The concept of ‘personalised’ medicine has been a buzzword in medicine for many years. In some disease areas, we are only just beginning to live up to the promise. However, in breast cancer, personalisation is now well-established for some biomarkers: patients are stratified and treated according to the presence or absence of various receptor molecules, including the estrogen receptor (ER), progesterone receptor and the human epidermal growth factor receptor 2 (HER2).
ER-positive breast cancer
About 75% of all breast cancers are ER-positive (Osborne & Schiff 2011). Such tumours typically grow in response to circulating estrogen and can often be treated with endocrine therapy – for example, by blocking estrogen binding to the receptor or by reducing the production of estrogen (Osborne & Schiff 2011).
Endocrine therapy remains the most effective treatment for ER-positive metastatic breast cancer, but its effectiveness is ultimately limited by resistance to endocrine therapies, either de novo or acquired during treatment. This is because, while important, estrogen is not the only survival pathway that drives most of these tumours, and various escape pathways exist that are already functioning or begin to function during treatment (Osborne & Schiff 2011).
However, although many tumours progress from being estrogen- and ER-dependent (and therefore amenable to endocrine therapy) to a resistant state in which they are independent of both, some patients experience an intermediate condition in which the tumour is no longer dependent on estrogen, but does still require ER.
In this intermediate state, ER remains a major driver of tumour growth, even in the absence of estrogen, as a result of activation by other factors (Figure). In these patients, ER continues to be a key therapeutic target.
ER-dependent, estrogen-independent metastatic breast cancer:
Adapted from Glück 2014 and Osborne & Schiff 2011.
Targeting escape pathways
Some existing therapies may be effective against estrogen-independent, ER-dependent tumours, particularly those that act not just by reducing estrogen binding to ER, but also by accelerating degradation of ER (Howell 2006).
In addition, a number of new compounds are in development that directly target ER-stimulating (estrogen-independent) escape pathways. As shown in the figure, hyperactivation of the intracellular phosphatidylinositol 3-kinase/AKT /mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is thought to be one such bypass route (Ciruelos Gil 2014).
Here at AstraZeneca, we are developing several compounds that target this pathway in breast cancer. We are working with a number of collaborators worldwide, both to better understand the pathological importance of the PI3K/AKT/mTOR pathway and to progress inhibitor molecules through clinical trials. Drug combinations that bring together both an existing ER antagonist and a novel inhibitor of the PI3K/AKT/mTOR pathway are particularly promising.
If the development of these compounds is successful in the coming years, we hope that this will lead to further personalisation of breast cancer treatment, and to improved outcomes for patients.
Ciruelos Gil. (2014). Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. Cancer Treat Rev 40(7):862-71.
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(2):75-84.
Howell. (2006). Pure oestrogen antagonists for the treatment of advanced breast cancer. Endocr Relat Cancer 13(3):689-706.
Osborne & Schiff. (2011). Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233-47.