Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer

Abstract

Tamoxifen is an unlikely pioneering medicine in medical oncology. Nevertheless, the medicine has continued to surprise us, perform, and save lives for the past 40 years. Unlike any other medicine in oncology, it is used to treat all stages of breast cancer, ductal carcinoma in situ, and male breast cancer and pioneered the use of chemoprevention by reducing the incidence of breast cancer in women at high risk and induces ovulation in subfertile women! The impact of tamoxifen is ubiquitous. However, the power to save lives from this unlikely success story came from the first laboratory studies which defined that 'longer was going to be better' when tamoxifen was being considered as an adjuvant therapy. This is that success story, with a focus on the interdependent components of: excellence in drug discovery, investment in self-selecting young investigators, a conversation with Nature, a conversation between the laboratory and the clinic, and the creation of the Oxford Overview Analysis. Each of these factors was essential to propel the progress of tamoxifen to evolve as an essential part of the fabric of society.

Keywords: breast; endocrine therapy.

Figure 1

The use of the dimethyl benzanthracene (DMBA)-induced rat mammary carcinoma model to demonstrate that longer or continuous therapy with daily tamoxifen (50μg subcutaneous injection) was superior at preventing the appearance of mammary tumors when compared to short therapy of 30 days. Fifty day old female Sprague Dawley rats were each given 20mg DMBA by gavage in 2 mls peanut oil. In nontreated control groups of 20 animals, all rats had multiple palpable tumors by 150 days. The model design for therapy groups first administered the DMBA at 50 days of age but the 30 day or continuous treatment was delayed for 30 days to permit mammary carcinogenesis of initiation and promotion to occur. The goal was to establish whether a short 30 day course of tamoxifen (estimated to be equivalent to 1 year of adjuvant tamoxifen in patients) could destroy the deranged microscopic cancer cells in the mammary glands or whether continuous therapy was required for complete tumor control and suppression. Continuous therapy is necessary. The strategy was to use tamoxifen only in the patients with ER positive tumors (Jordan and Koerner 1975) and use continuous therapy. This new strategy was first reported at the King College Cambridge, ICI Pharmaceuticals Division, Medical Symposium September 1977.

Figure 2

The participants at the King College, Cambridge ICI Pharmaceuticals Division Medical Symposium September 1977. The author (top) presented the new strategy, Professor Michael Baum (right) was the session chair and leader of the proposed NATO trial that was planned to advance the current 1 year adjuvant tamoxifen trials to a 2 year treatment period. Helen Stewart (left), was in the audience and had plans to compare placebo and tamoxifen at first recurrence with 5 years of immediate adjuvant tamoxifen in the Scottish trial. Both trials (NATO and the Scottish trial) were to demonstrate, for the first true, survival advantages for adjuvant tamoxifen used for longer than 1 year.

Figure 3

The principal players in the discovery of ICI 46,474 at ICI Pharmaceuticals Division, Cheshire, UK in the 1960’s that eventually evolved into tamoxifen a decade later. Arthur Walpole (Walop) (left) was the head of the Fertility Control Program tasked with the mission to discover safer compounds to “regulate the sexual cycle”. Dora Richardson (center), the team organic chemist who synthesized all of the isomers of the triphenylethylene derivatives that would be tested as antifertility agents in rats by Mike Harper, the team reproductive endocrinologist. Arthur Walpole would be the author’s PhD examiner, scientific supporter and administrative link to ICI until his untimely death on July 2^nd 1977. Dora Richardson would provide the metabolites of tamoxifen to the author to be tested as anticancer agents and Mike Harper would offer the author a two year BTA (Been to America) at the Worcester Foundation, MA. Each individual was generous with important opportunities, investment and support for a young investigator starting their adventure to investigate “failed morning after pills” as future important therapeutic agents in women’s health.