Endocrine therapy is widely accepted as the most important treatment for all patients with hormone receptor-positive breast cancer. However, despite the positive effect of endocrine therapy on clinical outcome, resistance to these drugs inevitably develops. This article reviews the problem of resistance to hormonal therapy and addresses potential approaches to overcome intrinsic or acquired mechanisms of resistance.

https://clincancerres.aacrjournals.org/content/clincanres/12/16/4790.full.pdf

Estrogen Receptor Pathway: Resistance to Endocrine Therapy and New Therapeutic Approaches

Purpose: Raloxifene is a second-generation selective estrogen receptor modulator that reduces the incidence of breast cancer in postmenopausal women. Exemestane, a steroidal aromatase inhibitor, decreases contralateral new breast cancers in postmenopausal women when taken in the adjuvant setting. Preclinical evidence suggests a rationale for coadministration of these agents to achieve complete estrogen blockade. Experimental design: We tested the safety and tolerability of combination exemestane and raloxifene in 11 postmenopausal women with a history of hormone receptor-negative breast cancer. Patients were randomized to either raloxifene (60 mg PO daily) or exemestane (25 mg PO daily) for 2 weeks. Patients then initiated combination therapy at the same dose levels for a minimum of 1 year. Pharmacokinetic and pharmacodynamic data for plasma estrogens, raloxifene, exemestane, and their metabolites were collected at the end of single-agent therapy and during combination therapy. Results: Plasma concentration–time profiles for each drug were unchanged with monotherapy versus combination therapy. Raloxifene did not affect plasma estrogen levels. Plasma estrogen concentrations were suppressed below the lower limit of detection by exemestane as monotherapy and when administered in combination with raloxifene. The most common adverse events of any grade included arthralgias, hot flashes, vaginal dryness and myalgias. Conclusions: In this small study, coadministration of raloxifene and exemestane did not affect the pharmacokinetics or pharmacodynamics of either agent to a significant degree in postmenopausal women. The combination of estrogen receptor blockade and suppression of estrogen synthesis is well tolerated and warrants further investigation.

Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer

Tamoxifen, once the gold standard adjuvant endocrine therapy for early breast cancer, is being challenged by third-generation aromatase inhibitors (AIs) that have demonstrated improved disease-free survival in a variety of adjuvant settings for early breast cancer. Tamoxifen and AIs have different safety profiles, which should allow physicians to begin to individualize treatment based on a patient’s comorbidities and risk factors. Because of its properties as a partial estrogen agonist, tamoxifen has a positive effect on serum lipids and may confer a cardioprotective benefit, as well as a beneficial effect on bone health. However, tamoxifen increases the risk for endometrial cancer and cerebrovascular/thromboembolic events. In comparison, the major side effect of AIs is increased bone loss, which may heighten the risk for osteoporotic fractures and bone pain. Because of their superefand manageable side efsIs are a cost-effective alternative to tamoxifen, and clinical guidelines now embrace AIs as appropriate adjuvant therapy for hormone-sensitive early breast cancer. The anticipated results of ongoing trials will provide further insights into the long-term safety and application of AI therapy in the adjuvant setting.

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.11-10-1058

Appraising Adjuvant Aromatase Inhibitor Therapy

Cardiovascular disease is the most frequent cause of death in North American women, and so death resulting from cardiovascular disease, rather than from malignancy, is not uncommon in breast cancer patients. This may be a consequence of the shared risk factors for developing breast cancer and cardiovascular disease, as well as the difficulty of managing cancer patients at higher risk for developing cardiovascular disease. Recently, much attention has focused on understanding the cardiovascular risk factors associated with breast cancer therapies. Tamoxifen has a lowering effect on serum lipids and is reported to decrease the risk of myocardial infarction but to increase the risk of thromboembolic events. Current data indicate that aromatase inhibitors (AIs) are not associated with an increased risk of thromboembolic or cerebrovascular events. Reports of a greater incidence of hypercholesterolaemia when AIs are compared head-to-head with tamoxifen may be a result of the intrinsic lipid-lowering effects of tamoxifen therapy and may be confounded by differences in data collection among trials. The incidence of cardiovascular events associated with AIs in large trials has been reported to be higher in trials comparing AIs with tamoxifen; comparisons within the MA.17 trial, which evaluated an AI versus placebo, did not show increases in hypercholesterolaemia or in cardiovascular events with the AI. When treating breast cancer patients, oncologists should consider the same positive lifestyle changes that are proposed to lower the risk of cardiovascular disease in patients who do not have breast cancer. Moreover, physicians should assess cardiovascular risk, and monitor and treat patients already diagnosed with or at risk for coronary heart disease, according to established guidelines.

Cardiovascular health and aromatase inhibitors.

