Our milestones: How anastrozole became a number one hit

In this instalment of our Milestones series, we look at Cancer Research UK’s pivotal trials, proving that a drug called anastrozole should be the gold standard for treating breast cancer in postmenopausal women.

In the late 90s, Cancer Research UK’s Professor Jack Cuzick was the lead statistician on a large breast cancer trial. “So I was in the privileged position of knowing the results before everyone else,” he recalls.

“Before I presented the results to the trial committee, I asked them to vote on what they thought would be the outcome.

“Most of them got it wrong!”

The trial was set up to compare two drugs: tamoxifen – the hormone-blocking drug that was then the mainstay of treatment for women with ‘oestrogen-receptor positive breast cancer, against anastrozole, a newer, more sophisticated drug designed to shut off oestrogen production.

The results went on to change clinical practice the world over.

How it all began

But let’s start at the beginning. The year was 1984. The Olympics were in LA, The Smiths had just released their first album, the coal miners’ strike was warming up.

And at the Royal Marsden’s Cancer Research Campaign laboratories (later to become part of Cancer Research UK after CRC’s merger with the Imperial Cancer Research Fund) – Dr. Charles Coombes was studying a molecule called aromatase, an enzyme produced by the body to convert male sex hormones (androgens) into oestrogen.

The ultimate aim was to work out how to interfere with this process, halting oestrogen production and providing a new way to treat breast cancer, particularly in postmenopausal women.

Oestrogen is important in breast cancer – around three quarters of women with the disease are classified as oestrogen receptor positive (ER positive). This means that their cancer cells need oestrogen to grow and survive.

Before the menopause, a woman’s oestrogen is mainly produced by her ovaries. But after menopause, oestrogen production in the ovaries falls dramatically. Instead, postmenopausal women use aromatase to convert androgens – produced by her adrenal glands – into oestrogen.

So, in the 80s, researchers began to wonder whether drugs which block aromatase – so-called aromatase inhibitors – could be particularly effective at lowering oestrogen levels in postmenopausal women, and so could potentially be used to treat breast cancer.

And early laboratory research backed up the idea – chemicals that blocked aromatase successfully reduced oestrogen levels and killed breast cancer cells.

But the real test was still to come. Would aromatase inhibitors work the same way – and be safe to use – in women? The only way to know was to run a clinical trial.

The first of its kind

So Professor Coombes did just that. With support from Cancer Research Campaign, he and his collaborators at the University of Maryland carried out the first ever clinical trial of an aromatase inhibitor in people.

This tested whether injections with aromatase inhibitor called 4-hydroxyandrostenedione (4-OHA) could be used to treat breast cancer that had spread (‘metastatic’ breast cancer) in postmenopausal women.

It was a small trial, but the results were convincing.

The study showed 4-OHA was safe to use, and didn’t cause many side-effects – the main ones reported by patients on the trial were hot flushes, and pain at the drug injection site. And the trial showed that 4-OHA worked as expected – it successfully lowered oestrogen levels in these women.

But, most importantly, 4-OHA induced a ‘clinical response’ in more than one-third of patients – their tumours shrank. In other words, the study showed that an aromatase inhibitor can treat metastatic breast cancer in postmenopausal women.

This was good news.

Anything you can do I can do better – or can I?

Fast forward several years and it’s the mid-90s – the Internet has arrived, every woman seems to want a Rachel ‘do’, and is going crazy about Jurassic Park.

And following the impressive results of the 4-OHA trial, scientists have started to take more of an interest in aromatase inhibitors and are developing new, better versions of them.

So, as Banarama gave way to the Spice Girls, 4-OHA gave way to a new aromatase inhibitor – anastrozole (often known by its brand name, Arimidex).

Anastrozole was more potent than 4-OHA but – just as important – it could be taken as a tablet, rather than an injection.

So the next step was to put anastrozole to the test in a clinical trial. But this time things were a little different. As well as proving it worked, researchers also had to prove it was better than a drug already being given to patients – tamoxifen.

Because when it came to breast cancer treatment in the mid-90s, tamoxifen was the number one hit.

