Bringing a new drug to patients is a long and winding road. But the journey doesn’t stop once a drug is approved for use – researchers continue to study and refine how best to give it to patients.
Around 8 in every 10 breast cancers diagnosed in the UK are classified as ‘oestrogen receptor-positive’ (or ER positive for short). The cancer cells in ER-positive tumours contain large quantities of a protein called the oestrogen receptor. This means the tumours grow in response to the female hormone, oestrogen, which circulates in a woman’s bloodstream.
Being dependent on oestrogen gives ER-positive cancers an Achilles heel: it makes them sensitive to drugs like tamoxifen, which block oestrogen from affecting cancer cells.
Tamoxifen works like a broken key in a lock – it sticks to the oestrogen receptor, preventing the normal ‘key’ (oestrogen) from fitting anymore, thereby stopping the tumour in its tracks. Its precision targeting of ER-positive breast cancer cells in this way mean it is, in effect, a ‘targeted treatment’.
Since its approval in the UK in 1972, tamoxifen’s effectiveness and affordability have earned it a place on a global stage – it appears on the World Health Organisation’s list of essential drugs for the treatment of breast cancer in both developing and developed countries. So, how was this widely used, remarkable drug discovered?
A phoenix from the pharmaceutical ashes
Tamoxifen was, in fact, a rather accidental discovery. ICI46,474 – as tamoxifen was known back then – was first made in 1966 by scientists working for Imperial Chemical Industries Pharmaceuticals (ICI, now AstraZeneca), who had been tasked with finding a new emergency contraceptive.
But despite showing promise in the laboratory, early versions of tamoxifen had no contraceptive effect in humans at all, so ICI Pharmaceuticals lost interest, and the drug nearly ended up in the bin.
As luck would have it though, a member of the team saw the potential of tamoxifen to treat breast cancer. The determination of a few key scientists kept tamoxifen alive, and in 1970 the world’s first clinical trial testing it as a breast cancer treatment was carried out at the Christie Hospital in Manchester.
Tamoxifen had been resurrected from the ashes and was on its way to global success; if you’re interested you can find a fuller account of tamoxifen’s discovery here.
What role did Cancer Research UK play?
Bringing a new drug to market is a long, expensive and complicated process. But after a drug is granted a license, so-called ‘phase IV’ clinical trials, also known as post-marketing studies, collect valuable further information about a drug’s risks, contraindications, benefits, and optimal usage. And so it was with tamoxifen; it had been licensed but doctors were uncertain of exactly how the drug should best be used, and which women would benefit the most.
This is where Cancer Research UK stepped in. In a nutshell, we helped fund the essential piece of work that put together all the individual clinical trials of tamoxifen, pinpointing its overall benefits for different age groups of women, and the best dosing schedules to give them.
The key players in this were a group of Cancer Research UK-funded scientists and clinicians called the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Set up in 1983 and based in Oxford, the group regularly reviews the results from clinical trials involving women who have breast cancer, and publishes consensus opinions on new treatments for the disease, forming the big picture out of all the pieces of a jigsaw puzzle.
Their opinions are held in high esteem by medical professionals, scientists and policy makers alike, and help to support the decisions made for treating breast cancer within the NHS. We’re still funding them to do this work today.
In 1983, following the publication of a large, successful trial of tamoxifen, the EBCTCG decided to begin to gather together all the available information, to paint a clearer picture of how the drug should be used.
By 1988 the group had collated the results of 28 tamoxifen trials of from across the world, involving more than 16,000 participants, and carried out what’s known as a ‘meta-analysis’ – an overall analysis of all the data from all the trials. They published their landmark findings in The New England Journal of Medicine.
What did they show?
Using some clever statistics, the group showed that women over the age of 50 treated with tamoxifen had much better outcomes than those given chemotherapy. According to their calculations, doctors had saved or prolonged the lives of at least 300 of the 16,000 women enrolled in the trials by giving them tamoxifen instead of (or as well as) chemotherapy.
Their number crunching also showed that tamoxifen was just as potent alone as it was in combination with chemotherapy – a finding which would save women months of unnecessary side effects. They also suggested that a longer course of treatment (2 years compared to 1 year) could be more beneficial. Which we now know to be true – our current research clearly shows that women boost their chances of surviving breast cancer by completing a full five-year course of tamoxifen instead of just two years. Lastly, they also proved that a lower dose regime was just as good as giving tamoxifen at higher doses.
This was concrete proof that tamoxifen was an effective treatment for women with breast cancer, and it also gave a better idea of who should be given it, at what dose and for how long. All this information helped doctors make the best decisions when prescribing tamoxifen back in the days when it was a new treatment.
What impact did this research have?
The number of women (and, although a rare occurrence, men) diagnosed with breast cancer has been climbing steadily over the years. Since 1997 breast cancer has become the most common form of cancer in the UK. Eight in every ten of the 48,000 women diagnosed with breast cancer every year in the UK will have ER positive breast cancer – that’s roughly the same number of women it would take to fill 500 double-decker buses.
Our research defining the potency of tamoxifen helped ensure it became a mainstay treatment for women with this type of breast cancer. Today, partly as a result of this, almost two thirds of women diagnosed with breast cancer this decade are predicted to survive their disease for 20 years or more.
The future for hormone therapies
Doctors and scientists are still carrying out research and clinical trials shaping the most effective ways to use tamoxifen and newer oestrogen-blocking therapies like anastrozole and exemestane. They are looking for ways to reduce the side effects, refine the timings and duration of treatment.
Other researchers – including our own – are also running large clinical trials studying the potential benefits of giving women at high risk from breast cancer hormone therapies as a preventative measure (chemprevention). Results from these trials are already very promising, suggesting that in future we might be able to stop some women ever developing breast cancer simply by prescribing tamoxifen or related drugs.
The concept of turning off hormones to treat cancer was a true innovation of its day, and using tamoxifen to treat breast cancer pioneered new treatments for other hormone driven cancers (like ovarian and endometrial cancers) and even diseases other than cancer (such as osteoporosis).
And the same thought process has successfully been applied to prostate cancer, which is driven by the male hormone testosterone. This led to the development, by Cancer Research UK-funded scientists at the Institute of Cancer Research, of abiraterone, a drug which switches off testosterone production, and which can substantially prolong the life of men with advanced prostate cancer.
We hope that in the coming years many more drugs that are built out of our basic knowledge of how cancers work come to the fore. And, as these drugs reach the clinic, we’ll be there to fund yet more research, to help show the world how best to use them, and save even more lives.
Effects of Adjuvant Tamoxifen and of Cytotoxic Therapy on Mortality in Early Breast Cancer (1988). New England Journal of Medicine, 319 (26) 1692. DOI: 10.1056/NEJM198812293192601