Combining endocrine therapies for metastatic breast cancer

Breast cancer remains the most commonly diagnosed cancer among women worldwide and is a leading cause of cancer-related death (1). In 2018, more than two million new cases were diagnosed, and more than 600,000 deaths were attributed to breast cancer. Breast cancers that have metastasized, or spread to other organs, often benefit from treatment with a cocktail of drugs. Strategic selection of drugs is based on molecular analysis of a tumor biopsy.

Approximately 70% of breast cancers express the estrogen receptor (ER) and are amenable to therapies that block estrogen or ER activity (2). These therapies are often classified within a larger category of drugs called endocrine or hormone therapies. There are many types of endocrine therapies, each with different mechanisms of inhibiting hormone action. Aromatase inhibitors (AIs), such as anastrozole, block estrogen synthesis, whereas selective ER down-regulators, such as fulvestrant, bind and reduce levels of the ER. Because of their different mechanisms of action, drugs from different endocrine therapy classes may be combined to exert increased inhibitory effects on ER-positive breast cancer. This type of combination approach was used in the S0226 phase 3 trial (NCT00075764). In this trial, postmenopausal women with previously untreated metastatic breast cancer were treated with the combination of anastrozole plus fulvestrant and compared with patients who received anastrozole alone. The combination treatment was previously reported to increase progression-free survival compared with the single agent (15 vs 13.5 months) (3).

Updated outcomes of the S0226 trial were recently reported at a median follow-up of seven years (4). About 45% of patients in the single-drug arm had crossed over to the combination treatment by the time of follow-up evaluation. Among 694 patients included in the updated report, progression-free survival remained significantly higher for the group treated with the combination. In addition, median overall survival was significantly higher for those receiving the combination treatment vs anastrozole alone (49.8 vs 42.0 months). Importantly, the differences in overall survival appeared to be dependent on whether patients had previously been treated with another endocrine agent, the selective ER modulator tamoxifen. Among those who did not have a history of tamoxifen treatment, median overall survival was significantly different with the combination vs anastrozole alone (52.2 vs 40.3 months). However, if patients had previously received tamoxifen, median overall survival did not significantly differ between the combination and anastrozole-alone groups (48.2 vs 43.5 months). The authors of the updated report noted the importance of considering differences in patient populations when interpreting and comparing results across studies. Previous trials that failed to show significant differences between single-agent AIs and cocktails of AIs with fulvestrant included patients previously treated with endocrine agents. Response rates and survival outcomes may be lower in some patients in this subgroup due to underlying endocrine resistance resulting from prior exposure to other endocrine agents. In addition, any time more than one drug is used, there are increased concerns about safety and side effects. However, high-grade (≥3) side effects were similar between the two treatment groups, suggesting that safety and toxicity were not compromised by the combination treatment.

Overall, the updated results from this phase 3 trial support the efficacy of combining the AI, anastrozole, with fulvestrant as a first-line option for patients with postmenopausal ER-positive metastatic breast cancer. This treatment combination has the potential to improve survival outcomes in patients who have not previously been treated with endocrine therapy.

References: (1) Bray et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. (2) Waks and Winer. Breast Cancer Treatment: A Review. JAMA. 2019 Jan 22;321(3):288-300. (3) Mehta et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. (4) Mehta et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234.