When was tamoxifen created

However, he had examined my Curricum Vitae and there were no publications at all! It was the summer of Each paper should be linked to other related studies to create a theme for a topic. Most importantly, I had learned an important lesson; I set about correcting this deficit. As a result, I built a bibliography of my 2 years during my BTA with a number of refereed papers: prostaglandins and tamoxifen. I have never stopped writing papers ever since.

His advice to me made this honour possible. I was supported by my Department Chairman Professor Michael Barrett and most importantly Dr Arthur Walpole to create a translation research path for tamoxifen. Their investment in my laboratory and development of my research ideas would put the pieces in place for future clinical development and all my new career opportunities. I had two unanswered questions that I chose to address at Leeds. What is the pharmacology of the identified metabolites of tamoxifen in animals and humans Fromson et al.

Perhaps there was species-specific metabolism to oestrogens? Marc would dissect the mechanism of action of tamoxifen in breast cancer. Could I demonstrate the cure of an animal tumour model with tamoxifen?

At the University of Leeds, I built my first tamoxifen team to address the answers to my questions supported by unrestricted funds i. The members of my team were the final year pharmacology degree students who would conduct a one-term final year research project but then they would either become a PhD student sponsored by an ICI Pharmaceutical Division scholarship or would be employed as a technician in my laboratory. Most importantly, the clinical monitor for tamoxifen, Dr Roy Cotton, was essential for success.

He played a critical role in our productivity at University of Leeds. I was asked what would be the most important factor for the success of my tamoxifen team. My reply was the game changer.

I asked for unlimited Alderley Park rats to be sent weekly to the medical school at the University of Leeds. This Roy Cotton did, with rats for both DMBA-induced rat mammary carcinoma studies and immature rats to study the pharmacology and mechanisms of action of tamoxifen metabolites. These rats were chauffeured weekly to Leeds, for 5 years. He became the Chief Scientist at Alderley Park.

Dr Sandy Todd has the distinction of being the genetic result of two Nobel laureates: his father Lord Todd affectionately known as Lord Todd Almighty and his grandfather on his mother side was Sir Henry Dale. Dr Todd focused on the international business plan for tamoxifen.

The answers to my questions developed quickly as we had an excellent evaluation system. Every 6 months my Leeds tamoxifen team would travel to Alderley Edge near Alderley Park and we would spend a couple of days on each visit.

We wrote a report and made presentations as a cohesive group. So, what was achieved? Question 1: Can the pharmacology of tamoxifen metabolites explain the unusual species-specific actions of tamoxifen in mice and rats? Dora Richardson provided two hydroxylated metabolite of tamoxifen: 4-hydroxytamoxifen and 3,4-dihydroxytamoxifen.

In the ligand-binding assay of rats, mouse or breast tumour cytosols a homogenized protein extract of tissue spun down in a centrifuge to create a protein solution we discovered Clive Dix and Graham Prestwich actually that the hydroxylated metabolites bound to the ER as tightly as oestradiol.

This was unheard of in the scientific literature at the time Korenman , Skidmore et al. It was a discovery! When tested in immature female rats, the metabolites were both anti-oestrogens but more potent than tamoxifen. Never before had high-affinity anti-oestrogens been found. The idea that non-steroidal anti-oestrogens fell off the ER because of low affinity was no longer plausible.

To a pharmacologist, it was the structure of the anti-oestrogen and the position of the anti-oestrogen side chain that determined anti-oestrogen action at the ER. My plan was to use structure—function relationships to prove that tamoxifen was being metabolically activated to a metabolite that bound to the ER and the metabolite was really the active agent.

Lois Trench and I had maintained communications during the time she was battling successfully to get FDA approval for tamoxifen in America. She was also the Godmother to my daughter Alexandra. Lois requested I present the basic science tamoxifen talk at the symposium she had organized in Key Biscayne in Florida in During the telephone call to Alderley Park from Leeds, I agreed to say nothing about my work on the metabolites as the legal people were still trying, unsuccessfully as it turned out, to get the patent for tamoxifen in the USA before FDA approval.

The disclosure that tamoxifen was metabolized to a super-anti-oestrogen would complicate progress with tamoxifen and commercialization.

