Tamoxifen – incremental progress, massive impact

“Tamoxifen is the most important drug in the history of medical oncology.” Dr. Harold J. Burstein, Dana-Farber Cancer Institute, Boston.

Tamoxifen is a drug that blocks the action of the hormone oestrogen – a job that sounds simple. So is it really one of the greatest advances in cancer treatment? It’s a pretty grandiose claim.

But when you consider the impact it’s had on extending and saving the lives of women breast cancer, and the fact that breast cancer is the most common form of cancer in the UK, you can see why some oncologists hold it in such high regard.

It’s certainly saved the lives of millions of women around the world. But the drug is usually only given for five years because cancer cells develop resistance to its effects over time.

That’s why today’s announcement – that scientists have worked out how tamoxifen resistance develops – paves the way for even more improvements in breast cancer care.

In the beginning

The story of tamoxifen starts back in 1896, when pioneering cancer surgeon Dr George Beatson found that he could extend the lives of women with breast cancer by surgically removing their ovaries – a major oestrogen source. This gave researchers the first clue that oestrogen was involved in the growth and development of breast cancer.

Over the next five decades, doctors experimented with a variety of man-made oestrogen-like chemicals (such as stilboestrol, developed by Cancer Research UK scientist Professor Charles Dodds in 1937) to try to treat breast cancer. Although sometimes these efforts were successful, the side-effects were too severe for widespread use. By the mid 60s, the research had hit a dead end.

Contraceptive research

At roughly the same time, researchers at ICI (now AstraZeneca) in the UK, were investigating the effects of various oestrogen-like chemicals on the reproductive systems of rats, with the aim of trying to find new contraceptives and cholesterol-lowering drugs.

They developed several promising drug candidates, including one with the catchy name ICI46,474. But for various reasons, including lack of support and competing priorities, its development stalled.

War on cancer

Eventually, due to a combination of luck, good judgement, a bit of trans-Atlantic to-ing and fro-ing, and the declaration of a ‘war on cancer’ by President Nixon, there was a renewed interest in developing an oestrogen-blocker to treat breast cancer.

ICI46,474 was developed into tamoxifen, and doctors started giving it to patients in the early 70s. And the drug was licensed for the treatment of advanced breast cancer in the UK in 1972.

Tamoxifen for breast cancer treatment

However, tamoxifen is a complicated beast. Its effects, and side-effects, seem to depend on the exact dose and duration of therapy. There were also genuine fears about women becoming resistant to tamoxifen if they were given it for too long.

So clinicians were unsure how best to use it, and many clinical trials were carried out during the 70s and 80s, both in the US and Europe – including several funded by Cancer Research UK – to answer these questions.

The answers started to become clear in the 1980s, when the Early Breast Cancer Trialists’ Collaborative Group, funded by Cancer Research UK, published a series of papers analysing all the data from these trials. They showed that tamoxifen was effective at preventing breast cancer from returning when given for a few years after chemotherapy.

The group have since published a series of updates of their work, and their papers have been hugely influential in improving tamoxifen treatment for women worldwide. For example, in 1998 they found that tamoxifen was also effective for treating premenopausal women, potentially saving many more lives.

Tamoxifen for cancer prevention

Another striking finding by Cancer Research UK’s Professor Jack Cuzick was that tamoxifen stopped new cancers developing in the opposite breast in women who had been treated for breast cancer. This suggested that tamoxifen – or drugs based on it – might actually be able to prevent breast cancer. Cancer Research UK has supported two large trials, IBIS-I and IBIS-II, to answer this question (you can see a video about IBIS-II here).

Slow, steady progress

These have all been incremental steps, over a long time, but they add up.  The tamoxifen story is yet another example of how scientific research can seem like it proceeds with the pace of a snail – but with the momentum of a glacier.

Today saw another small but incredibly important chapter in the tamoxifen story – the discovery, again involving Cancer Research UK scientists in London and Cambridge, of how tamoxifen stops cells dividing, and how cells eventually develop resistance to the drug.

The ins-and-outs of this complex mechanism involve a molecular switch inside cells, which is made up of two proteins – Pax2 and ErbB2. Dr Jason Carroll, the lead author on the paper, which was published in Nature, explains:

“We knew that women developed resistance to tamoxifen, but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.

“We have discovered that for tamoxifen to work it has to block the gene ErbB2 and it does this by using a control switch that is hidden in the background of the genome, within the ErbB2 gene itself. In order for tamoxifen to be effective, this switch must be held in the off position by Pax2. Now we understand how women can develop tamoxifen resistance.”

You can listen to a longer interview with Jason by clicking on the player below:

Link to download.

The important thing about this discovery is that it now allows scientists to develop and test drugs to block tamoxifen resistance. This may be a way off, but the glacier keeps on ploughing inexorably down the mountain.

The drug is one of the best examples of how the cumulative work of cancer researchers around the world has come together to save the lives of millions of women. And the story’s far from over.

Henry

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NB The history outlined above was adapted from the following (excellent) article:

Jordan, VC: Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer. Br J Pharmacol. 2006 January; 147(S1): S269–S276.