Endocrine therapy has been a mainstay of breast cancer treatment for over a century, and the prospects are bright that understanding the molecular pathways driving disease progression and resistance to endocrine agents will lead to the rational development of additional agents to improve outcomes for our patients.— William J. Gradishar, MD, FASCO, FACP
The role of endocrine therapy for hormone receptor–positive metastatic breast cancer is well established, and clinicians are strongly encouraged to consider one of several therapeutic options for the majority of patients who present with metastatic disease. The recent ASCO guideline on this topic, reported in the Journal of Clinical Oncology by Rugo and colleagues1 and summarized in this issue of The ASCO Post, reaffirms many of the principles that should be considered when making treatment decisions in this patient population.
In addition, the options available for treating hormone receptor–positive metastatic breast cancer have expanded in the past few years, with the introduction of specific targeted therapies that can be partnered with endocrine agents to potentially improve outcomes for patients with advanced disease. Knowing which patients should receive these new agents and which ones can still be treated with single-agent endocrine therapy is a challenge and falls under the domain of the “art of medicine.” As new approaches for managing hormone receptor–positive metastatic breast cancer expand, so does the cost of treatment as well as the potential for adverse events not typically associated with traditional endocrine therapy.
Affirming the Role of Endocrine Therapy
To begin, principles still dictate that endocrine therapy should be offered to most patients with hormone receptor–positive disease and continued until there is evidence, either clinically or with other objective measures, of progressive disease. Additionally, using endocrine agents in sequence over time is also encouraged, unless the tempo of the disease is rapidly changing or visceral organs are on the cusp of compromise (so-called visceral crisis). In these circumstances, a change to chemotherapy is warranted. A focus on utilizing endocrine agents for as long as possible is predicated on both efficacy and maintenance of quality of life.
In premenopausal women, although tamoxifen can be used as monotherapy, rendering a patient postmenopausal by ovarian suppression or ablation enhances benefit and also affords the opportunity to introduce aromatase inhibitors if indicated. For postmenopausal women, multiple endocrine therapy options exist, but a first-line preference is an aromatase inhibitor unless disease progression occurred on adjuvant aromatase inhibitor therapy.
With greater understanding of the molecular pathways governing disease progression and the mechanisms of resistance to endocrine agents, clinical trials have established the utility of the mTOR (mammalian target of rapamycin) inhibitor everolimus (Afinitor, Zortress) in combination with the steroidal aromatase inhibitor exemestane in patients who developed disease progression following treatment with a nonsteroidal aromatase inhibitor. The side-effect profile of this combination is increased over that expected with exemestane alone.
The recently approved CDK4/6 inhibitor palbociclib (Ibrance) has been shown to enhance progression-free survival significantly when combined with an aromatase inhibitor in the first-line setting, whereas the combination of fulvestrant (Faslodex) and palbociclib improved progression-free survival in patients who had received prior aromatase inhibitor therapy. This combination also is associated with some side effects (neutropenia), which are more often associated with chemotherapy management, although the vast majority of patients remain asymptomatic.
Reliable Biomarkers Needed
One of the issues associated with combining targeted therapy with endocrine agents is the significant increase in monthly cost—which begs the question of whether we can identify those patients most likely to benefit from this strategy or alternatively those who have such indolent disease that monotherapy with an endocrine agent is sufficient. To date, such decisions are based on clinical judgment, or a gestalt, of what is best.
As we go forward, the hope is that reliable biomarkers that provide clinicians with the objective tools to make these decisions or at least complement our clinical acumen may become available. Endocrine therapy has been a mainstay of breast cancer treatment for over a century, and the prospects are bright that understanding the molecular pathways driving disease progression and resistance to endocrine agents will lead to the rational development of additional agents to improve outcomes for our patients. ■
Disclosure: Dr. Gradishar has received clinical research support and/or participated on a data safety monitoring board for Genentech and Pfizer; he also served on a scientific advisory board, as a consultant, or expert witness for Eisai and Genentech.
1. Rugo HS, Rumble RB, Macrae E, et al: Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. May 23, 2016 (early release online).
Hope S. Rugo, MD
As reported by Hope S. Rugo, MD, of the University of California San Francisco Comprehensive Cancer Center, and colleagues in the Journal of Clinical Oncology, ASCO has released a clinical practice guideline on endocrine therapy for hormone receptor–positive metastatic...!-->!-->