positive breast cancer. Our improved understanding of endocrine-resistance mechanisms over the past 15 years has produced tangible benefits for patients and we should continue to carefully study mechanisms of resistance to further refine therapy. In particular, we need to better identify which patients are most likely to derive the most benefit from
Funding source
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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