Aman U. Buzdar, MD, FACP
Endocrine therapy for breast cancer has evolved over the years. Initial endocrine therapies consisted of ablative procedures (oophorectomy, adrenalectomy, and hypophysectomy). With the availability of pharmaceutical estrogens, progestins, and androgens, ablative procedure utilization begin to decrease. Subsequently, with the discovery and availability of tamoxifen, this antiestrogen agent became the standard initial therapy, as its efficacy was similar to ovarian ablation in premenopausal women and to estrogen therapy in postmenopausal patients, but tamoxifen had a better safety profile.1
Second-line ablative therapies (adrenalectomy and hypophysectomy) were subsequently replaced by aminoglutethimide, trilostane, and other nonspecific antiadrenal agents.2 Third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) were the first endocrine agents to have demonstrated better antitumor activity than previously available agents and became the new standard of care for breast cancer, initially in metastatic disease and subsequently in the adjuvant setting.3
New Class of Agent
Fulvestrant (Faslodex), which represents a newer class of endocrine agent, is a selective estrogen receptor antagonist that causes conformational change in estrogen receptors, resulting in their degradation. It has been available since 2002 as a second-line therapy for metastatic, hormone-dependent breast cancer in postmenopausal woman.4
Initial studies of fulvestrant at a 250-mg dose demonstrated modest antitumor activity, but subsequent studies with higher doses (500 mg) have established the better therapeutic index of fulvestrant compared to anastrozole.5,6 In the recent FALCON study reported by Robertson et al and reviewed in this issue of The ASCO Post,7 the antitumor activity of the 500-mg dose of fulvestrant was compared against anastrozole as first-line therapy in postmenopausal patients with metastatic, hormone receptor–positive, and HER2/neu–negative breast cancer. Most of these patients had not received prior endocrine therapy.
The FALCON data illustrated that patients treated with fulvestrant had a similar clinical benefit rate to those on anastrozole. However, progression-free survival was significantly longer in the fulvestrant group compared to the anastrozole group (median progression-free interval = 16.6 vs 13.8 months). Survival data were immature, with additional follow-up needed.
These data provide important new information: In untreated postmenopausal women with hormone receptor–positive and HER2-negative disease, fulvestrant has a better therapeutic index than anastrozole, as it results in longer control of disease compared to aromatase inhibitor treatment.
Clinical Implications
These data provide level 1 evidence for utilization of this drug as a first-line therapy for postmenopausal women with hormone receptor–positive and HER2-negative metastatic breast cancer, but in reality, most breast cancer patients following local therapy would have been treated with antiestrogen agents and/or aromatase inhibitors in the adjuvant setting. The antitumor activity (response rate and duration of response) of fulvestrant and other endocrine agents in previously treated disease is modest.8
In untreated postmenopausal women with hormone receptor–positive and HER2-negative disease, fulvestrant has a better therapeutic index than anastrozole, as it results in longer control of disease compared to aromatase inhibitor treatment.— Aman U. Buzdar, MD, FACP
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Our improving understanding of mechanisms of resistance to endocrine therapy in hormone receptor–positive disease (which involve a number of pathways, including EGFR/HER2, cyclin-dependent kinase [CDK], mammalian target of rapamycin, phosphoinositide 3-kinase, and many others) has resulted in a number of preclinical and clinical studies to exploit these mechanisms and has resulted in a number of novel combination
therapies.9,10
At the present time, patients with hormone receptor–positive disease who had previously been treated with endocrine agents have a better likelihood of clinical benefit by utilizing either everolimus (Afinitor) or a CDK inhibitor in combination with the aromatase inhibitors or a CDK inhibitor with fulvestrant.11,12 Previous studies have shown that an aromatase inhibitor or fulvestrant alone produces low response rates in previously treated patients.8
In clinical practice, for postmenopausal patients with hormone receptor–positive disease who have been previously treated with aromatase inhibitors, the optimal therapy would be the combination of fulvestrant and palbociclib (Ibrance), which was recently approved by the U.S. Food and Drug Administration based on randomized clinical trial data.13 Fulvestrant as an initial therapy is an appropriate option for postmenopausal women with hormone receptor–positive and HER2-negative disease who had not received prior endocrine therapy.
These data also raise the question of whether fulvestrant would be a better adjuvant therapy than aromatase inhibitors and provide an appropriate rationale for evaluating fulvestrant in the adjuvant setting. ■
Disclosure: Dr. Buzdar reported no potential conflicts of interest.
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