New hope for hormone resistant breast cancer
A new finding provides fresh hope for the millions worldwide with oestrogen receptor positive breast cancer. Australian scientists have shown that a specific change, which occurs when tumours become resistant to anti-oestrogen therapy, might make the cancers susceptible to treatment with chemotherapy drugs.
Seventy percent of breast cancer patients have oestrogen receptor positive cancer, and most patients respond well to anti-oestrogen therapies, for a few years at least. Within 15 years, however, 50% will relapse and eventually die from the disease.
Dr Andrew Stone, Professor Susan Clark and Professor Liz Musgrove, from Sydney’s Garvan Institute of Medical Research, in collaboration with scientists from Cardiff University, have demonstrated that the BCL-2 gene becomes epigenetically ‘silenced’ in resistant tumours. This process is potentially detectable in the blood, providing a diagnostic marker. Their findings are now online in the international journal Molecular Cancer Therapetics.
Epigenetics involves biochemical changes in our cells that directly impact our DNA, making some genes active, while silencing others. Epigenetic events include DNA methylation, when a methyl group - one carbon atom and three hydrogen atoms - attaches to a gene, determining the extent to which it is ‘switched on’ or ‘switched off’.
Dr Stone and colleagues have shown in human disease, as well as in several different cell models, that BCL-2 is silenced in oestrogen-resistant tumours by DNA methylation.
“The main purpose of the BCL-2 gene is to keep cells alive, so when the gene is silenced, cells become more vulnerable to chemotherapy,” said Dr Stone.
Breast and prostate cancers are the most common malignant disease in female and male world population, respectively. Both of these tumors are predominantly hormonal-dependent, what is rationale for the widely used endocrine treatment, with specific approach in each of them. Although endocrine treatment is obviously effective and responsible for prolonged progression-free survival and even survival, the problem is that breast and prostate cancers inevitably become “hormone-resistant”. The paradigm of treatment has to be changed and today there are some ways to overcome these lack of endocrine responsivness. It is known better today which mechanisms are involved in hormone-resistance, and they are numerous, so the designation of new drugs with key features necessary activity in hormone-resistant tumors. In breast cancer, there are selective estrogen modulators as a way to overcome this problem; there is also a combination of receptor-tyrosine kinase and hormonal treatment documented as active in such cases.
On the other hand, abirateron-acetat and enzalutamide as a new androgen-receptor-signalling inhibitors proved that androgen signalling cascade is still active even in a castration-resistant prostate cancer.
B reast- and prostate cancer are two the most common invasive cancers in women and men, respectively. Although these tumors seem to be considerably different due to diverse anatomical and physiological features of the organs where they arise, they share a common feature of “hormonal-dependence”. Both of organs require gonadal steroids for their development and tumors arising from them have remarkable underlying biological similarities. Recently, it has been made a great improvement in our understanding of the pathophysiology of breast and prostate cancers which paved the way for new treatment strategies.
The very beginning was George Beatson’s treatment of metastatic breast cancer by oopherectomy at the end of 19 th century. Similarly, castration for the treatment of prostate cancer was such an important advance that it earned Charles Huggins a Nobel Prize in 1966. The sex steroid hormones oestrogen and androgen are key drivers of both breast and prostate cancer. The discovery and characterization of receptors for oestrogen and androgen (that is, oestrogen receptor-a (ERa) and ERa and androgen receptor (AR)), as well as key enzymes involved in the issues-specific metabolism of steroids led to designing different therapeutic approaches that either inhibit steroid-biosynthesis (gonadal, adrenal, peripheral and intratumoral) or block receptor function (receptor-antagonists). For metastatic disease, hormone therapy has become a standard of care in receptor-positive breast cancer and prostate cancer. The success of current hormone therapies relies on breast and prostate cancer recapitulating the dependence of the parent organ on a specific gonadal steroid for its growth and function. However, although there is initially good response to hormone therapy resulting in inhibition of tumor growth, inevitably these tumors after some time stop responding to hormone therapy and become “hormone-resistant”. This is crucial event in evolution of disease which is, with no exception, fatal. Nevertheless, some variations of hormone therapies in breast and prostate cancer might confer additional short-term responses, suggesting that the correct sequencing in breast and prostate cancer is important to improve patient outcomes. The challange is to target steroid receptor signalling pathways that continue to influence tumor growth even after tumor became “hormonal (castration)-resistant”.
Furthermore, common to breast cancer and prostate cancer, hormonal homeostasis is not confined to “classic” hormones – that is, androgens in prostate cancer and oestrogens in breast cancer: oestrogens are also crucial to prostate cancer and androgens to breast cancer development and progression, respectively. There is also a general need to better understand the action and effect of steroid precursors and metabolites, as the levels of these can be altered by hormone therapy, thereby contributing to hormone resistance in breast and prostate cancer. Interestingly, men and women synthesize both androgens and oestrogens, although in different amounts depending on age, and the idea that oestrogens are also important for prostate cancer and androgens for breast cancer has profound implications for developing strategies to treat and prevent both cancers. Namely, knowing the different effects of ERs and their antagonists in different tissues, it is to assume that possible therapeutic implications are to arise in near future.
“The next step will be to test our findings in clinical studies. We propose that if the BCL-2 gene is silenced, patients with oestrogen receptor positive breast cancer would benefit from combination therapy. In other words, tamoxifen could be used in combination with a chemotherapy drug, to kill off vulnerable tumour cells.”
“Excitingly, this is something that could be implemented into clinical practice very quickly, since the technology now exists to profile methylation of BCL-2 in all patients - both oestrogen responsive and oestrogen resistant patients. In addition, the proposed chemotherapy drugs are already in use.”
“If such a test were to be implemented, we believe it could help patients much earlier - hopefully shutting down tumours at an early stage.”
NOTES TO EDITORS
Oestrogen is a hormone that drives reproduction, menstruation and menopause in women. Oestrogens are also present in men, but to a lesser degree.
Many breast cells have oestrogen receptors on their surface. When one of those cells becomes malignant and starts to multiply, an oestrogen receptor positive tumour develops. Typically these tumours are fed by high concentrations of oestrogen in the bloodstream, triggered by circumstances such as late first pregnancy, not breastfeeding, or too much body fat.
At present, there are three different therapeutic strategies for oestrogen receptor positive breast cancer: blocking the body’s production of oestrogen with aromatase inhibitors; preventing oestrogen from ‘binding’ to the oestrogen receptor by ‘binding’ the drug tamoxifen instead; and destroying the oestrogen receptor completely.
Tamoxifen, now the gold standard treatment, became available in the 1970s.
Endocrine therapies, including tamoxifen, are inexpensive and well-tolerated, and are usually given for 5 years. Over time, however, many tumours become resistant to therapy. When one form of treatment starts to fail, a second is put in place, and then a third. Response times shrink, and tumours start to spread to other parts of the body, usually the brain, lungs, liver and bone.
At this late stage, there is little that can be done to help someone, as the brain, lungs, liver and bone are parts of the body that cannot be biopsied or operated upon.
While breast cancer predominantly targets women, with 1 in 9 women being affected, it also affects 1 in 100,000 men, some of whom have oestrogen responsive cancers.
ABOUT GARVAN
The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent’s Hospital in Sydney, it is now one of Australia’s largest medical research institutions with over 600 scientists, students and support staff. Garvan’s main research areas are: Cancer, Diabetes & Obesity, Immunology and Inflammation, Osteoporosis and Bone Biology and Neuroscience. Garvan’s mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan’s discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.
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Alison Heather
Science Communications Manager
M: + 61 434 071 326
P: +61 2 9295 8128
E: a.heather “a” garvan.org.au