A Brief History of Breast Cancer: Discovery of Tamoxifen, the First Targeted Drug

The female breast has always symbolized beauty, fertility and femininity. As a disease, breast cancer has attracted and challenged physicians since antiquity. Surgery, the foundation of treatment, inevitably left an unpleasant appearance, particularly in ancient times. Stories of treating breast cancer resemble a complex labyrinth, because this now largely treatable disease has many types, understood only through great effort.

Discovering that some breast cancers are sensitive to estrogen, known as a female hormone, is a good example of efforts to understand breast cancer. Estrogen, a major hormone secreted by the ovaries, is important for maintaining and growing normal breast tissue.

In the 1920s, breast cancer regression was observed in some women whose ovaries were removed for various reasons. This prompted the question, “Does breast cancer obtain its fuel from ovarian estrogen?”

In the mid-1960s, young chemist Elwood Jensen was among those approaching the answer. Hormones function by binding to a receptor in the target cell, as Jensen knew, but the estrogen-binding receptor had not yet been identified. In 1968, Jensen radioactively labeled estrogen and thereby found this receptor—the molecule binding estrogen and transmitting its message to the cell.

Jensen was even more surprised when he investigated whether breast cancer cells carried this receptor: some did and others did not. Breast cancer cells could thus be divided into two types: those with many receptors (hormone-positive or ER-positive) and those with few (hormone-negative or ER-negative).

This discovery initiated a search for an antiestrogen drug to suppress estrogen function. No such drug was then known. Drug companies focusing on menopause treatments and new contraceptives (using synthetic estrogens) had long abandoned antiestrogen development. Cell-killing cytotoxic chemotherapy drugs, now called conventional chemotherapy, were just being developed then and were the darling of cancer treatment. Developing hormone-based cancer treatments therefore attracted little interest.

Consequently, Imperial Chemical Industries’ tamoxifen chemical patent application in 1962 attracted no attention. Initially conceived as a contraceptive pill, tamoxifen had been developed by a team led by hormone biologist Arthur Walpole and synthetic chemistry expert Dora Richardson. However, instead of switching estrogen signaling on as required for contraception, it unexpectedly switched signaling off in many tissues. It was therefore an estrogen opponent, an “antagonist.” Perhaps ineffective for contraception, could it be different in estrogen-sensitive breast cancer?

To test this idea, Walpole and Richardson found a collaborating clinician: Mary Cole, an oncologist and radiotherapist with a particular interest in breast cancer at Manchester’s Christie Hospital. Known as devoted, proactive, courageous and meticulous, she cared for patients with advanced, spread breast cancer. She was willing to do and try anything to save these women’s lives—even a contraceptive discarded as useless.

Cole’s experiment began in 1969, treating 46 women with breast cancer using tamoxifen pills. Expecting little beyond partial improvement, she was surprised when ten patients responded quickly and clearly. Breast tumors shrank, lung metastases regressed, bone pain disappeared and lymph nodes softened.

Cancer reappeared after a time in a substantial proportion of responders, but the experiment was clearly successful and the principle it proved historic. This new hormone drug, successfully shrinking even spread tumors, had become a drug designed to target a particular process in the cancer cell, a cellular poison discovered through trial and error (like cytotoxic chemotherapy drugs).

Later, in 1973, biochemist V. Craig Jordan used a molecular staining technique to identify which breast cancer cells carried estrogen receptors. Receptor-bearing cells could bind tamoxifen; this antiestrogen drug prevented estrogen from functioning in the cell, stopping growth and proliferation. ER-negative cells lacking drug-sensitive receptors were unresponsive. For the first time in cancer history, a drug, its target and the cancer cell came together through a fundamental molecular rationale. In other words, tamoxifen is the first targeted drugdeveloped for cancer treatment.