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.

Immunotherapy for triple-negative breast cancer

The FDA has granted accelerated approval for the combination of atezolizumab with nab-paclitaxel for locally advanced or metastatic triple-negative breast cancers that cannot be surgically resected and express programmed death ligand-1 (PD-L1).

Triple-negative breast cancers, which account for about 15% of breast cancers, lack detectable expression of three molecules- estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Drugs targeting ER and HER2 are approved and available for subgroups of patients whose breast tumors express these molecules. However, few options outside of standard chemotherapy exist for patients with triple-negative breast cancer.

The majority of chemotherapy drugs target non-specific processes, such as DNA synthesis or cell division, which are increased in cancer cells but also occur in many normal cells. Because of this non-specific effect on normal cells, many chemotherapy drugs cause debilitating side effects, such as nausea, fatigue, hair loss, and increased risk of infection. In an attempt to improve tumor-targeting and reduce non-specific toxicities, cancer researchers have developed many classes of molecularly targeted agents, including those that target ER and HER2 as mentioned above.

Immunotherapy is a relatively new cancer therapy approach that attempts to stimulate the patient’s immune response against cancer cells. There are many types of immunotherapies in development or approved for other types of cancer. Atezolizumab is an antibody that targets a molecule called PD-L1, which is expressed on some cancer cells. PD-L1 normally interacts with a group of immune cells, inhibiting their function. By blocking PD-L1, atezolizumab disrupts cancer-immune cell interactions, theoretically allowing immune cells to function and kill cancer cells.

This week’s drug combination approval is based on results from a phase 3 trial of atezolizumab combined with the chemotherapy agent nab-paclitaxel (1). The trial included more than 900 patients with previously untreated metastatic triple-negative breast cancer. The combination showed a statistically significant increase in median progression-free survival of about 2 months, including among those with PD-L1-positive tumors, compared with the chemotherapy plus a placebo. Although this increase in progression-free survival may appear modest, metastatic triple-negative breast cancer currently carries a poor overall survival rate.

Progression-free survival is viewed as a potential marker of overall survival. The FDA grants accelerated approvals to agents that show promise based on a marker of clinical benefit, such as progression-free survival, in patients with serious diseases. Ongoing trials will seek to determine whether the combination successfully extends overall survival of patients with advanced or metastatic triple-negative breast cancer compared with chemotherapy alone.

(1) Schmid et al. N Engl J Med. 2018 Nov 29;379(22):2108-2121