I had already written up our work for publication at Leeds in and was ready to submit, but I now agreed to give Dr Sandy Todd Fig. A year later, I was informed I could submit my work for publication, and it became my most cited article in laboratory research. We subsequently proved that tamoxifen was metabolically activated to 4-hydroxytamoxifen Allen et al. A similar study of structure function relationships in vitro Lieberman et al. This was important, as there were several competing theories of anti-estrogen action at the time in the early s.

What I was to discover later, was that it was the policy at ICI Pharmaceutical Division, that all compounds entering clinical trial testing, would also have all known metabolites patented just in case it was discovered that the potential medicine was a pro-drug.

It seems that there had been a previous case that a medicine had been patented and used successfully, but a competitor patented and marketed the active metabolite. That was never to happen again. If tamoxifen was unsuccessful and was abandoned, why waste time and money patenting metabolites. Few were believers! Though this did not come to pass, the idea was pursued successfully by Drs Jean Bowler Fig. An early candidate ICI , was first tested in transplantable tamoxifen-resistant breast cancer cells in vivo in immune-deficient mice Gottardis et al.

This success in a relevant animal model of acquired resistance to tamoxifen was followed by fulvestrant. This publication Gottardis et al. And so it was in clinical trials a decade later. Aromatase inhibitors now took the lead with three companies competing for market share with exemestane, letrozole and anastrozole and prices many times higher than tamoxifen.

Question 2: Can adjuvant tamoxifen treatment cure some rats with mammary cancer? To answer the question my experimental plan was to induce mammary tumours in to year-old female rats with 20mg of DMBA dissolved in 2 mL peanut oil and then 4 days later, start to treat animals for either a month with tamoxifen equivalent to a year in a patient, the then-current duration for adjuvant clinical trials of tamoxifen in women or continuous tamoxifen treatment for 5 months i.

Tumours appeared when tamoxifen was cleared from the body. The solution was to keep giving tamoxifen as an adjuvant therapy. However, first I presented my new strategy of long term adjuvant tamoxifen was superior to short term adjuvant tamoxifen at a symposium at King College, Cambridge 28—29 September Figs 6 and 7 Jordan Unlike my positive experiences with the now, ICI America with Clinical Cooperative Groups in America between and , there was less acceptance of the contribution of translational research within clinical community in the UK in the s.

Part of this stemmed from the real concern that tamoxifen, unlike combination cytotoxic chemotherapy, did not kill cancer cells. The view was this palliative therapy should be reserved for the end of life. Nevertheless, the data for the translational research was published Jordan et al. These important contributions Nolvadex Adjuvant Trial Organisation , Scottish Cancer Trials Office both demonstrated survival advantages for patients treated for longer than 1 year of adjuvant tamoxifen.

However, my DMBA tumour studies would, within a few months of the Cambridge meeting, change the course of my career. The first report of the effectiveness of continuous long-term tamoxifen treatment to prevent the development of rat mammary carcinoma versus no treatment. This was published following the Kings College meeting September The trial had not opened. Dr Helen Stewart was a participant and there was a plan to initiate recruitment of patients to examine toxicity issues with 5 years of treatment.

In reality, it was to establish whether there was sufficient evidence to offer me a job. In , Dr Jordan organized a 3-day symposium to review and publish all that was known about non-steroidal anti-oestrogen Jordan Armed with my latest data shown at the King College meeting in September, Graham and I met in Madison after I had spent weeks telling him how wonderful the campus was and how much fun we would have.

It was October and the worst winter in living memory with snow falling every day. We had no car so just staying alive at the bus stop before the bus came was a challenge.

Be that as it may, the opportunities were there for the taking. Dr Harold Rusch Fig. What I did not know was that Dr Rusch had recently lost his daughter to breast cancer and he had regrets that he had focused his career on identifying the causes of cancer and not enough time on innovative treatments.

I gave my talk of my vision to target breast cancer through the tumour ER, treat breast cancer with surgery and then use long term adjuvant tamoxifen therapy based on my DMBA model-no publications yet and raised the possibility of preventing breast cancer again based on my DMBA publication Jordan b. Afterwards, I discovered that this strategy was just what the new Cancer Center needed.

The University of Wisconsin Comprehensive Cancer Center would have a translational research plan to implement. But first, it was back to the Department of Pharmacology at the University of Leeds. Dr Arthur Walpole had died suddenly on July 2, He never knew of the enormous success of the medicine that he had fought so hard to create. He brought me into the loose team of committed individuals who wanted to make ICI 46, into a medicine to treat breast cancer.

