What is endocrine therapy for breast cancer?
Breast cancer endocrine therapy is a medical treatment that primarily targets estrogen or progesterone levels in patients with hormone receptor-positive breast tumors. Its purpose is to suppress the growth of hormone-driven tumors or reduce the risk of cancer recurrence.
Hormone-sensitive tumors consist of cells that contain hormone receptors—special proteins that bind to specific hormones. Such receptors may bind to progesterone in progesterone receptor-positive (PR+) tumors, estrogen in estrogen receptor-positive (ER+) tumors, or both (ER/PR+ tumors). These hormones stimulate the growth and spread of hormone-receptive cancer cells. Endocrine therapy prevents cancer cells from binding to these hormones, helping to slow or stop disease progression.1
The primary forms of endocrine therapy for all three types of hormone receptor-positive breast cancer often target estrogen first. Due to the hormonal interdependence between estrogen and progesterone, where estrogen is involved in the regulation of the pathway for progesterone receptors and stimulation of their expression, patients with PR+ cancer can also potentially benefit from suppressing estrogen production with endocrine therapy.
The primary forms of breast cancer endocrine therapy include:
- Selective estrogen receptor modulators (SERMs), such as tamoxifen, which bind to estrogen receptors and block the hormone’s action without lowering its levels;
- Aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane, which block the activity of the enzyme aromatase, responsible for converting androgens into estrogen in postmenopausal women;
- Estrogen receptor downregulators (ERDs), such as fulvestrant, which target the estrogen receptors on tumor cells, preventing estrogen from stimulating breast cancer growth;
- Ovarian suppression through gonadotropin-releasing hormone (GnRH) agonist medications, such as goserelin and leuprolide, or oophorectomy, the surgical removal of the ovaries, which stops this organ from producing estrogen.2
The effectiveness of endocrine therapy for breast cancer
Endocrine therapy is widely used to treat hormone receptor-positive breast cancers because of its effectiveness. However, its success can be influenced by several factors, including the tumor grade, the patient’s age, menopausal status, and overall health. Additionally, endocrine therapy is associated with side effects that can be severe in some patients and should be carefully considered to avoid worsening certain conditions. All these factors should be taken into account to select the optimal treatment.
Endocrine therapy is frequently used as an adjuvant treatment, administered after surgery to lower the risk of cancer recurrence. In such a scenario, tamoxifen and AIs are commonly prescribed. AIs are also often selected for controlling tumors in advanced stages of cancer, with fulvestrant being another popular option.
Menopausal status often dictates the choice of therapy due to the different sources of estrogen in the female body. Therapies targeting the ovaries, such as tamoxifen or ovarian suppression, are typically prescribed for premenopausal women but are less effective for postmenopausal women, whose ovaries are no longer the primary organ producing estrogen. In these patients, estrogen is synthesized in various tissues, including fat, skin, muscle, breast tissue, and adrenal glands.
As a result, ERDs like fulvestrant and aromatase inhibitors (AIs) like letrozole are more commonly used to treat postmenopausal women. However, these medications can increase the risk of bone loss, which is already a concern for this patient group, as well as raise the risk of cardiovascular diseases.
Tamoxifen can also cause serious side effects, including pulmonary embolism, deep vein thrombosis (DVT), blood clots, and uterine cancer.
Combination of endocrine therapy with other treatments
To further enhance the effectiveness of endocrine therapy, breast cancer is often treated with a combination of methods.
A common approach to administer endocrine therapy alongside or before the surgery in neoadjuvant therapy. Endocrine therapy can shrink tumors to assist in their removal or be administered after surgery to reduce the risk of recurrence as a part of adjuvant therapy. To boost treatment effectiveness, endocrine therapy may be combined with chemotherapy before or after surgery. Alternatively, radiation therapy may be used.
A more innovative approach involves combining endocrine therapy with targeted drugs specifically designed to disrupt the mechanisms of cancer cells, increasing the chances of prolonged progression-free survival. CDK4/6 inhibitors, such as ribociclib, palbociclib, and abemaciclib, are examples of synthetic suppressors that target cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), enzymes supporting cancer cell division.3
Duration of breast cancer endocrine therapy
The duration of endocrine therapy in breast cancer depends on whether it is part of neoadjuvant or adjuvant treatment. As mentioned earlier, many patients continue the treatment after tumor removal to reduce the risk of cancer recurrence. The standard duration of adjuvant endocrine therapy is 5 years. However, in patients with higher risk factors, such as high-grade tumors or extensive lymph node involvement, the administration of medications may be extended to 10 years.
This does not always mean using a single medication. For example, some treatment plans may start with tamoxifen and later switch to an aromatase inhibitor.
Endocrine therapy resistance
Although endocrine therapy is commonly used for HR+ breast cancer, it is not always effective due to natural or acquired resistance.
Some patients show intrinsic resistance to primary endocrine therapy because their cancer cells do not respond to hormone-blocking medications, often as a result of genetic mutations. Additionally, patients with advanced cancer are especially at risk of developing resistance to endocrine therapy over time.
References:
- “Breast Cancer Hormone Receptor Status.” American Cancer Society.
https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html - “Hormone therapy for breast cancer.” Mayo Clinic.
https://www.mayoclinic.org/tests-procedures/hormone-therapy-for-breast-cancer/about/pac-20384943 - Doss W. “Combination Treatment Beats Chemotherapy in Breast Cancer.” Northwestern Medicine.
https://news.feinberg.northwestern.edu/2019/11/14/combination-treatment-beats-chemotherapy-in-breast-cancer/