Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer Treatment & the Importance of Testing for the ESR1 Mutation

For the significant number of women with breast cancer whose cancers are estrogen receptor-positive (ER+), endocrine therapies such as Selective Estrogen Receptor Modulators (SERMs) and aromatase inhibitors have long been the cornerstone of treatment.

However, resistance to these therapies, often due to mutations such as ESR1, has posed a significant challenge in clinical management. The advent of Selective Estrogen Receptor Degraders (SERDs) offers a promising new direction in overcoming resistance, especially in patients harboring ESR1 mutations​.

“When they have this ESR1 alteration, there is an attractive option for them that could still allow them to experience the convenience of oral therapy and endocrine therapy without having to switch to chemotherapy just yet. But it’s specifically for tumors that have acquired that ESR1 mutation, and this happens in over a third of our tumors that have been previously treated with endocrine therapy such as aromatase inhibitors,” Dr. Maryam Lustberg, Chief of Breast Medical Oncology Department at Yale, tells SurvivorNet Connect.

“We’re continuing to raise awareness among both clinicians as well as patients. That testing for ESR1 mutation is an absolute must progression after that first line endocrine therapy. We need to raise awareness of that.” 

Understanding ESR1 Mutations in Breast Cancer

ESR1 mutations, particularly in the ligand-binding domain of the estrogen receptor, are a well-recognized mechanism of acquired resistance to endocrine therapy, including aromatase inhibitors. These mutations result in constitutive activation of the estrogen receptor, allowing cancer cells to grow even in the absence of estrogen​. Notably, ESR1 mutations are often detected in metastatic settings, especially after prolonged exposure to aromatase inhibitors, and are less common in primary, untreated tumors.

ESR1 mutations are clinically significant because they alter the tumor’s sensitivity to conventional endocrine therapies, making the cancer less responsive to treatments like tamoxifen and aromatase inhibitors​. Testing for ESR1 mutations is, therefore, crucial in guiding subsequent lines of therapy, as it helps identify patients who might benefit from alternative treatments such as SERDs.

Testing for ESR1 Mutations

Routine testing for ESR1 mutations in patients with metastatic hormone receptor-positive breast cancer can provide critical insights for personalizing therapy. The detection of ESR1 mutations can be achieved through liquid biopsies, such as circulating tumor DNA (ctDNA), which allows for non-invasive and timely monitoring of tumor evolution and response to treatment​. Common detection methods include next-generation sequencing (NGS) and droplet digital PCR, which offer high sensitivity in identifying ESR1 mutations.

“It can be tested either through a tumor tissue biopsy or what we call a liquid biopsy, which is a blood test,” Dr. Lustberg explains. 

“The most important takeaway is that testing for ESR1 changes needs to happen after exposure to an aromatase inhibitor or another endocrine therapy agent.” 

“If a patient has had testing early on in their diagnosis, they probably didn’t have the alteration, because it’s an acquired alteration that can happen over time. So it’s really important to test for it at the time of progression,” she adds.

Identifying ESR1 mutations early in disease progression enables clinicians to adjust treatment strategies, avoiding less effective therapies and potentially opting for SERDs, which target and degrade the estrogen receptor, directly combating the resistance mechanism induced by the mutation.

SERDs: A Novel Approach

SERDs represent a novel class of endocrine therapy that not only binds to the estrogen receptor but also induces its degradation, effectively reducing the overall estrogen receptor activity in cancer cells. Unlike SERMs, which can act as both agonists and antagonists depending on the tissue, SERDs function purely as antagonists, providing a more targeted and comprehensive blockade of estrogen signaling pathways in cancer cells​.

One of the key advantages of SERDs is their ability to target ER+ breast cancers that have developed resistance to other endocrine therapies, particularly in patients with ESR1 mutations. Fulvestrant (brand name Faslodex) , the first FDA-approved SERD, has been a cornerstone in treating advanced ER+ breast cancer, particularly in patients who have developed resistance to other therapies​.

In January 2023, the FDA has approved elacestrant (brand name Orserdu), an oral SERD, for the treatment of postmenopausal women and adult men with estrogen receptor-positive (ER+), HER2-negative, ESR1-mutated advanced or metastatic breast cancer after at least one line of endocrine therapy. This approval was based on the results of the EMERALD Phase III clinical trial, which demonstrated a significant improvement in progression-free survival compared to standard endocrine therapy.

“The EMERALD study was an important study that has led to the approval of a new class of drugs known as selective estrogen receptor degraders or SERDs. And the first drug to be approved in this category is Orserdu. The current indication is for patients who have acquired a mutation or an alteration in the estrogen receptor receptor. For these patients, some of our traditional endocrine therapy agents will no longer be effective,” Dr. Lustberg explains.

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 phase III EMERALD trial 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).

In the ESR1 mutant population, the progression-free survival (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.

Who Benefits from SERDs?

SERDs are particularly beneficial for patients with advanced or metastatic ER+ breast cancer who have shown resistance to other forms of endocrine therapy, especially those with identified ESR1 mutations. In clinical trials, SERDs such as giredestrant have demonstrated superior efficacy compared to traditional aromatase inhibitors in reducing tumor markers like Ki67, which are associated with cell proliferation​.

Moreover, second-generation SERDs, including novel oral formulations, are currently under investigation and offer improved bioavailability and patient compliance compared to injectable fulvestrant. These oral SERDs show promise in overcoming the limitations of earlier therapies and expanding treatment options for patients with endocrine-resistant breast cancer​.

Clinical Implications and Future Directions

The clinical integration of SERDs into breast cancer treatment represents a significant advancement in managing endocrine resistance. As more SERDs enter clinical practice, particularly those that can be administered orally, the landscape of breast cancer treatment is set to evolve, offering more personalized and effective care options for patients.

Testing for ESR1 mutations will continue to be a critical factor in determining the best therapeutic approach. As our understanding of the molecular underpinnings of endocrine resistance deepens, the role of SERDs is expected to expand, potentially in combination with other targeted therapies such as CDK4/6 inhibitors, PI3K inhibitors, and more.