Hormone therapy for metastatic breast cancer: understanding resistance, improving outcomes


John Boyer, Global Medical Affairs Leader, Breast Cancer, AstraZeneca

Metastatic breast cancer presents a major challenge to treating physicians. However, the molecular profile of these tumours often provides opportunities for targeted treatment.

For example, around two thirds of breast cancers express the hormone receptor (HR) (Sini et al. 2016). Such tumours typically grow in response to the binding of estrogen and progesterone to these receptors, and hence they are often sensitive to ‘hormone therapy’ – treatments designed to sever the link between hormones (particularly estrogen) and tumour growth.

Indeed, for many patients with metastatic HR-positive breast cancer, hormone therapy is a recommended first-line treatment in international clinical guidelines (Cardoso et al. 2012; NCCN 2016).   

There are currently three main types of hormone therapy used for women with metastatic breast cancer (Sini et al. 2016):

  • Aromatase inhibitors (AIs): These block the enzyme aromatase, which is involved in the synthesis of estrogen, thereby reducing the amount of estrogen available to stimulate the growth of HR-positive breast cancer cells.
  • Selective estrogen receptor modulators (SERMs): These block the estrogen receptor in HR-positive cancer cells, reducing the ability of estrogen to stimulate tumour growth.
  • Selective estrogen receptor degraders (SERDs): These down-regulate and cause degradation of the estrogen receptor, leading to blockage of downstream tumour growth activity.

Resistance mechanisms

Although very important, the binding of estrogen to its receptor is not always the only pathway driving tumour survival in patients with metastatic breast cancer (Osborne & Schiff 2011). Escape mechanisms often arise that lead to resistance of these tumours to some or all forms of hormone therapies, making them less effective.

Various escape mechanisms have been studied. For example, mutations in the ESR1 gene that encodes the endocrine receptor may play an important role (Murphy & Dickler 2015). These mutations are more frequent in metastatic and pre-treated HR-positive breast cancer, and could drive resistance to hormone therapy.

In addition, some HR-positive tumours may develop a mechanism for activating the estrogen receptor without requiring estrogen binding at all. The phosphoinositide 3-kinase (PI3K) pathway has been implicated as a key component of this mechanism, with hyperactivation of the PI3K pathway promoting activity of the estrogen receptor, even in the absence of estrogen (Figure).

Adapted from Glück 2014 and Osborne & Schiff 2011.

Importantly, however, these resistance mechanisms may have different implications for the effectiveness of different types of hormone therapy.

In particular, some of these resistance mechanisms may be associated with a state in which the tumour is estrogen-independent but still estrogen receptor-dependent. Hence, such tumours could be resistant to therapies that target estrogen (such as AIs) but remain sensitive to therapies that target its receptor (such as SERDs).

Of course, the real test of these treatments is how effective they are in preventing tumour progression and helping patients to live longer. Third-generation AIs are currently the mainstay of first-line hormone therapy (Sini et al. 2016). However, data being presented by AstraZeneca at this week’s European Society for Medical Oncology Annual Congress in Copenhagen may have the potential to challenge the status quo.


  • Cardoso et al. (2012). Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(Suppl 7):11-19.
  • Glück. (2014). Extending the clinical benefit of endocrine therapy for women with hormone receptor-positive metastatic breast cancer: differentiating mechanisms of action. Clin Breast Cancer 14:75-84.
  • Murphy & Dickler. (2016). Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies. Endocr Relat Cancer 23:R337-52.
  • National Comprehensive Cancer Network. (2016). Clinical practice guidelines in oncology. Breast cancer. Version 2.2016.
  • Osborne & Schiff. (2011). Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233-47.
  • Sini et al. (2016). Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice. Crit Rev Oncol Hematol 100:57-68.

Page Atlas ID: 1013120.011
Date of preparation: 06 October 2016
Date of expiry: 06 October 2017