Overall, this focused translational research programme built on the clinical database for the treatment of Stage IV breast cancer and Walpole fought, successfully, to keep the momentum going despite all expectations of non-profitability. However, the impossible happened — again! Sales of tamoxifen worldwide were increasing, and all manufacturing of the tablets occurred at an ICI plant outside Macclesfied. The orphan medicine tamoxifen was starting to become a blockbuster.

Only two hundred and thirty handpicked employees, who had been directly involved to accomplish this milestone in drug discovery and development, were invited. I discovered that I was the only nonmember of ICI staff invited to attend. My invitation was in recognition of my translational research work that provided the future road map for drug development. Dr Roy Cotton, the successful initial clinical drug monitor for tamoxifen who also shipped my rats to Leeds , and I dined at the same table Fig.

Barry Furr Fig. The celebration is only for those considered to have been instrumental in making the award a reality, that is, tamoxifen. A carefully selected group of employees were present and Dr Jordan was the only one invited from outside of the company.

A better photograph of Dr Todd is in Fig. Total 25 publications. I quality controlled all their ER laboratories and established lifelong friendships. I was her thesis supervisor in the Department of Human Oncology. The path to progress was daunting but within 3 years we had a vibrant laboratory with about 18 tamoxifen team members in all consisting of PhD students, post-doctoral fellows, technicians, and student helpers in the laboratory. The story of the Wisconsin tamoxifen team and their accomplishments have recently been told in detail Jordan and will not be retold in detail here.

The members of the Wisconsin tamoxifen team in the latter half of the s are shown in Fig. Members of the Wisconsin tamoxifen team approx.

The clinical plan was long-term adjuvant tamoxifen treatment and chemoprevention. Unfortunately, little was known of the pharmacology and toxicology of tamoxifen. He also served as the Vincent T. Your gift makes a difference in the lives of cancer patients by supporting innovative patient care, research, education and prevention programs.

My Chart. Donate Today. For Physicians. Cancer Moonshots. Previous Article. Next Article. Related Posts. Send us your stories. Email your stories, comments and suggestions to promise mdanderson. Jones, J. Landquist, B. Langley, W. Waring, and of the Biochemistry Group: W. It was hoped that, with such increased resources, ICI could improve upon both clomiphene and a new Upjohn product with similar activity, U 11,, by finding alternatives with less estrogenic and pituitary-inhibitory activity relative to their anti-fertility activity.

For, by then, clinical studies of ICI 33, had produced disappointing results: not only did it have unpleasant and worrying side effects nausea, drowsiness, a fall in thyroid function measured by thyroidal I uptake, and a rise in serum cholesterol 14 , but the inhibition of ovulation could not be achieved without suppressing menstruation, which made it undesirable as an oral contraceptive in women Among the newly synthesized triphenylethylenes, Harper drew up a short list for further study, primarily as potential anti-fertility agents.

These included the dimethylamino ethoxy compound ICI 46, later known as tamoxifen, brand name Nolvadex. It had been synthesized in by Richardson, and Harper selected it for additional tests and for preliminary toxicity studies. At the same time, the company lodged patent applications to protect ICI 46, and related compounds from competitors As well as providing basic data on these compounds, Patent GB covered a number of potential therapeutic uses, including cancer.

It read:. The alkene derivatives of the invention are useful for the modification of the endocrine status in man and animals and they may be useful for the control of hormone-dependent tumors or for the management of the sexual cycle and aberrations thereof.

They will also have useful hypocholesteraemic activity Although marred by a number of dead ends, which were partly due to ICI's strategy of closely following their competitor's activities and using their compounds as leads in the search for new, patentable products, the early phase of the Oral Contraception programme shaped tamoxifen and determined its future in many ways. The compounds developed within this programme were designed to act as contraceptive pills, yet from the beginning their usefulness in breast cancer was explored in close parallel.

This dual objective was pursued as a result of Walpole's own research interests, and thanks to the fruitful collaborations he established both with endocrinologists and with clinicians working in cancer. The feedback loops between bench and bedside which this relationship created, and which led to a series of twists and turns that would become the hallmark of the tamoxifen story, meant that the compounds functioned both as research tools to study hormone function and metabolism in the laboratory, and as experimental treatments in the clinic.

