In the 1970’s, the initial clinical studies of tamoxifen were focused entirely on its application as a treatment for metastatic breast cancer. The efficacy of tamoxifen was the same as that of high dose oestrogen therapy (diethylstilboestrol 15 mg. daily), but the advantage of tamoxifen was fewer serious side effects (13
). The translation of the early laboratory findings with tamoxifen (1
) to the treatment of advanced breast cancer showed an association between the efficacy of tamoxifen as an antitumor agent. and OER status (49
). However, it was the transition from the use of tamoxifen as a palliative therapy to adjuvant therapy that was to have the greatest impact on survivorship and to establish tamoxifen as the gold standard for antihormonal therapy from 1980–2000.
The goal of adjuvant therapy is to destroy the micrometastases that have spread around the body at the time of primary surgery. Early results with chemotherapy were extremely promising (50
) and some significant improvements were noted once the overview analysis of worldwide randomized clinical trials was analyzed and published (52
). However, the use of tamoxifen in this application was less readily accepted because of the belief that tamoxifen was only a palliative therapy. As a prelude to the application of tamoxifen as an adjuvant therapy, I introduced the antioestrogen first to the Eastern Cooperative Oncology Group (ECOG) (53
) and subsequently to the National Surgical Breast and Bowel Project (NSABP) (55
). Early adjuvant clinical trials selected one year of adjuvant therapy (56
) because of the fact that tamoxifen was effective in unselected patients with advanced breast cancer for about one year and there was a sincere concern that longer therapy would induce premature drug resistance. These beliefs were to change in the mid 1970’s with the laboratory finding that long term antihormonal therapy was more effective than short term therapy.
Marc Lippman published an important paper in 1975 on the actions of tamoxifen in cell culture (61
). He demonstrated that oestradiol could reverse the action of tamoxifen to stop cell replication and that tamoxifen could actually kill breast cancer cells at high concentrations. We decided to test the idea that tamoxifen was cytotoxic in vivo
using the DMBA-induced rat mammary carcinoma model.
We reasoned that daily treatment with tamoxifen for a month in the rat would be equivalent to a year in a woman. Administration of DMBA (20 mg in 2 mls peanut oil po) to 50 day old female Sprague-Dawley rats resulted in the development of multiple mammary tumours in all animals about 150 days later (62
). The experimental approach we used was to administer different daily doses of tamoxifen for a month starting one month after DMBA administration. This design was to allow carcinogenesis to proceed following DMBA administration so that we could assess the effectiveness of tamoxifen to destroy the microfoci of deranged cells in the mammary tissue. This was as close as one could get to an endocrine adjuvant model in the 1970’s.
Tamoxifen was compared with 4-hydroxytamoxifen because we had found it was the most potent antioestrogen then known (31
); at least ten times more potent than tamoxifen. We chose to test 4-hydroxytamoxifen because we anticipated that it would be a more potent antitumour agent than tamoxifen. To our surprise, not only was 4-hydroxytamoxifen not as effective as tamoxifen, but short-term tamoxifen was unable to “cure” animals. High doses of tamoxifen were superior to low doses of tamoxifen in reducing tumour numbers and controlled tumour appearance, but all animals eventually developed at least one tumour. Clearly, there was a link between dose and anticancer action, but it was because higher doses were cleared from the body more slowly and not that the higher dose was more active. Tamoxifen was acting as a tumouristatic agent – the drug was effective as long as the drug was present to suppress tumour growth () (3
). We proved this concept experimentally by showing that antioestrogens were effective at controlling tumorigenesis as long as treatment was continued. Indeed, if tumours occurred during antioestrogen therapy, they would respond to a second antihormone therapy, in this case, oestrogen withdrawal following ovariectomy. We concluded “It was clear that antioestrogens do not destroy all the foci of hormone dependent tumour cells and long courses of therapy or the use of antihormonal methods e.g. ovariectomy, are essential to control tumour growth.”
) This notion lead to the idea that longer was going to be better as a strategy to employ for adjuvant tamoxifen therapy and provided a scientific foundation for the successful use of subsequent oestrogen deprivation, i.e. an aromatase inhibitor following 5 years of tamoxifen treatment (65
Figure 2 Participants at a Breast Cancer Symposium in September 1977 at Kings College, Cambridge, England. The concept of extended adjuvant tamoxifen treatment was first proposed at this meeting. Clinical studies of a 1-year adjuvant tamoxifen were in place; regrettably, (more ...)
The overview analysis of randomized clinical trials that occurs about every five years at Oxford has really revolutionized clinical thinking. The publications summarize treatment progress through the clinical trials mechanism. The clinical proof that longer tamoxifen therapy is better than shorter tamoxifen therapy is most readily demonstrated in the OER positive premenopausal patients. One year of tamoxifen was ineffective, but 5 years produced a dramatic effect on disease-free survival and overall survival (67
). More importantly, tamoxifen produced a survival advantage for women, of a magnitude that would change the perception of endocrine agents as only palliative. The key to success was targeting women with the right tumour with the correct duration of treatment at the right stage.