Debu Tripathy, MD
For more than 100 years, endocrine therapy has been used for the treatment of breast cancer, initially with the use of oophorectomy when breast cancer was commonly seen in younger patients and at a more advanced stage. Since that time, we have learned much about the role of estrogen in the biology of normal breast development and in breast cancer.
The development of pharmacological therapy with tamoxifen in the late 1960s and early 1970s was a significant inflection point in the overall management of breast cancer. There was a clear demonstration of benefit as adjuvant therapy, cutting the risk of recurrence by half and breast cancer deaths by one-third. However, it is becoming clear that patients with early-stage breast cancer treated with endocrine adjuvant therapy face an ongoing risk of metastasis that does not seem to attenuate for up to 20 years.
In the metastatic setting, both endocrine and cytotoxic therapies can bring about responses and temporary remissions, but their impact on mortality has never been formally assessed because controlled trials are not appropriate given the palliative effects of these treatments. Other trials comparing combinations of treatments have shown incremental benefits in progression-free survival (PFS), but impacts on overall survival (OS) have been modest at best.
For endocrine-sensitive metastatic breast cancer, defined as the presence of estrogen receptors (ERs) or progesterone receptors (PRs) on 1% or more of the tumor cells, additional options have become available. The results of population studies suggest that patients with metastatic disease are living longer and better lives, but the exact impact of various therapies remains murky given changes in imaging technology that increasingly detect asymptomatic or minimally clinically evident metastatic recurrence along with improvements in supportive care. Furthermore, individual trials and tumor registries do not follow patients over the entire sojourn of their disease through multiple lines of therapy, limiting our understanding of the evolving natural history of advanced breast cancer.
Endocrine-Only Therapy for Metastatic Breast Cancer
In the last 3 decades, aromatase inhibitors (AIs) and the downregulator fulvestrant (Faslodex) were added as options for advanced disease. Comparative trials of AIs, initially tested against tamoxifen, have shown small benefits in disease-free survival and OS but fewer complications such as thrombotic events; thus, AIs have been adopted as standard therapy for postmenopausal patients. Additionally, numerous consensus panels, supported by findings from several randomized trials, have advocated for endocrine therapy versus chemotherapy as initial treatment for most cases of ER-/PR-positive metastatic breast cancer.
Exceptions to this approach would include patients with symptomatic and rapid progression, including those with “visceral crisis.” These recommendations have clearly affected treatment patterns worldwide, with a higher proportion of patients now receiving endocrine therapy as first-line and even subsequent therapy.
Fulvestrant is commonly used in the second line and, with the appreciation that the dose of 500 mg every 4 weeks is better than the initially approved dose of 250 mg, the pivotal FALCON trial, which compared this agent with the AI anastrozole, showed a slight PFS benefit with fulvestrant. The population studied had no prior exposure to endocrine therapy for breast cancer. Patients in this study were therefore enriched for those with de novo disease presenting initially with advanced disease as opposed to recurrent from prior early-stage breast cancer. At the current time, both agents are appropriate as first-line therapy, and fulvestrant is recommended for patients recurring on or within 1 to 2 years of adjuvant AI therapy.
Mechanisms of Resistance to Endocrine Therapy
Discoveries of mechanisms of resistance to endocrine therapy from the laboratory and correlative tumor analyses have shown that activation of growth factor–signaling pathways is a key mediator. Therapies that block these pathways, most notably through the inhibition of mammalian target of rapamycin (mTOR), a nodal point of this network, with the mTOR inhibitor everolimus (Afinitor), have been shown to be effective in nearly doubling PFS when added to either tamoxifen, exemestane, or fulvestrant.
However, no survival advantage has been demonstrated. Everolimus is commonly used in the second-line setting and is accompanied by toxicities such as stomatitis, significantly reduced with the use of a preventive steroid mouthwash containing 1% dexamethasone; hyperglycemia, fatigue, and nausea and, less commonly, pneumonitis, skin rash, and immune suppression. Newer strategies are targeting other components of signal transduction, including AKT (protein kinase B), PI3K (phosphoinositide 3-kinase), FGFR (fibroblast growth factor receptor), and other pathways.