Importantly, the dual objective of developing a contraceptive pill whilst assessing the usefulness of compounds in breast cancer even if as we have seen this was also a means of testing drugs before administering them to healthy women , also meant a constant preoccupation with side effects, and the low toxicity of tamoxifen relative to its potency would turn out to be one of its crucial advantages over its competitors.

A triphenylethylene derivative, with groups and side chains to enhance its anti-estrogenic and pituitary-inhibitory effect and prolong its duration of action, without interfering with its anti-fertility activity, ICI 46, had been demonstrated as the most potent and least toxic of all the compounds tested by June But what exactly was it?

In the process of gathering data for patent applications, scaling up production and preparing a submission to the newly formed Committee on Safety of Medicines CSD , uncertainty arose as to the precise structure of the compound. Using an NMR spectrometer recently acquired by the company, in G. Bedford, a spectroscopist who had joined ICI's Pharmaceutical Division in , showed that many of the active compounds synthesized so far were a mixture of isomers.

However, it was unclear in which isomer the anti-estrogenic activity resided did it reside in the cis , or the trans isomer? The isomers were separated by fractional crystallization by Richardson. This represented quite a feat at the time 19 , and revealed ICI 46, to be more active as an anti-implantation agent than its cis isomer ICI 47,, which was more estrogenic Bedford and Richardson, ; Harper and Walpole, In the meantime, Merrell had carried out a spectroscopic analysis of their own drug clomiphene, and disagreed with ICI's interpretation of the spectroscopic data, attributing the anti-estrogenic activity to the cis , not the trans isomer.

The controversy led to some confusion among researchers, and eventually the matter was settled by X-ray analysis, which confirmed ICI's findings that the anti-estrogenic activity did indeed reside in ICI 46,, that is to say in the trans isomer of the compound Kilbourn et al. So how did tamoxifen work?

Before making a submission to the CSD, which in the wake of the thalidomide disaster had been set up to review all laboratory data on potential drugs in advance of their introduction into human patients, a basic understanding of their mechanism of action, as well as knowledge about any toxic effects, had to be achieved see Quirke, a.

Therefore, unsurprisingly perhaps since it was intended for use in contraception, the first teratogenic test ever to be performed by ICI was carried out with tamoxifen. Tamoxifen was most effective in preventing implantation in rats when given on day 4 of the pregnancy, and virtually inactive on day 5.

This suggested that it acted by interfering with a crucial event that had already occurred by the 5th day. It was suspected that ICI 46, prevented implantation by interfering with the critical estrogen release on the uterus that occurs between 12 and 20—21 h on the 4th day However, it was unclear whether the estrogen released at this time acted directly on the uterus or whether its action was mediated by vasodilating amines such as histamine.

As there was evidence to support the latter hypothesis, ICI 46, was thought to act either as a direct estrogen antagonist, or by preventing the release of histamine, or as an antagonist of the amine.

To explore this hypothesis, whilst carrying out further toxicity tests, experiments were devised in additional animal species as well as rats, in mice, rabbits, dogs, monkeys, and sheep, for by then the compound was also being considered for use in veterinary medicine Although it was still hoped that ICI While these further studies were being carried out, ICI began planning a trial with Dr.

Klopper at Aberdeen, for the induction of ovulation in amenorrheic women rather than contraception Indeed, by then, clomiphene had been found to stimulate ovulation and prolong luteal function in amenorrheic women, and in was approved for the treatment of infertility in the US Moreover, obtaining approval to evaluate ICI 46, in oral contraception was problematic, not only because it involved long-term administration, but because of persisting fears among British gynecologists that it might lead to fetal malformation.

In their eyes, unlike the conventional pill which contained familiar ingredients such as estrogens and progestins that had traditionally been given to pregnant women without harm to the fetus, evidence of a lack of teratogenic effect in animal experiments with an unknown compound like ICI 46, did not constitute an adequate safeguard. Therefore, they believed that the first women to receive ICI 46, as a contraceptive must be offered an abortion, but under the terms of the Abortion Act this could only be offered to a very limited number of women Two solutions to this conundrum were envisaged: 1 to arrange a consortium of gynecologists to contribute such patients to a central unit in the hope of collecting a reasonable number fairly quickly; 2 to go abroad to a country, such as Hungary, where abortion was accepted as a means of population control.

