Breast cancer remains the leading cause of death for women in South America, the Middle East, and most of Europe1. 90% of breast cancer deaths are caused by metastatic disease, in which the cancer spreads to other parts of the body or recurs at a distant site. Between 20 and 30% of patients diagnosed with primary breast cancer will develop metastatic disease.2 Unfortunately, metastatic breast cancer cannot currently be cured but it is treated to prevent the cancer cells spreading further and extend a patient’s life.
Endocrine therapy is commonly used to treat estrogen receptor positive recurrent breast cancer and metastatic breast cancer. The wide variety of available endocrine agents act to prevent the stimulation of breast cancer cells by the hormone estrogen. This is achieved through several different modes of action; these can generally be assigned to one of three main categories: aromatase inhibition, selective estrogen-receptor modulation, and selective estrogen-receptor degradation. These various types of endocrine therapy have been successfully used to significantly reduce cancer recurrence rates and extend survival.
Since endocrine therapy targets only estrogen and the estrogen receptor, it can be associated with fewer and less severe side effects than cytotoxic treatments. The side effects of endocrine therapies are typically a response to reduced estrogen stimulation which manifest as menopausal symptoms, such as hot flushes, night sweats and mood changes.
However, anti-tumor efficacy can only be achieved with an endocrine therapy if the breast cancer is hormone-sensitive. This typically necessitates expression of the estrogen receptor on the surface of the tumor cells (i.e., they are ER+). Depending on the type of endocrine therapy used, it will either reduce the amount of estrogen available to activate the receptor, reduce the binding of estrogen to the receptor or reduce the number of estrogen receptors. In each case the cancer cells no longer receive the estrogen stimulation that promotes their growth.
By virtue of maintaining a better quality of life, endocrine therapy is often the first-line treatment of choice for ER+ metastatic breast cancer. The majority of breast cancers (75‑80%) are hormone responsive, so this is the most common course of action. In pre-menopausal women, endocrine therapy will be used in conjunction with an ovarian-suppression treatment to prevent the ovaries from producing large quantities of estrogen. After the menopause, women naturally produce only small amounts of estrogen and so the endocrine therapy can be used alone as estrogen suppression is not required.
The efficacy of endocrine therapy may be impaired if the tumor also tests positive for human epidermal growth factor receptor (HER2/HER+), in which case a HER2/HER targeted therapy can be used concomitantly.3
Tumor cells that do not express the estrogen receptor are described as ER‑ and are not dependent on estrogen. Consequently, their growth is not hindered by endocrine therapy. If a tumor is not responsive to estrogen, strategies to reduce estrogen stimulation will have no impact on the growth of that tumor. Such tumors are said to have intrinsic endocrine resistance.4
An alternative first-line therapy is thus required for cases of ER‑ metastatic breast cancer. This commonly takes the form of chemotherapy. If the tumor is HER2/HER+, treatment with an HER2/HER targeted therapy may be used alone or in combination with chemotherapy.
A further obstacle to the success of endocrine agents in the treatment of breast cancer is the tendency of ER+ tumor cells to progressively develop resistance to endocrine therapy during the course of treatment (acquired resistance). It is estimated that with ongoing endocrine therapy, around a third of women with early-stage breast cancer will become refractory to the treatment within 2 to 5 years.
The development of resistance to an endocrine therapy does not necessarily mean the patient has to start chemotherapy, although this is likely to be required in the longer term. Efficacy may be restored by switching to a different endocrine therapy that has an alternative mode of action. Indeed, a patient may benefit from switching treatment several times in order to extend the duration of efficacy with a better-tolerated endocrine agent.
The precise mechanism underlying the development of endocrine resistance has yet to be determined, but it is thought to arise as a result of complicated crosstalk, both genomic and non-genomic, between estrogen receptors and growth factors. Although the precise pathways have yet to be elucidated, treatments have been identified that reverse endocrine resistance, presumably by disrupting such pathways. These treatments include cyclin-dependent kinase (CDK) inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors, which can be used in combination with endocrine therapies to restore sensitivity and promote tumor shrinkage.
For patients with ER+ metastatic breast cancer endocrine therapies provide tumor control whilst maintaining a good quality of life. However, such a treatment strategy is thwarted over time by the development of endocrine resistance. Ultimately, endocrine therapies become inadequate to control tumor growth and chemotherapy will be required. With the aim of treatment being to extend a patient’s life as long as possible, the optimal sequencing to do this can be complicated and depends on a range of factors in addition to tumor status, including prior adjuvant therapy, disease-free interval, side effects, and patient quality of life. In the future, it may be possible to overcome resistance for a while by using combination treatments to interfere with resistance mechanisms used in combination with endocrine and other therapies.
- Globocan & WHO. World Health Organization Mortality Map. (2018). Available at: https://wol-prod-cdn.literatumonline.com/cms/attachment/d232ed31-b4b4-4473-a300-f1e097462fec/caac21492-fig-0006-m.jpg. (Accessed: November 30th 2019)
- Metastatic Breast Cancer: Symptoms, Treatment, and More. Available at: https://www.breastcancer.org/symptoms/types/recur_metast. (Accessed: November 30th 2019)
- Mitri, Z., Constantine, T. & O’Regan, R. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother. Res. Pract. 2012, 743193 (2012).
- Receptors for breast cancer – Understanding cancer – Macmillan Cancer Support. Available at: https://www.macmillan.org.uk/information-and-support/breast-cancer/treating/treatment-decisions/understanding-your-diagnosis/receptors-for-breast-cancer.html. (Accessed: November 30th 2019)
- D’Souza A, et al. Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer. Journal of Hematology & Oncology 2018;11:80. https://doi.org/10.1186/s13045-018-0620-6
- Fan W, et al. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future Med. Chem. 2015; 7(12):1511–1519. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558537/
- Reinert T, et al. Endocrine therapy for ER-positive/HER2-negative metastatic breast cancer. Chin Clin Oncol. 2018 Jun;7(3):25. doi: 10.21037/cco.2018.06.06. https://www.ncbi.nlm.nih.gov/pubmed/30056727
- Rugo HS, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 2016;34:3069–3103.