It all started in Cheshire, England, in 1962. A company called Imperial Chemical Industries (ICI) was testing a compound that promised to become a birth control pill.
And the promise seemed firm.
The agent known as ICI46474, which had been synthesized unusually for the time by a woman, chemist Dora Richardson, did indeed have contraceptive effects in rats.
Potentially, it could become a morning-after pill, such as some women take in the hours after intercourse to prevent pregnancy.
But almost a decade later it was discovered that in humans it had the opposite effect: far from inhibiting fertility, it increased it by stimulating ovulation.
The research with ICI46474 would have been completely abandoned, had it not been for the intervention of the leader of the team of scientists, Arthur Walpole, who threatened to resign if another project was not pursued.
Parallel to the study of the compound as a contraceptive, it had been tested as a treatment for breast cancer.
In 1971 the first clinical trial of ICI46474 had been conducted at the Christie Hospital in Manchester, and had yielded positive results, with “the particular advantage of the low incidence of troublesome side effects.”
However, even that did not excite ICI.
As Dora Richardson recounted in her history of the drug, what Walpole and his colleagues were told was that they were supposed to be looking for a contraceptive pill, not an anticancer agent.
Despite growing clinical evidence of the compound’s usefulness in that field, the market for an anticancer drug was considered small, in part because of the poor prognosis associated with the disease.
Sales estimates produced by ICI’s marketing department indicated that it would never cover research and development costs, and would not generate an adequate return for the company.
“It’s all about money in the pharmaceutical story,” Professor V. Craig Jordan, who would help push the drug further down the line, told BBC Witness.
However, by the time the company made the decision to shut down the program, the breast cancer trials had already resulted in a number of publications, sparking worldwide interest in the compound.
Under such pressure, ICI reversed its decision, Walpole stayed on, and the project was saved.
In February 1973, ICI applied for a product license, and that year Nolvadex was launched in the UK for anovulatory infertility and for the palliative treatment of breast cancer.
But the drug sat on ICI’s shelves, ready for further research, but without sufficient funds or will to do so and offer it to women… at least for the time being.
From ashes to success
ICI46474 had been designed to act as an anti-estrogen.
In 1896 George Beatson, a pioneering cancer surgeon, had discovered that he could extend the lives of women with breast cancer by surgically removing their ovaries, a major source of estrogen.
That gave researchers the first clue that these female hormones were involved in the growth and development of breast cancer.
Over the next five decades, doctors experimented with a variety of artificial estrogen-like chemicals to treat breast cancer.
Although their efforts were sometimes successful, the side effects were too severe for widespread use.
By the mid-1960s, when ICI46474 was being experimented with, despite a growing awareness of breast cancer, research seemed to have reached a dead end.
Mastectomy, in which the cancerous area of a woman’s breast is removed, along with chemotherapy or radiation therapy, was thought to be the only way forward.
That would soon change.
Thanks to a combination of luck, good judgment and the declaration of a “war on cancer” by U.S. President Richard Nixon in 1971, there was renewed interest in developing an estrogen blocker to treat breast cancer.
But in the U.S., the market most coveted by pharmaceuticals, ICI46474, which came to be called tamoxifen, was slow to be approved.
Dr. Walpole died in 1977, without seeing his drug become a worldwide success.
That same year “there was a breakthrough when Dora Richardson gave me the metabolites of tamoxifen,” Jordan said.
A metabolite is a byproduct of what happens when the body breaks down the drug into a different substance.
“The team in my lab showed that a metabolite of tamoxifen was 100 times more potent than tamoxifen as an anti-estrogen.
“It was a drug like none ever seen, because of how strong it was.
“When I reported it to ICI, the shocked silence in the room was simply astounding. I was asked to respect a gentleman’s agreement not to say anything about what I had discovered. I agreed because I wanted tamoxifen to succeed in the United States.
“My lips were sealed while ICI received the metabolite package. Then I was able to publish a paper announcing the discovery of the world’s most potent antiestrogen, which became the basis for all subsequent antiestrogens.”
Tamoxifen was approved for use in the U.S. in late 1977, an important milestone on the drug’s route to worldwide success.
Thus, that chemical compound that failed to deliver as promised, became a miracle compound that was included in the World Health Organization’s (WHO) list of essential medicines.
But what does it do?
The key to its success
Breast cancers that have estrogen receptors are called estrogen receptor positive (or ER+) cancers.
This means that the tumors feed on the female hormones circulating in the woman’s blood.
Being estrogen-dependent is the Achilles heel of ER+ cancers: it makes them sensitive to drugs like tamoxifen, which prevent estrogen from affecting cancer cells.
It works like blocking a door: it attaches to the estrogen receptor, and prevents the hormone from being able to enter, thus stopping the tumor in its tracks.
That’s why it is said to be one of the biggest breakthroughs in cancer treatment.
It’s a very grandiose-sounding claim, until you take into account that, according to the WHO….
- breast cancer is the most commonly diagnosed cancer, accounting for 1 in 8 cancer diagnoses worldwide….
- in 2020 alone, there were about 2.3 million new cases of breast cancer worldwide and about 685 000 deaths from this disease…
- and about 70% of breast cancers are ER+.
Its impact on extending and saving the lives of women (and men) with breast cancer explains why so many oncologists hold it in such high regard.