Managing ESR1 Mutations in HR+, HER2- Metastatic Breast Cancer

Hormone receptor-positive (HR+) and HER2-negative (HER2-) metastatic breast cancer represents a substantial portion of advanced breast cancer cases. This subtype is generally characterized by the expression of estrogen and/or progesterone receptors and the absence of HER2 overexpression.

The key therapeutic strategy for HR+/HER2- metastatic breast cancer relies primarily on endocrine therapy (ET), often combined with targeted agents — however, a significant subset of these patients do go on to develop the ESR1 mutation due to hormone therapy. Fortunately the drug elacestrant is now available to target these mutations.

“Under the pressure of hormone therapy, tumors can acquire ESR1 mutation. Those are estrogen receptor mutations. That’s what the ESR stands for. We how have commercially available drug in the form of elacestrant, which targets ESR1 mutations, which are prevalent in about 40% of breast cancers, again acquired under the pressure of hormone therapy and typically aromatase inhibitor therapy,” Dr. Heather MacArthur, Director of Breast Cancer at UT Southwestern in Dallas, Texas, tells SurvivorNet Connect.

In recent years, treatments for advanced HR+, HER2- breast cancer have evolved significantly, focusing on extending survival, improving quality of life, and addressing disease-related symptoms. Elacestrant represents another important addition to the treatment toolkit.

Goals of Treatment

The overarching goals of treatment for metastatic HR+/HER2- breast cancer are to:

1. Prolong overall survival
2. Improve quality of life
3. Alleviate symptoms associated with cancer progression

Because metastatic disease is often incurable, treatments aim to control the disease for as long as possible while minimizing treatment-related toxicities. Therapeutic decisions must be individualized based on factors such as tumor biology, patient preferences, and response to prior therapies.

Endocrine Therapy

Endocrine therapy (ET), also known as hormone therapy, remains the backbone of treatment for patients with HR+ metastatic breast cancer. ET exploits the dependence of HR+ breast cancer cells on estrogen signaling for growth. The primary types of ET include:

• Selective Estrogen Receptor Modulators (SERMs) like tamoxifen,
• Aromatase Inhibitors (AIs), including anastrozole, letrozole, and exemestane,
• Selective Estrogen Receptor Degraders (SERDs) like fulvestrant.

For most patients with HR+/HER2- metastatic breast cancer, especially those without extensive visceral involvement or symptomatic disease, first-line therapy consists of an aromatase inhibitor (AI) or tamoxifen combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. This combination has demonstrated improvements in progression-free survival (PFS) and, in some cases, overall survival (OS).

Cyclin-Dependent Kinase 4/6 Inhibitors

CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib have transformed the treatment landscape for HR+/HER2- metastatic breast cancer. These agents inhibit the CDK4 and CDK6 proteins, which are involved in driving the cell cycle from the G1 to S phase, thereby reducing the proliferation of cancer cells. In combination with endocrine therapy, CDK4/6 inhibitors significantly extend progression-free survival and have been shown to improve overall survival, particularly in the first-line setting.

• Palbociclib (brand name Ibrance): When combined with an aromatase inhibitor, palbociclib improves PFS compared to endocrine therapy alone.
• Ribociclib (brand name Kisqali): In the MONALEESA trials, ribociclib combined with endocrine therapy also demonstrated a significant survival benefit.
• Abemaciclib (brand name Verzenio): The MONARCH trial showed similar improvements in PFS and OS with abemaciclib plus ET.

ESR1 Mutation in Hormone Receptor+ Breast Cancer

As previously mentioned, tumors can acquire the ESR1 mutation under the pressure of hormone therapy.

These mutations can be detected in tumor tissue as well as in circulating tumor DNA (ctDNA), which provides a non-invasive method for monitoring disease progression .

Implications for Treatment

The presence of ESR1 mutations has important clinical implications, particularly for the management of endocrine resistance. However, these cancers may still respond to selective estrogen receptor degraders (SERDs), such as fulvestrant (brand name Faslodex) or the newer oral SERD elacestrant (brand name ORSERDU).

In patients with ESR1-mutated breast cancer, elacestrant has shown superiority over fulvestrant. The EMERALD trial demonstrated that elacestrant improved progression-free survival (PFS) compared to standard of care endocrine therapy, particularly in patients with ESR1 mutations

Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus standard-of-care both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Treatment Sequencing and Individualization

The sequence of therapies should be tailored to the patient’s disease characteristics, prior treatments, and comorbidities. While endocrine therapy remains the preferred first-line option, the development of resistance often necessitates a switch to combination therapies or chemotherapy.

Endocrine therapy continues to be a cornerstone of treatment, offering effective disease control with minimal toxicity, especially in the early stages of metastatic disease. The challenge remains in overcoming endocrine resistance and determining the optimal sequencing of therapies to maximize patient outcomes.