patient care perspectives
First-line Therapy for Advanced HR+ HER2- Breast Cancer
Overview
Endocrine therapy remains the foundational treatment for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer. The addition of CDK4/6 inhibitor therapy has also become standard in the treatment of advanced or metastatic breast cancer.
Expert Commentary
Joseph A. Sparano, MD, FACPEzra M. Greenspan, MD Professor in Clinical Cancer Therapeutics |
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“Since estrogen stimulates the growth of estrogen-dependent breast cancer, antiestrogen therapy is the bedrock of the first-line treatment of advanced HR+/HER2- breast cancer.”
HR+/HER2- breast cancer accounts for approximately two-thirds of all breast cancers in the United States. Since estrogen stimulates the growth of estrogen-dependent breast cancer, antiestrogen therapy is the bedrock of the first-line treatment of advanced HR+/HER2- breast cancer. For postmenopausal women, this would generally include either the nonsteroidal aromatase inhibitors anastrozole or letrozole or the steroidal aromatase inhibitor exemestane. For premenopausal women, ovarian function suppression is combined with the aromatase inhibitor.
Over the last 5 to 7 years, CDK4/6 inhibitors have also become a component of standard therapy for these patients. Initial studies showed that all 3 of the available CDK4/6 inhibitors (ie, palbociclib, ribociclib, and abemaciclib) improve progression-free survival and objective response when added to first-line endocrine therapy. In addition, within the last year or so, several studies have demonstrated that these agents improve overall survival, although this has mainly been observed with ribociclib and abemaciclib, and not consistently with palbociclib.
Aromatase inhibitor–plus–CDK4/6 inhibitor therapy would generally be the paradigm for patients who present with metastatic breast cancer at their initial diagnosis or for patients who previously had localized disease and experienced relapse while not receiving adjuvant endocrine therapy, which could happen because they had either completed at least a 5-year course of adjuvant endocrine therapy or discontinued adjuvant endocrine therapy because of side effects. For patients who relapsed on an aromatase inhibitor or tamoxifen, they would generally receive fulvestrant plus a CDK4/6 inhibitor.
Regarding side effects, neutropenia is a main side effect of palbociclib, which became commercially available back in 2015, and ribociclib, which became available a couple of years thereafter; both of these are given on a 3 weeks on, 1 week off schedule that minimizes the neutropenia. In addition, there is the issue of QT interval prolongation with ribociclib, and precautions include cardiac monitoring and electrolyte monitoring as described in the prescribing information. Abemaciclib, the third CDK4/6 inhibitor that is US Food and Drug Administration approved, causes less neutropenia than the other approved CDK4/6 inhibitors and is generally given on a continuous basis, twice daily as opposed to once daily for palbociclib and ribociclib. The most common adverse event that is associated with abemaciclib is diarrhea, which can be severe but is usually mild to moderate and tends to improve with time. All 3 CDK4/6 inhibitors are metabolized primarily by CYP3A and SULT2A1 enzymes and are time-dependent inhibitors of CYP3A.
Overall, approximately 10% to 20% of patients in the pivotal trials discontinued CDK4/6 inhibitors due to adverse events, and approximately one-third to one-half of patients require dose interruptions or dose reductions with these agents. Fortunately, these dose interruptions and reductions do not seem to adversely affect efficacy.
References
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