ReviewTamoxifen: Catalyst for the change to targeted therapy
Introduction
A new dynasty gives dominion over the ruling dynasty through perseverance and not by sudden action (Ibn Khaldun 14th Century Arab Historian) – and so it is with changes in the approach to cancer therapy. This article will focus specifically on a cluster of scientific papers1, 2, 3 published in the European Journal of Cancer that presaged the dramatic changes that have occurred in the past 35 years in our approach to cancer therapy. To set the scene, it is first appropriate to describe the research and treatment philosophy for breast cancer before tamoxifen.
In the 1960s, the use of combination cytotoxic chemotherapy for the treatment of breast cancer had moved to centre stage in the wake of an abstract presented at the American Association for Cancer Research.4 The cytotoxic ‘cocktail’ presented by Cooper, containing cyclophosphamide, methotrexate, 5 fluorouracil, vincristine and prednisone (CMFVP), produced a dramatic response rate of >80% in patients with advanced breast cancer. In the 1960s, there was every reason to believe that cancer would be curable if (1) the right drug combination could be found; (2) the patient could be kept alive through the aggressive high dose regimens; and (3) patients could be treated with a low tumour burden. Cytotoxic chemotherapy became king and a new dynasty was established with the initiation of a lexicon of drug combinations and schedules and ultimately, bone marrow transplantation. The introduction of adjuvant therapy, as it turned out, would be essential for the successes we see today when the move occurred from cytotoxic chemotherapy to tamoxifen treatment. The initial hypothesis for the use of cytotoxic chemotherapy was reasonable and logical; adjuvant chemotherapy would destroy undetected micrometastases harboured around the patient’s body after surgical removal of the primary tumour. The perfect result would be enhanced cures for women with breast cancer but the biology of breast cancer conspired to defeat the best attempts of oncologists to deploy non-specific cytotoxic chemotherapy effectively. The hypothesis was flawed.
It is the responsibility of each new generation to challenge the fashions in medicine created by the ruling dynasty. Progress by defying the dynasty can be profound and today we witness the results of an unlikely revolution in thinking that had its roots in the 1970s. Around the world, death rates from breast cancer are declining and patients are living longer, recurrence-free lives with less morbidity. Tamoxifen is an integral reason for current progress, but this was unanticipated in the 1970s. Thirty-five years ago it would have been unthinkable to suggest that ‘hormone therapy’ would enhance survivorship and that breast cancer risk reduction would now be a clinical reality.
Our knowledge of human oncogenes, an unknown idea in 1972 (C-src the first oncogene was described in 1976) now provides invaluable clues to exploit, selectively, the metabolic vulnerabilities in cancer. This knowledge is creating justifiable optimism by targeting the disease specifically with new agents. The current generation has witnessed the clinical (and economic!) success of agents like trastuzumab that targets gene amplified HER2-neu5 in select breast cancers to produce disease control6, 7, 8 not previously thought possible. However, the new era of individualised targeted medicines that promises ‘to kill or prevent the cancer but not harm the patient’ did not start with biotechnology.
The origins of targeted therapy started in the 1970s by challenging cytotoxic chemotherapy with an alternative approach to treatment which was achieved by adapting the pharmacological principles of drug receptor theory to cancer care. At that time, cancer research was considered to be a hopeless career choice, but a series of events put the right people in the right place at the right time to recognise a unique opportunity to advance cancer therapeutics. No advances occur in isolation; they build on the work of previous generations and in this case, by collegial interaction.
Section snippets
Tamoxifen (ICI 46,474) before targeting
ICI 46,474, the antioestrogenic trans isomer of a substituted triphenylethylene, was discovered in the laboratories of Imperial Chemical Industries (ICI) Ltd. Pharmaceuticals Division (now AstraZeneca). The team, Dora Richardson (Chemist), Michael J.K. Harper (Reproductive Endocrinologist) and Arthur L. Walpole (Head of Reproduction Research) was tasked with developing a post-coital contraceptive during the early 1960s based on the structural clues already published by other pharmaceutical
Foundations
In 1969, I was seduced by the idea of crystallising the oestrogen receptor (OER) with an oestrogen and a non-steroidal antioestrogen. My supervisor thought it would be a little uninteresting, but at least the project would be straightforward as Leeds had a premier X-ray crystallography department called the Astbury Department of Biophysics. The OER protein could be easily extracted from uteri,19, 20 but I quickly found that purification was not a simple task. I switched my PhD topic to study
Transition to targeting Tamoxifen (Jordan VC, Koerner S. Tamoxifen (ICI 46,474) and the human carcinoma 8S oestrogen receptor. Eur J Cancer 1975;11:205–6)
Lars Terenius published two important papers in the European Journal of Cancer that described the action of nafoxidine for the treatment of DMBA-induced rat mammary tumours21 and the ability of the first non-steroidal antioestrogen MER 2522 to prevent rat mammary carcinogenesis.23 These studies demonstrated ‘proof of principle’ for the application of antioestrogens to treat breast cancer, but neither compound showed any promise in the clinic because of serious toxic side-effects.24, 25 In fact,
Tamoxifen for prevention? (Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinoma. Eur J Cancer 1976;12:419–24)
In 1936, Profession Antoine Lacassagne suggested, based on his animal studies, that ‘a therapeutic antagonist should be found to prevent the congestion of oestrone in the breast’ so that breast cancer could be prevented.38 Forty years later, the first experiment I was to complete with tamoxifen showed that just two injections of the ‘antioestrogen’ would almost completely prevent carcinogenesis in the rat mammary gland.2, 39 I concluded that the mechanism was most likely blocking oestrogen
Long-term adjuvant tamoxifen therapy (Jordan VC, Allen KE. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer 1980;16:239–51)
In the 1970s, 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, 48 The translation of the early laboratory findings with tamoxifen1, 2 to the treatment of advanced breast cancer showed an association between the efficacy of tamoxifen as an
Conclusion
What were the consequences of reinventing a failed contraceptive ICI46,47416 to become tamoxifen, the first targeted agent for the treatment of breast cancer9? The laboratory strategy of targeting OER positive tumours1 with long-term adjuvant therapy3, 64 ultimately resulted in the improved survivorship of hundreds of thousands of women 67, 68 around the world. Indeed, the fact that tamoxifen is cheap and accessible to under-funded healthcare systems worldwide means that this form of targeted
Conflict of interest statement
None declared.
Acknowledgements
Dr. Jordan is supported by the Department of Defense Breast Program under Award Number BC050277 Center of Excellence (Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense), FCCC Core Grant NIH P30 CA006927, R01-1620905, The Alfred G. Knudson Endowed Chair in Cancer Research and the Weg Fund of Fox Chase Cancer Center.
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