Tamoxifen, which has been used for over 40 years, is 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.
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An unintentional discovery
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.
At this time, tamoxifen was originally referred to as ICI 46,474, 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, as it caused ovulation.
A challenging market
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 studies were at a standstill.
Many reasons contributed to this, the primary one being a limited demand for the drug. In fact, during this time, only a small proportion of people were estimated to benefit from the palliative drug therapy, most of whom would only require it for about a year. Due to this, the financial return from marketing the drug was not expected to be particularly rewarding. On the other hand, there was also no market opportunity for it as a fertility drug.
Testing tamoxifen against breast cancer
In 1972, Craig Jordan began testing tamoxifen for its ability to prevent the formation of mammary tumors in mice. This experimentation involved using the known carcinogen dimethylbenzanthracene (DMBA) to induce mammary tumors in mice, which was followed by treatment with tamoxifen. Jordan had received assistance from Elwood Jensen, who, in 1958, was the scientist that originally isolated the estrogen receptor in target tissues.
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 procedure specifically targets that receptor.
Current use of tamoxifen
From the 1980s onwards, numerous clinical trials followed exploring the role of tamoxifen as adjuvant therapy. An interesting finding concluded that 1 year of tamoxifen adjuvant therapy conveyed no benefit in estrogen receptor-positive, early stage, invasive breast cancer. However, this study found that while 2 years of therapy with tamoxifen provided some benefit, 5 years of treatment ultimately proved to be the most effective.
Further trials have shown an association between prolonged treatment of up to 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.