Investigation of Fulvestrant and Anastrozole Combination for HR+ Breast Cancer

Understanding Breast Cancer

Breast cancer presents a significant challenge in treatment due to its complexity. It is categorized into various types, each necessitating specific treatment approaches. The two main classifications are hormone receptor positive (HR+) breast cancer and triple-negative breast cancer. HR+ breast cancers possess receptors for estrogen, progesterone, or both on their cell surfaces. The binding of these hormones to the receptors prompts the tumor cells to grow and multiply. In contrast, triple-negative breast cancers lack receptors for estrogen, progesterone, or HER2 (human epithelial growth factor receptor 2).

Hormone Therapy for HR+ Breast Cancer

Patients diagnosed with HR+ breast cancer frequently undergo hormone therapy, also known as endocrine therapy, which modifies hormone levels using medications. The primary categories of drugs used in HR+ breast cancer treatment include estrogen-receptor blockers and aromatase inhibitors, both of which influence estrogen levels in the body.

Aromatase Inhibitors

Aromatase inhibitors function by preventing aromatase enzymes from converting androgen hormones into estrogen, effectively halting estrogen production. These inhibitors are effective only in postmenopausal women, as estrogen production shifts to peripheral tissues like fatty tissue, bone, skin, and the brain after menopause. An example of an aromatase inhibitor is anastrozole (Arimidex).

Estrogen-Receptor Blockers

Estrogen-receptor blockers are medications that interact with estrogen receptors to inhibit their function. Tamoxifen (Nolvadex) is a well-known drug in this category, binding to estrogen receptors and blocking estrogen from signaling cell division. Fulvestrant (Faslodex) is another estrogen receptor blocker with a unique mechanism; it destabilizes the estrogen receptor upon binding, leading to the degradation of the faulty proteins, thereby reducing the cell’s response to growth signals.

Combination Therapy for Cancer Treatment

The dynamic nature of cancer complicates treatment, as tumors often adapt to therapies, developing resistance. Combining drugs that target different mechanisms may enhance treatment efficacy, making it more challenging for tumors to survive. This principle underlies the use of chemotherapy, which typically involves a combination of various drugs.

Study on Fulvestrant and Anastrozole Combination

A recent study published in the New England Journal of Medicine explored the effectiveness of combining fulvestrant and anastrozole in treating HR+ metastatic breast cancer patients. The researchers hypothesized that by simultaneously depriving cancer cells of both the estrogen receptor (via fulvestrant) and estrogen production (via anastrozole), the likelihood of developing drug resistance would diminish. This hypothesis led to the SWOG S0226 clinical trial, a phase 3, randomized, open-label study where both researchers and participants were aware of the treatment assignments.

Trial Participants and Methodology

The trial enrolled 694 postmenopausal women (average age of 65) with HR+ metastatic breast cancer, dividing them into two groups: one received anastrozole alone, while the other received both fulvestrant and anastrozole. The focus of the analysis was on progression-free survival—the duration during which a patient’s condition remained stable—and overall survival rates.

Results of the Combination Therapy

The results indicated that the combination therapy led to a prolongation of overall survival by 7.8 months and an increase in progression-free survival by 1.5 months. Further subgroup analysis examined whether women with prior tamoxifen treatment benefited from the combination therapy. The findings revealed that overall survival improvements were significant only in women without prior antiestrogen treatments.

Conflicting Clinical Trial Results

The results from the SWOG S0226 trial have sparked debate, as earlier studies, including the FACT (Fulvestrant and Anastrozole Combination at First Relapse Trial) and SoFEA (Study of Faslodex with or without Concomitant Arimidex vs. Exemestane Following Progression on Nonsteroidal Aromatase Inhibitors), reported that the combination of fulvestrant and anastrozole was not superior to either treatment alone.

Rationale Behind Conflicting Findings

The authors of the SWOG S0226 trial contend that the inclusion of premenopausal women and those with previous antiestrogen therapy in the FACT and SoFEA trials could explain the absence of observed benefits in combination therapy.

Conclusions on Combination Therapy Efficacy

Current evidence suggests that the combination of fulvestrant and anastrozole may provide significant benefits for postmenopausal HR+ metastatic breast cancer patients without prior antiestrogen treatments. While the findings from the SWOG S0226 trial are promising, further research is necessary to validate the efficacy of this combination before its widespread clinical application.

Expert Commentary

Dr. Rita Mehta, MD, the lead author of the study, expressed optimism about the results, stating, “Women who are treated with fulvestrant up front live about eight months longer. That’s a lot of extra time to do the things you love with the people you love.”

References

Ma, C. X., Reinert, T., Chmielewska, I. & Ellis, M. J. Mechanisms of aromatase inhibitor resistance. Nature Reviews Cancer 15, 261 (2015).
Simpson, E. R. Sources of estrogen and their importance. J Steroid Biochem Mol Biol 86, 225-230 (2003).
Nathan, M. R. & Schmid, P. A review of fulvestrant in breast cancer. Oncology and therapy 5, 17-29 (2017).
Reinert, T. & Barrios, C. H. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Therapeutic advances in medical oncology 7, 304-320 (2015).
Mehta, R. S. et al. Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. New England Journal of Medicine 367, 435-444, doi:10.1056/NEJMoa1201622 (2012).
Mehta, R. S. et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. New England Journal of Medicine 380, 1226-1234 (2019).
Lawton, W. Fulvestrant plus anastrozole extends lives of women with advanced HR+ breast cancer (2019).