Evidence is accumulating that although chemotherapy and hormonal drugs are both effective for patients with early breast cancer, the greater gains are being found from hormone therapy. The future for fighting cancer using novel hormone treatments is bright, Professor Mitch Dowsett, Professor of Biochemical Endocrinology at the Royal Marsden Hospital and the Institute of Cancer Research, London, UK, told a news briefing at the 3rd European Breast Cancer Conference in Barcelona on Wednesday (20 March)
"It is becoming increasingly clear that whilst chemotherapy and hormonal drugs both improve survival in early breast cancer and that these effects are additive, the gains from hormonal therapy are greater. Recent improvements in hormonal therapy and the understanding of molecular mechanisms promise to extend these gains further in the next few years," he said. "It is particularly exciting to recognise that these agents are sufficiently well tolerated for trial as prophylactics of breast cancer."
Most breast cancer cells ‘feed’ off the female hormone oestrogen, so the rationale for the most widely used medical endocrine therapies is invariably based around blocking or withdrawing the stimulation that oestrogen provides to oestrogen receptor positive breast cancers. How that is done depends on whether the patient is pre or post-menopausal.
In pre-menopausal women GnRH agonists* are used to block ovarian stimulation, but their disadvantage is that they initially stimulate the ovaries and also do not suppress oestrogen production by the ovary completely. So the challenge is to find drugs that overcome this problem.
"GnRH antagonists, such as antarelix, abarelix and cetrorelix, are under trial in prostate cancer and in vitro fertilisation (IVF). These don’t initially stimulate the ovaries and appear to achieve immediate, persistent and complete ovarian suppression. To my knowledge these have not yet been tested in breast cancer, but they clearly have potential for treating breast cancer in younger women so now we need to investigate these drugs in breast cancer patients," said Professor Dowsett.
Post-menopausal women still produce oestrogen – not from their ovaries but by converting hormones produced by the adrenal gland into oestrogen via an enzyme called aromatase. A class of drugs called aromatase inhibitors is effective in older women.
"The latest, third generation aromatase inhibitors, anastrazole (Arimidex), letrozole (Femara) and exemestane (Aromasin), can achieve almost complete oestrogen shutdown. Recent findings indicate that this is why the new aromatase inhibitors are proving even more effective than tamoxifen, a selective oestrogen modulator or SERM. Although tamoxifen acts largely as an antioestrogen in breast cancers it actually exhibits pronounced oestrogenic activity when oestrogen levels are very low," said Professor Dowsett.
He said there were data from laboratory studies that supported published clinical evidence that the differential effectiveness of oestrogen deprivation and tamoxifen was greater in tumours expressing the growth factors HER2 (up to a quarter of breast cancers) and/or EGFR (about 20% of breast cancers).
"This means that we need to try to find a new generation of SERMs lacking this oestrogenic activity in breast cancer and it provides a rationale for ICI 182780 (Faslodex) a pure anti-oestrogen currently being studied in advanced breast cancer. Unfortunately Faslodex seems to be the only one of its type under substantive clinical development."
Professor Dowsett concluded that it was likely that tamoxifen will become less important and the new aromatase inhibitors will become the treatments of first choice in postmenopausal women, possibly in combination with chemotherapy and the novel antibody treatments such as trastuzumab (Herceptin).
Some such combinations were already being investigated.
- GnRH or gonadotrophin releasing hormone regulates the synthesis of the gonadotrophins - FSH (follicle stimulating hormone), LH (luteinizing hormone) - both produced by the pituitary gland - and hCG (human chorionic gonadotrophin), produced by the placenta. The pituitary hormones are produced throughout the menstrual cycle and stimulate the growth and differentiation of follicles and steroid production in the ovary.
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