March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
For some women with a particular type of advanced, or metastatic, breast cancer, a new treatment option is showing really promising results.
Metastatic breast cancer can be hard to treat, especially when some of the traditional hormone/endocrine therapies do not work. This may happen with particular types of breast cancer, like estrogen receptor-positive (ER+), human epidermal growth cancer-2 negative (HER2-negative) breast cancers, which harbor a mutant estrogen receptor-1 (ESR1). Elacestrant (tradename: Orserdu) is a new medication tailored especially for these stubborn cancers. It was recently approved by the Food and Drug Administration (FDA).
The Current Approach to Breast Cancer Treatment
Breast cancer is one of the most common cancers in the US. In 2023, the American Cancer Society estimates that around 300,000 new cases of breast cancer will be diagnosed within the US. Additionally, around 43,000 women will ultimately succumb to their disease. In other words, breast cancer accounts for a third of all cancer diagnosed in women. At the time of her diagnosis, an average woman will be 62 years of age. However, this cancer can occur in much younger women. Given the prevalence of this cancer and the resources devoted to its research, treatments have come a long way. Even patients with metastatic disease can expect to live up to a decade with some of the new, cutting-edge treatments.
On a more microscopic level, breast cancer cells have certain proteins on their surface which contribute to their growth and progression. The most important of these proteins are the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor-2 (HER2). The first two, ER and PR, bind the hormones estrogen and progesterone respectively. If cancer cells carry both proteins on their surface, the cancer is termed a hormone receptor-positive (HR+) cancer. Advanced and metastatic cases of such cancers are treated with hormone (also called endocrine) therapies, such as Tamoxifen. Tamoxifen binds to ERs, preventing it from interacting with estrogen. This prevents the breast tumor cells from growing and multiplying.
HER2 protein also contributes to rapid breast cancer growth. Cancers with high levels of HER2 tend to be more aggressive. However, they can be specifically and effectively targeted by drugs such as Herceptin. This generally makes the cancers that lack HER2, so-called HER2-, the more clinically dangerous cancers.
Mutations Like ESR1 Make Breast Cancer Resistant to Treatment
Breast cancer patients may harbor mutations, some of which can make them resistant to traditional hormonal treatments. One of those is the ESR1 mutation, which makes breast cancer cells relatively immune to estrogen deprivation by hormonal therapies.
The prevalence of this mutation in breast cancer patients is variable. It partially depends on whether a patient has been exposed to hormonal therapies in the past. Forty percent of the patients with metastatic breast cancer who have received endocrine therapy in the past may harbor this mutation. However, people with early-stage cancers who have finished their appropriate treatment have a relatively low 4-5% chance of their cancer possessing such a mutation if it recurs.
How Does Elacestrant Work?
Elacestrant is a selective estrogen receptor degrader or downregulator (SERD). These drugs work by coupling with the ER receptors on breast cancer cells. By doing so, they prevent estrogen, a key driver for breast cancer growth, from interacting with the receptor and promoting cancer progression. Moreover, they can reduce the overall number of estrogen receptors as well as the shape and configuration of the receptors, making them effete.
There are other drugs in this class, such as AstraZeneca’s camizestrant, which has shown great promise in recent clinical trials. AstraZeneca in fact pioneered SERDs after gaining approval for faslodex in 2002. Faslodex, however, is given via an intramuscular injection. Elacestrant is taken orally, which makes it an arguably more convenient drug than faslodex.
How Effective is Elacestrant for These Advanced Breast Cancers?
The EMERALD trial is a phase 3 trial that enrolled 478 post-menopausal women and men. These patients had ER+, HER2- advanced or metastatic breast cancers and had previously received treatment with and failed at least one endocrine therapy. 228 of these patients had identifiable ESR1 mutations before the start of the study. All patients were randomly assigned to receive either elacestrant or another hormone therapy medication selected by their treating physician (faslodex, anastrozole, letrozole, or exemestane).
The investigators measure progression-free survival (PFS), which is the time patients can live without any worsening of their disease. In the ESR1 mutant population, the PFS was 3.8 months for those who received elacestrant and only 1.9 months for those who received traditional therapies. In the 250 patients without this mutation, the risk of death was reduced by 14% but this finding was not statistically significant. This signals that the ESR1 mutants are the main patient population that benefit from the use of this new medication.
Potential Side Effects
Like all drugs, elacestrant is not without its side effects. The most common side effects associated with the medication include:
- Abdominal pain
- Decreased appetite
- Pain in the muscles and bones
- Laboratory abnormalities including decreased hemoglobin, increased cholesterol, and increased creatinine (a marker of kidney function)
Occasionally, elacestrant can cause serious side effects, such as:
- Allergic reaction:
- Difficulty breathing
- Swelling of the lips, throat, and tongue
In the EMERALD study, the most reported side effects were musculoskeletal pain, decreased appetite, diarrhea, headache, constipation, abdominal pain, indigestion, and laboratory abnormalities.