Drugs

Researchers investigate whether a combination of fulvestrant and anastrozole will increase survival in HR+breast-cancer patients.

 

Breast cancer is a complex disease that is difficult to treat. There are different types of breast cancer and each type requires its own unique treatment strategy. There are two broad categories of breast cancer: hormone receptor positive (HR+) breast cancer and triple-negative breast cancers.

HR+ breast cancers have proteins on the surface of their cells that are receptors for either estrogen, progesterone, or both. When these hormones attach to their receptors on the surface of the tumor cell, they signal the cells to grow and divide. Triple-negative breast cancers do not have receptors for estrogen, progesterone, or HER2 (human epithelial growth factor receptor 2).

Hormone therapy and HR+ breast cancer

Individuals with HR+ breast cancer are often treated with hormone therapy, also called endocrine therapy). This therapy manipulates hormone levels through the use of drugs. In the case of HR+ breast cancer, there are two main kinds of drugs used:estrogen-receptor blockers and aromatase inhibitors.Both types affect estrogen levels in the body.

Aromatase inhibitors: Aromatase inhibitors as the name suggests, stop aromatase enzymes from converting androgen hormones into estrogen. The inhibitors stop the production of estrogen. However, these inhibitors only work in postmenopausal women. This is because estrogen production takes place in peripheral tissues such as fatty tissue (breast), bone, skin, and brain after menopause.

In pre-menopausal women, the ovaries are responsible for estrogen production and aromatase inhibitors do not work in the ovaries. An example of an aromatase inhibitor is anastrozole (Arimidex).

Estrogen-receptor blockers: Estrogen-receptor blockers are drugs that interact with estrogen receptors and stop them from working. Tamoxifen (Nolvadex) is the most well-known example of this type of drug, it works by binding to the estrogen receptor. It, therefore, prevents estrogen from interacting with its receptor and consequently prevents cells from receiving the signals telling it to divide.

Fulvestrant (Faslodex) is another example of an estrogen receptor blocker but it has an additional mechanism of action. When fulvestrant binds to the estrogen receptor it makes the proteins unstable and this signals the cells to destroy the faulty proteins. With fewer estrogen receptors on its surface, the cell is less likely to react to signals telling it to proliferate.

Combination therapy to treat cancer

The reason cancer is so difficult to treat is because it is highly dynamic; the tumors often adapt to treatments and become resistant. It seems logical that a combination of drugs that use different mechanisms may be more effective than a single treatment strategy. This makes it much harder for the tumor to adapt and survive and is why chemotherapy is often a cocktail of different drugs.

Combination of fulvestrant and anastrozole

In a recent study published in the New England Journal of Medicine, researchers in the USA wanted to know if treating HR+ metastatic breast cancer patients with a combination of fulvestrant and anastrozole would be more effective than treating them with anastrozole alone.

Fulvestrant would cause the degradation of the estrogen receptor while Anastrozole would prevent estrogen from being made. The researchers reasoned that by depriving the cancer of both molecules, it could not become drug resistant. This resulted in the SWOGS0226 clinical trial which was a phase 3, randomized,open-label trial. The researchers, doctors and patients were aware of what treatments they were receiving during the trial.

The researchers enrolled 694 postmenopausal women (65 years in age) with HR+ metastatic breast cancer and divided them into two groups. One group received Anastrozole only and the other group was treated with both Fulvestrant and Anastrozole.

The scientists looked at progression-free survival, this is the length of time where a patient’s disease is stable and did not get any worse. They also analyzed overall survival rates for the patient populations. The group found that the combination therapy prolonged overall survival by 7.8 months and increased progression-free survival to 1.5 months.

They went on to do sub-group analysis and looked at whether or not women who had received prior treatment with tamoxifen would benefit from the combination therapy. They found that the improvements in overall survival with combination therapy were only seen in women who had no prior treatment.

Conflicting clinical trial results

The results of this clinical trial are controversial as there have been previous clinical trials that show different results. The FACT (Fulvestrant and Anastrozole Combination at First Relapse Trial) and the SoFEA (Study of Faslodex with or without Concomitant Arimidex vs. Exemestane Following Progression on Nonsteroidal Aromatase Inhibitors) clinical trials showed that the combination of fulvestrant and anastrozole was not more effective than either treatment alone.

The authors of the SWOG S0226 trial argue that the FACT and SoFEA trials included premenopausal women as well as women who had prior antiestrogen therapy in their analysis and this accounted for why no benefit in the combination therapy was observed.

Does fulvestrant and anastrozole combination therapy work?

On the evidence presented so far, it seems that this combination therapy has the potential to help post-menopausal HR+ metastatic breast cancer patients that have had no prior antiestrogen treatments. Although the findings of the SWOG S0226 trial are optimistic, it may be prudent to wait for further evidence of the efficacy of this combination therapy before it is implemented in the clinic given the conflicting results.

“These results are very exciting.” said lead author Dr. Rita Mehta, MD, in a press relase. “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.”

Written by Tarryn Bourhill MSc, PhD Candidate

References:

  1. Ma, C. X., Reinert, T., Chmielewska, I. & Ellis, M. J. Mechanisms of aromatase inhibitor resistance. Nature Reviews Cancer15, 261 (2015).
  2. Simpson, E. R. Sources of estrogen and their importance. J Steroid Biochem Mol Biol86, 225-230 (2003).
  3. Nathan, M. R. & Schmid, P. A review of fulvestrant in breast cancer. Oncology and therapy5, 17-29 (2017).
  4. Reinert, T. & Barrios, C. H. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Therapeutic advances in medical oncology7, 304-320 (2015).
  5. Mehta, R. S. et al. Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. New England Journal of Medicine367, 435-444, doi:10.1056/NEJMoa1201622 (2012).
  6. Mehta, R. S. et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. New England Journal of Medicine380, 1226-1234 (2019).
  7. Lawton, W. Fulvestrant plus anastrozole extends lives of women with advanced HR+ breast cancer <https://www.eurekalert.org/pub_releases/2019-03/s-fpa032519.php> (2019).

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