Tamoxifen has been used for over 40 years as one of the most widely used therapies in the world for the treatment of breast cancer. It has been demonstrated that tamoxifen therapy reduces the rate of breast cancer recurrence for up to at least 15 years following the onset of treatment.
Tamoxifen has saved numerous lives since its introduction in cancer therapy however, scientists had not originally intended for its use in this field. In fact, its debut in the clinical setting was as a post-coital contraceptive in a trial led by Arthur L. Walpole in the early 1960s.
It was referred to as ICI 46,474 at the time, having been manufactured in the laboratories of Imperial Chemical Industries (ICI) which is now AstraZeneca. While the drug was found to be effective in rat studies, it was actually found to induce the opposite effect in humans i.e. it caused ovulation.
Following the failure of ICI 46,474 as a contraceptive in humans, Walpole directed the team and their studies towards cancer research. Even though it showed some promise in breast cancer therapy, further study was held at a standstill.
Many reasons contributed to this, the primarily the limited demand for the drug – only a small proportion of people would benefit from the palliative drug therapy and would only require it for only a year. Due to this, the financial return from marketing the drug was not expected to be particularly rewarding. On the other side, there was also no market opportunity for it as a fertility drug.
In 1972, Craig Jordan began testing with tamoxifen to successfully prevent the formation of mammary tumors in mice. This experimentation involved using a known carcinogen (dimethylbenzanthracene i.e. DMBA) to induce mammary tumors in rats and then applying tamoxifen to study its action as an anticancer agent. Jordan had received assistance from Elwood Jensen who had been the scientist to isolate the estrogen receptor in target tissues in 1958.
Shortly after, in 1974, an estrogen-receptor assay was determined. This assay would involve quantifying the level (if any) of estrogen receptor present in a tumor through a biopsy. The level of this receptor protein offers great predictive power; in essence, only in the presence of the receptor would there be a high probability that a tumor will respond to hormone-ablative surgery (as this targets that receptor).
From the 1980s onwards, numerous clinical trials followed exploring the role of tamoxifen as adjuvant therapy. An interesting finding was that 1 year of tamoxifen adjuvant therapy conveyed no benefit in estrogen receptor-positive, early stage, invasive breast cancer, 2 years was of some benefit, but it was 5 years that was the most effective.
Further trials have shown an association between prolonged treatment (10 years), tamoxifen resistance and possible, serious side effects (e.g. clotting abnormalities, endometrial cancer).
The incidence of tamoxifen resistance (whether existing or developing) has also been revealed in approximately 20-30% of patients receiving tamoxifen therapy. The resistance is thought to be associated with a change in the estrogen receptor expression which in turn steers the target tissues to proliferate even in the absence of estrogen-induced signalling). Studying this will prove to be incredibly beneficial as a biomarker to predict therapy outcome in an individual patient.