Improving treatment outcomes in HR+ metastatic breast cancer
If you’re living with hormone receptor-positive (HR+) metastatic breast cancer (mBC), you’ve likely heard about hormone therapy. Hormone therapies, also called endocrine therapies, are the foundation of treatment for this type of breast cancer. These treatments work by blocking estrogen, the hormone that helps HR+ breast cancer grow.
For many patients, hormone therapies eventually stop working. This is called treatment resistance. Fortunately, researchers developed a new generation of hormone blockers that show promise in overcoming resistance and extending treatment benefits.
In this article, we’ll explain how standard hormone therapies work, why treatment resistance happens, what these new types of therapies are, and how they could help you.
Hormone therapy: the cornerstone of HR+ mBC treatment
HR+ breast cancer cells have special receptors that respond to estrogen or progesterone. These receptors act like docking stations that allow hormones to attach and send signals telling the cancer cells to grow. Hormone therapies stop this process by either lowering estrogen levels, blocking the receptors, or destroying the receptors altogether.
Commonly used hormone therapies include aromatase inhibitors, such as letrozole, anastrozole, or exemestane, which lower the amount of estrogen in your body. Another category, selective estrogen receptor modulators (SERMs), like tamoxifen, works by blocking the receptors, preventing estrogen from attaching and activating them. Fulvestrant, the only currently approved selective estrogen receptor degrader (SERD), goes a step further by binding to the receptor and breaking it down, removing the cancer’s ability to use estrogen to grow.
These treatments can keep the cancer under control for months or even years. However, many patients eventually experience treatment resistance, when these therapies stop working and the cancer begins growing again.
Why does treatment resistance happen?
Over time, cancer cells can sometimes bypass the effects of hormone therapy. One common reason is a mutation in the estrogen receptor gene, known as an ESR1 mutation. These mutations can make the receptor stay active even when estrogen levels are lowered or blocked. The cancer is then able to keep growing despite treatment.
Cancer cells can also activate other growth pathways that don’t rely on estrogen at all. This means that even if you successfully block estrogen signaling, the cancer might find another way to survive and spread. Finally, not all hormone therapies fully block or degrade every receptor, which can allow some cancer cells to continue to grow.
Researchers have been hard at work trying to solve these challenges, developing next-generation hormone therapies designed to better target hormone-resistant cancer cells.
What are novel SERDs?
SERD stands for Selective Estrogen Receptor Degrader. The first SERD to receive FDA approval was fulvestrant (brand name: Faslodex). Fulvestrant works by binding to the estrogen receptor, blocking the effects of estrogen and marking the receptor for destruction. By degrading the receptor, fulvestrant cuts off the cancer’s ability to use estrogen;however, fulvestrant has limitations. Patients must receive it as a monthly injection into the muscle, which can be uncomfortable. It also doesn’t fully block all estrogen receptors in every patient, and it may be less effective against cancers with ESR1 mutations.
Novel SERDs have been designed to overcome these challenges. One of the biggest advantages of these new SERDs is that they are taken as oral pills instead of injections, making them more convenient. Additionally, they have shown promise in targeting cancers that have developed ESR1 mutations and in more effectively degrading estrogen receptors throughout the body.
The first of these next-generation SERDs to be FDA-approved is elacestrant (Orserdu), which was approved in 2023. This drug has shown benefit in patients whose tumors have ESR1 mutations. Other novel SERDs are currently being studied in clinical trials and may expand treatment options in the future.
What are SERCAs?
An exciting class of drugs under investigation is known as SERCAs, which stands for Selective Estrogen Receptor Covalent Antagonists. While SERDs work by degrading the estrogen receptor, SERCAs form a strong, permanent bond with the estrogen receptor, effectively locking it in an inactive state. This prevents the receptor from sending growth signals to the cancer cells.
Because this bond is permanent, SERCAs may be especially useful in overcoming cancers that have developed resistance to other hormone therapies. While SERCAs are still in early (Phase I/II) clinical trials, the research suggests they may offer another way to block the estrogen receptor more completely and help patients who have run out of other hormone therapy options. We look forward to these drugs becoming available in the next few years.
How could these next-generation therapies help you?
For patients whose cancer has an ESR1 mutation, oral SERDs like elacestrant have shown promising results in extending the time the cancer remains controlled. These new therapies also offer the advantage of being taken as pills, eliminating the need for injections.
By better targeting the estrogen receptor and more completely blocking or degrading it, these therapies may help slow cancer growth even when earlier treatments have stopped working. This means that they could potentially provide more time and more treatment choices for patients who have already gone through several rounds of hormone therapy.
It’s important to note that not all patients will benefit in the same way. Your doctor may recommend genomic testing to check for ESR1 mutations, which can help determine if these newer therapies are likely to work for you. You may also want to ask your doctor about clinical trials that are testing these and other next-generation treatments.
Are there side effects?
Like all cancer treatments, novel SERDs and SERCAs can cause side effects. Patients in clinical trials have commonly reported nausea, fatigue, hot flashes, joint pain, and diarrhea. Your care team will discuss the risks and benefits with you and help manage any side effects to keep you as comfortable as possible.
What it all means for patients
Hormone therapy remains a key part of treatment for HR+ metastatic breast cancer, but resistance can limit its long-term effectiveness. New therapies like novel SERDs and SERCAs offer hope by blocking or disabling the estrogen receptor, even in cancers that have adapted to earlier treatments.
While these therapies might not be right for everyone, they represent important progress in the fight against metastatic breast cancer. Talk with your oncologist about whether they fit into your treatment plan, and explore available resources to stay informed and empowered.
To learn more
- American Cancer Society – Hormone therapy for breast cancer
- Breastcancer.org – Hormonal therapy for breast cancer
- National Cancer Institute- Hormonal therapy for breast cancer fact sheet
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