Meanwhile, therapeutic studies would be conducted to provide the sort of doses to be used in contraceptive trials, and approval to carry these out was obtained from the CSM in These studies included ICI 46, now also referred to by its brand name Nolvadex for the treatment of anovulation or menorrhagia associated with high levels of endogenous estrogen to be carried out at Aberdeen, Manchester and the Women's Hospital in Chelsea , and of breast carcinoma in 30 menopausal and post-menopausal women at the Christie Hospital in Manchester.

The preliminary reports received from Dr. Klopper in Aberdeen and Drs. Murray and Osmond-Clarke in London helped to cast further light on the drug's mechanism of action, showing that that tamoxifen was capable of inducing ovulation at higher dose levels, while at lower doses it tended to have an anti-estrogenic effect As to the Christie breast cancer trial, although two of the women complained about hot flushes which was taken as evidence of its anti-estrogen effect , no toxicity was observed and the drug appeared to be well tolerated, even at the highest dose of 10 mg by mouth.

In her unpublished history of tamoxifen, Dora Richardson wrote of the team's excitement as the first trial results arrived. At a Development meeting on 28th August , sales estimates and quantities of bulk drug were set at 2 kg for initial stocks. However, fortunately, on the basis of the positive clinical results, the CSM granted the company permission to prolong the trials as well as extend them to other centers.

By the end of , 60 patients had been admitted to the Christie breast cancer trial, and of the 40 women who had been on the trial for more than 10 weeks, all had shown measurable and marked tumor regression. Although these results were comparable to those achieved with the established synthetic hormone diethylstilboestrol, the clinicians carrying out the trial, Drs.

Todd and Cole, reported how impressed they were with the absence of toxicity and the low incidence as well as trivial nature of any side-effects Cole et al. In return, the trials provided clinical material for laboratory studies of tamoxifen. By then, the estrogen receptor had been isolated and identified by Gorski Gorski et al. However, in a clinical setting, it was felt that a radio-immunoassay was more specific for measuring blood-estradiol levels in patients given tamoxifen The receptor-protein binding assay was therefore mainly used for experiments in laboratory animals, and showed tamoxifen to be a competitive inhibitor of estradiol binding to the uterine receptor protein in rabbits and in mice.

Receptors sensitive to anti-estrogen were also found in various parts of rats' brains, including the hypothalamus and the pituitary. The results of the receptor-protein binding experiments in both these test systems suggested that, like other anti-estrogens, the action of tamoxifen was due to a high association constant but low effectiveness of the complex it formed with estrogen receptors i.

This was a pharmacological action with which ICI researchers had become familiar in their work on the beta-blockers Quirke, It helped to cast further light on the physiological processes at a molecular level 36 , and made tamoxifen a particularly useful research tool for investigations of hormone-dependent tumors Jordan et al. Rendered confident by the clinical and laboratory studies carried out so far, Walpole's team began planning trials in contraception, and the Nolvadex Development Programme was drawn up This would play an important part in the drug's transformation from quasi-orphan to blockbuster drug Quirke, b.

ICI's first Development Programme had been written up in for the beta-blocker propranolol Inderal It followed a series of quarterly development reports 41 , and coincided with the hitherto separate Research and Development Departments coming together under the responsibility of a single Director, the Technical Director, as well as with the creation of the CSD in It therefore was a response to both internal and external factors and stimuli.

The Nolvadex Development Programme, which came 7 years after the Inderal Development Programme, included 16 rubrics, describing the work done up to June the date of the start of the Programme , making an assessment of the drug's potential market, and plans for future work:. Three important considerations were taken into account when planning future work. First and foremost were tamoxifen's possible clinical uses, based on the results of trials received to date.

These included: treatment of estrogen-dependent mammary carcinoma; induction of ovulation on women suffering from infertility due to failure to ovulate; menstrual disorders associated with abnormal levels of endogenous estrogen; oral contraceptive a for women, b for men; treatment for oligospermia; test for pituitary function; others. Secondly, the drug's position in North America was under question, following Ayerst's rejection of ICI's offer of Nolvadex for the American market, and the FDA's likely negative attitude toward its use in breast cancer.

This attitude may have been due to a report in JAMA which had suggested that there was a link between diethylstilbestrol and a rare form of vaginal cancer, and was promptly followed by an FDA bulletin warning against the use of DES FDA, Despite such competition from rival firms in America and Europe, tamoxifen had two advantages on which its market position would ultimately depend in relation to breast cancer: 1 its unique mode of action in being an estrogen-antagonist without androgenic properties, and since at the time it was the only product of its type its use should be larger; 2 it possessed very low incidence of side-effects compared with other forms of treatment.

