William J. Gradishar, MD
A majority of breast cancers are hormone receptor (HR) positive and are responsive to various types of hormone manipulation. Endocrine therapy is the preferred first-line therapy for patients with advanced estrogen receptor (ER)-positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapy is often continued in the second- and third-line settings, with chemotherapy deferred until the tumor becomes endocrine therapy refractory and/or a visceral crisis is imminent.
Therapeutic options vary based on clinical presentation and include single-agent therapies such as tamoxifen, aromatase inhibitors (AIs), and fulvestrant (Faslodex), as well as combination therapy options. Over the past few years, the results of multiple trials have shown significant improvement in outcomes when endocrine therapy is combined with CDK4/6 inhibitors or mammalian target of rapamycin (mTOR) inhibitors. Improved efficacy comes at a cost of a modest increase in toxicity.
Mechanisms of ER resistance have been defined, leading to multiple strategies to improve efficacy and overcome resistance. These include the combination therapy options mentioned above and other novel drugs that are in development.
A Long History
Hormonal manipulation has been an established paradigm in the treatment of breast cancer for over 100 years. Early trial results demonstrated the regression of advanced breast cancer after oophorectomy or ovarian radiation, and it It has since been shown that approximately 70% of breast cancers are HR positive. Although a majority of breast cancers are curable, approximately 20% to 30% of patients present with de novo metastatic disease or progress to metastatic disease following an early-stage diagnosis. Treatment of metastatic disease is influenced by menopausal status, HR status, and other molecular features. This discussion will focus on the postmenopausal patient with HR-positive metastatic breast cancer (MBC).
Endocrine therapy is the preferred choice of first-line therapy for patients with advanced ER-positive, HER2-negative breast cancer who do not have symptomatic visceral disease. Endocrine therapies work through various mechanisms including decreasing estrogen production (AIs), blocking signaling through the ER (tamoxifen), or antagonizing the receptor itself (fulvestrant).
First-line endocrine therapy is continued until disease progression or unacceptable toxicity. A change to second-line endocrine therapy can be considered at the time of disease progression. Chemotherapy is typically recommended when the benefit of endocrine therapy lessens (with each prior endocrine therapy), the tumor becomes endocrine therapy refractory, and/or a visceral crisis is imminent.
Although metastatic ER-positive breast cancers can respond well to sequential endocrine therapies, most patients will become resistant to these therapies, eventually require chemotherapy, and inevitably die of their disease. Mechanisms of ER resistance have been defined, however, leading to the development of novel therapies to improve efficacy and overcome resistance, including CDK 4/6 inhibitors, mTOR inhibitors, and others.
Evolution in Advanced Breast Cancer
In patients with hormone-sensitive advanced breast cancer, there is a rich history of investigation that started with ablation of hormonesecreting organs (ie, ovaries, adrenals and pituitary) long before there was a clear understanding of the underlying biology controlling the growth of breast cancer cells via the ER pathway. Over many decades, the use of agents in the clinic has largely supplanted ablative surgery, including progestins, aminoglutethimide, testosterones, and estrogens.
Once ER biology was elucidated, the development of drugs such as tamoxifen replaced older strategies because of their efficacy and a better toxicity profile. Eventually, AIs (eg, letrozole, anastrozole, and exemestane) were developed that bettered tamoxifen as a firstchoice for most postmenopausal women with advanced ER-positive MBC. Subsequently, fulvestrant, a selective ER down-regulator was developed; it can be used early in MBC or later in the sequence of treatment.
Ultimately, all of these agents lose their effectiveness and patients develop resistance to treatment, after which they often proceed to chemotherapy.
CDK 4/6 inhibitors
Cyclin-dependent kinases (CDKs) represent a major advance in the treatment of ER-positive MBC. Data from large, randomized clinical trials are robust and consistent. The benefit of adding CDK 4/6 agents to single-agent endocrine therapy has been observed in both premenopausal and postmenopausal women with MBC. CDKs regulate cell-cycle progression by interacting with specific cyclin proteins. Interfering with them leads to cell-cycle arrest.