Breast cancer is the second most common cancer among women globally, and it affects both men and women. Breast cancer is caused by the abnormal growth of cells in the breast tissue, which can lead to the formation of tumors.

Although there are many risk factors associated with breast cancer, genetic mutations play a crucial role in its development. In particular, mutations in the ESR1 gene have been linked to an increased risk of metastatic breast cancer progression.

This article discusses ESR1 mutations as well as patient perspectives on the topic from the Inspire Advanced Breast Cancer Community. This content should not be used as a substitute for professional medical advice, diagnosis, or treatment. As always, consult with your doctor before trying any new treatments or medications.

What is an ESR1 gene mutation?

The ESR1 (estrogen receptor 1) gene is known for its role in encoding estrogen receptor alpha. Estrogen receptor alpha is a protein that binds to estrogen. This protein then enters the nucleus of cells and regulates the expression of genes involved in growth and proliferation. 

What is the purpose of the ESR1 gene?

The ESR1 gene encodes estrogen receptor alpha, meaning it is responsible for ensuring this protein functions as intended throughout all of the cells in the body. If properly encoded, estrogen receptor alpha helps regulate cell division in certain tissues, including breast tissue. 

Estrogen receptors are present in many types of tissue and involved in various organ systems. Estrogen and estrogen receptors are important in regulating reproductive, skeletal, cardiovascular, and central nervous systems. Tissues that contain estrogen receptors include the mammary gland, uterus, ovary, bone, male reproductive tract, prostate, liver, and adipose tissues, among others. 

What does the ESR1 gene do in breast cancer?

Several studies have suggested that mutations in the ESR1 gene are associated with an increased risk of breast cancer. 

If there is a mutation in the ESR1 gene, this can lead to the over-activation of estrogen receptor alpha. Over-activation of this protein may lead to uncontrolled cell division, which may result in breast cancer tumor development and progression. 

Estrogen receptors are present in both normal and cancerous breast tissue. In fact, nearly 70% of breast cancers are hormone receptor positive (ER+). This means that most tumor cells contain estrogen receptors. The presence of these receptors can contribute to tumor growth. 

In particular, mutations in certain regions of the ESR1 gene have been linked to a higher risk of breast cancer recurrence and metastasis (spreading). For example, a mutation in the L536R region of ESR1 has been shown to increase the risk of developing metastatic breast cancer.

ESR1 mutations can also affect the response of breast cancer cells to hormone therapy. Hormone therapy is a type of treatment that works by blocking the effects of estrogen on breast cancer cells. However, if a breast cancer cell has a mutation in the ESR1 gene, it may be able to grow and proliferate even in the absence of estrogen. This means that hormone therapy may not be effective in treating breast cancer in patients with ESR1 mutations.

What does the ESR1 gene do in cancer? 

Research is underway to identify connections between the ESR1 gene and other types of cancer. For example, there have been some preliminary research studies to identify whether or not ESR1 mutations are linked to cervical cancer. Research is still ongoing in these areas.

How common is the ESR1 mutation in breast cancer?

ESR1 mutations are rarely found in primary breast cancer tumors—tumors that originate in the breast at the time of cancer diagnosis. Only 0% to 3% of primary tumors will have ESR1 mutations. However, ESR1 mutations are relatively common in certain kinds of breast cancer tumors, such as metastatic endocrine therapy-resistant breast cancer lesions. ESR1 gene mutations are found in 6% to 55% of these types of tumors. 

A higher abundance of ESR1 mutations has been reported among metastatic patients treated with multiple lines of endocrine therapy as opposed to early metastatic patients. This suggests that there is a difference between inherited ESR1 mutations and those that are acquired, with the majority being clinically acquired, or acquired during cancer treatment. Acquired ESR1 mutations have implications for treatment pathways, as these mutations may make tumors less responsive to certain treatments.

ESR1 mutations are acquired most frequently when a specific type of endocrine therapy, known as aromatase inhibitor therapy, is used to treat advanced breast cancer. In some studies, ESR1 mutations were acquired in 12% to 55% of metastatic breast cancers treated previously with endocrine therapy.

ESR1 mutation breast cancer prognosis and survival

Studies have shown that patients have worse overall survival with ESR1 gene mutations in their metastatic tumors. In contrast, about half of all non-metastatic breast cancer patients can be cured of the disease using various hormone and targeted therapies, including endocrine therapy. Of the 50% of patients who aren’t cured, about 30% of them will see clinical benefit from endocrine therapy. However, endocrine therapy loses its effectiveness in patients with acquired ESR1 gene mutations.

Targeted therapies for breast cancer include procedures such as mastectomy, a partial or complete removal of one or both breasts. Read more about what to expect before having a mastectomy. 

As one Inspire member shared in the Inspire Advanced Breast Cancer community, “I got genomic testing and one of the wonky genes discovered was the ESR1 D5836 subclonal mutation. I now understand (I think) that this gene is why an aromatase inhibitor did nothing for me.”

Other types of treatments beyond endocrine therapy may be more promising for those with ESR1 gene mutations. In one analysis, patients with ESR1 mutation breast cancer had higher overall survival rates when treated with therapies other than endocrine therapy. 

The identification of acquired ESR1 gene mutations can be challenging in standard clinical practice because repeat biopsies are not often conducted after initial treatment has started. Repeated biopsies of the same tumor after treatment has started may be able to reveal acquired ESR1 mutations that could impact treatment pathways.

Getting treated for breast cancer can be a life-altering experience. Read more about what to expect after breast cancer treatments.

Disclaimer

Member comments have been edited for length and clarity. This content is for general informational purposes only and does not necessarily reflect the views and opinions of any organization or individual. The content should not be used as a substitute for professional medical advice, diagnosis, or treatment. Consult your healthcare provider about any questions you have regarding a medical condition.