In 1896, George Beatson [1] showed that oophorectomy resulted in tumor remission in a proportion of women with metastatic breast cancer. With over two-thirds of breast cancers demonstrating high expression of estrogen receptor (ER), known to contribute to tumor growth and progression, Beatson’s findings revolutionized the management of this disease, paving the way to the discovery of anti-hormonal agents such as tamoxifen, known to selectively modulate the ER. Most recently, aromatase inhibitors that function by preventing extragonadal peripheral estrogen synthesis have also demonstrated clinical activity in various settings. In fact, both classes of agents have been shown in large randomized clinical trials to improve relapse-free survival and to reduce incidence of contralateral breast cancers in women with early-stage breast cancer and overall survival in patients with advanced disease [2–4]. Despite these tremendous advances in the therapeutic management of women with hormone-sensitive breast cancers, a significant proportion will experience disease progression secondary to either an inherently intrinsic or acquired resistance to endocrine agents. As a result researchers have focused both on clearly defining ER biology and subsequently discerning the mechanisms involved in developing endocrine resistance. Like other steroid hormones, the classic pathway of estrogen receptor signal transduction involves estrogen binding to the intracellular portion of the ER, triggering a series of events that lead to altered gene transcription, which results in the production of proteins that drive cell division and promotes angiogenesis and cell survival, resulting in breast cancer growth and progression [5]. However, further investigations have elucidated other mechanisms of ER activation such as the binding of estrogen ligand to the cell surface portion of the ER [6]. In addition, in the absence of an estrogen ligand the receptor can be activated via growth factor receptor-driven kinase pathways [5] followed by the activation of key downstream signaling kinases such as the p42/44 mitogen-activated protein kinase (MAPK) and Akt, resulting in subsequent cell proliferation and survival. It is this molecular cross-talk between ER and growth factor signaling pathways that is one of the most critical contributors to the development of resistance to endocrine therapy. In an attempt to overcome endocrine resistance, clinical studies have focused on developing novel agents that can reverse resistance at the ER level or target downstream estrogen signaling elements. Several studies have demonstrated that overactivity of the Akt pathway is involved in endocrine resistance. The principal enzyme involved in this pathway, phosphatidylinosital-3-kinase (P13K), cannot be directly inhibited, however; studies have focused on inhibiting its key target protein rapamycin (mTOR). In this issue of the journal, Beeram and colleagues [7] report on the use of an mTOR kinase inhibitor in reversing endocrine resistance in a breast cancer model in vivo. The authors generated an MCF-7 subline with constitutively activated Akt (myristolated or myrAkt1MCF-7) that demonstrated resistance both to the aromatase inhibitor letrozole and to fulvestrant. The authors successfully demonstrated that co-treatment with the mTOR inhibitor RAD-001 restored sensitivity of the breast cancer cell lines to both endocrine agents. Similarly, the mTOR inhibitor temsirolimus (CCI-779) has been shown in in-vivo models to restore sensitivity of cancer cells to tamoxifen [8]. This elegant work provides the support for prospectively designed clinical trials that have significant chances to improve the outcome of patients with hormone receptor (HR)-positive disease. Interestingly, data from a recently completed phase II trial showed efficacy when temsirolimus was combined with letrozole [9] and currently a phase II trial is assessing the combination of RAD-001 with letrozole in the neoadjuvant setting. If this combination proves to be effective it will represent one of only a few examples of rationally designed and clinically successful therapy in HR-positive disease. In fact, the complexity of the endocrine-related pathway in cancer cells means that attempts to propose new agents or to develop effective, rationally designed combinations have not always been successful. The realization that, despite the expression of ER, currently the best predictor of response to endocrine therapy, a proportion of women treated with tamoxifen in either the adjuvant or metastatic setting would eventually progress, led to the development of other endocrine agents with different mechanisms of action. Aromatase inhibitors have gained widespread acceptance, rapidly replacing tamoxifen as first-line treatment in both the adjuvant and metastatic setting. Fulvestrant, an agent that binds, blocks and degrades ER, has been shown in preclinical and clinical studies to retard growth of tamoxifen-resistant breast tumors [10, 11]. Despite these therapeutic advances our ability to take full advantage of ER inhibition is limited by the development of resistance, which ultimately develops to all forms of endocrine therapy. Continuous activation of growth factor signaling pathways, the major mechanism implicated in the development of endocrine resistance in breast cancer cells, is thought to occur as a result of either upregulation of growth factor receptors or excessive supply of their ligands, which ultimately leads to continuous activation of growth factor receptors and their e d it o ri a l

Endocrine resistance in breast cancer: what really matters?

LBA525 Background: This study addresses the principle of “complete estrogen blockade” by combining atamestane, an investigational steroidal aromatase inhibitor (AI) with toremifene, an approved fir...

Phase 3 study of atamestane + toremifene vs. letrozole in advanced breast cancer

600 Background: Aromatase inhibitors (AI) and anti-estrogens combined may more completely eliminate oestrogenic signaling than either compound alone. In contrast to earlier combinations the steroid...

The effects of atamestane, toremifene, and atamestane plus toremifene compared to letrozole on bone, serum lipids and uterus

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Phase 3 study of atamestane + toremifene vs. letrozole in advanced breast cancer

The effects of atamestane, toremifene, and atamestane plus toremifene compared to letrozole on bone, serum lipids and uterus