They also illustrate the pivotal part played by drug regulation in shaping the research and development activities of pharmaceutical firms.

The trials that followed the CSM's approval for Nolvadex in not only led to an increase in existing expenditure in areas such as biochemistry, but to new expenditure in areas such as formulation shown in bold.

As well as further trials in anovulatory infertility in Abderdeen, Oxford, London, and Dublin , and in breast cancer Manchester, Glasgow, and London , the Nolvadex Development Programme included plans for trials in contraception. Diczfalusy, co-founder and Director of the WHO Research and Training Centre on Human Reproduction at the Karolinska Institute in Stockholm 42 , where he had already carried out collaborative projects involving healthy human volunteers using estrogens and other compounds The Swedish trials led to the finding that, contrary to what might be expected from the laboratory studies in rats, tamoxifen stimulated rather than suppressed ovulation, and therefore would not work as a contraceptive pill in women.

The market for a fertility drug was small, as seemed the market for an anti-cancer drug, partly due to the poor prognosis associated with the disease. ICI's Main Board therefore made the decision to close down the Programme, but tamoxifen's champion, Walpole, threatened to resign. On this announcement, despondency spread through the entire research department.

Moreover, when informed of the company's decision, one clinician said that, in view of the encouraging trial results, ICI could not morally withdraw the drug By then, the breast cancer trials had led to a number of publications, which sparked world-wide interest in tamoxifen Under such pressure, the company reversed its decision, Walpole remained, and the project was saved.

In February ICI applied for a product license, which was granted a few months later, and in October of that year Nolvadex was launched in the UK for both anovulatory infertility and the palliative treatment of breast cancer.

Although there continued to be crossovers between the two projects, the rest of this paper will focus on breast cancer. It will show how tamoxifen was transformed from a research object and palliative therapy for advanced breast cancer, into a diagnostic and predictive tool, an adjuvant chemo-endocrine treatment first in post-menopausal, then also in pre-menopausal women with early breast cancer, and eventually into the first chemopreventative for cancer.

Among the large number of clinical trials now being carried out with tamoxifen, Dr. Einhorn's studies at the Karolinska Institute in Stockholm had included a measurement of the rate of DNA synthesis in breast tumors and the effect this had on treatment.

As a result, his group had been able to anticipate clinical response to, or relapse after, treatment with tamoxifen. From these observations, Walpole concluded that tamoxifen could be employed in pre-menopausal women with breast cancer for a short period as a tool to predict the usefulness of drastic treatments such as ophorectomy in these women. At the same time, he began making plans for a trial with Dr. Heuson of the European Breast Cancer Group, who was anxious to compare tamoxifen with Nafoxidine an Upjohn compound which like tamoxifen could bind to the estrogen receptor, but unlike tamoxifen had several toxic side effects.

The trial would include estrogen receptor determinations on biopsies taken from each patient to determine whether there was a correlation between clinical response to the compound and the presence of estrogen receptors in the tumor tissue By then, the clinical trials in fertility and contraception had also shown that in some instances tamoxifen led to the suppression of lactation. Walpole felt that this action would be of interest in the context of breast cancers which may be associated with high blood prolactin levels, and indeed at Westminster Hospital two patients who had responded well to tamoxifen had tumors which were thought to be prolactin-dependent Taken together, these observations on the measurement of DNA synthesis before and after treatment, of the content of estrogen receptors in breast tumors, and of blood prolactin levels led to the hope that it would be possible to predict the type of patient likely to respond to treatment with tamoxifen, i.

However for this to happen, better screens had to be devised, first in animals and then in humans. In her unpublished history of tamoxifen, Dora Richardson commented that no laboratory tests for anti-tumor activity had been carried out with tamoxifen until after its activity in patients had been confirmed. The laboratory model adopted by Walpole's team to test for tumor inhibition was the DMBA dimethyl benzanthracene induced tumor in rats also known as the Huggins tumor.

The next step was to design a simplified method of receptor analysis, which could be applied routinely on a large scale in this model, before being applied in humans 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.

Set up in 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.

In , 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.

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 of the 16, 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. The number of women and, although a rare occurrence, men diagnosed with breast cancer has been climbing steadily over the years.

Since breast cancer has become the most common form of cancer in the UK. 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.