Since UK approval in the 1970s, tamoxifen has been used to treat and save the lives of thousands of women with ER-positive breast cancer.

Unlike aromatase inhibitors, which stop oestrogen being made, tamoxifen stops breast cancer cells being able to use the hormone.

Like most drugs, tamoxifen has side-effects, including hot flushes, headaches and – most seriously – a slightly increased risk of developing womb cancer. This means the risks need to be balanced against the benefits for each woman. But based on the clear improvements in survival seen in women taking tamoxifen, from the mid-90s it was the drug used to treat most women – pre- and postmenopausal – with ER positive breast cancer, either alone or in combination with chemotherapy.

But could anastrozole be a better treatment than tamoxifen for postmenopausal women with breast cancer? Only a clinical trial would tell.

A question of ethics

So Cancer Research UK helped set up and support the ‘Arimidex, Tamoxifen Alone or in Combination’– or ATAC for short – clinical trial.

The trial had two main aims – to find out whether:

• Anastrozole was as good as, or better than, tamoxifen as a treatment for breast cancer in postmenopausal women and whether
• A combination of anastrozole and tamoxifen was better than either drug on their own

To find the answer, the trial randomly assigned more than 9,000 postmenopausal women to one of three treatments:

• Anastrozole on its own
• Tamoxifen on its own
• Anastrozole and tamoxifen together

While this might seem a straightforward, logical way to carry out the trial, at the time, not everyone thought so. In particular there were concerns about how ethical it was to deny the women in the ‘anastrozole only’ group tamoxifen, when it was known to work.

Professor Cuzick remembers: “When we were planning the trial, there were very strong concerns from ethical committees and doctors about giving some women neither drug, or anastrozole on its own, and deny them tamoxifen, when we knew it worked so well. We were in agreement that it absolutely wasn’t appropriate to include a group that didn’t receive either drug, but everyone involved in running the trial was adamant that there should be an anastrozole only group.”

Their determination paid off. “Thankfully in the end, and despite their concerns, we convinced the committees that we needed to do the three group trial, and include an anastrozole only group”, says Cuzick.

It’s a good job they did.

The results

Before the trial most people thought the combination of anastrozole and tamoxifen was going to work best.

But the ATAC trial results, published in 2002 in the journal The Lancet, showed quite convincingly that anastrozole was even better than tamoxifen as a treatment for ER positive breast cancer in postmenopausal women.

The trial showed that those women in the ‘anastrozole only’ group had a significantly lower recurrence rate than those in the ‘tamoxifen only’ group. This means that the number of women whose breast cancer returned was far lower in the ‘anastrozole only’ group than in the ‘tamoxifen only’ group.

Not only that, the number of women who developed cancer in their other breast was also significantly lower in the ‘anastrozole only’ group.

Professor Cuzick remembers: “Afterwards everyone said ‘I knew all along that would be the case’ but that’s not what they said beforehand – they all thought that two things were going to be better than one. But people were really excited – it was the first time anyone had shown that an aromatase inhibitor should be the treatment of choice for breast cancer in postmenopausal women. There was a real buzz about it.”

Anastrozole also appeared to have fewer side-effects than tamoxifen. In particular, two of tamoxifen’s more serious side-effects – an increased risk of developing a blood clotting disease, and an increased risk of developing womb cancer – were not seen in women on anastrozole.

But anastrozole does have its own side-effects, the most common being a decrease in bone density among women taking the drug, meaning their bones become weaker and can fracture more easily.

“Before the trial, we didn’t know all of the side-effects of anastrozole, so there weren’t any preventative measures put in place to stop bone damage. But pretty soon we noticed that the bone fracture rate was increased in the anastrozole group during treatment,” Cuzick says.

”But we also discovered that within a year of stopping anastrozole, these women’s bone fracture rates returned to normal. So it wasn’t a long-term effect, it was just a side-effect that happened during treatment.’

The legacy

The ATAC trial was the first of its kind. But since then there have been numerous other clinical trials which confirm its findings – aromatase inhibitors like anastrozole are a more effective treatment for breast cancer in postmenopausal women, with fewer side-effects.

Today anastrozole – and other aromatase inhibitors like exemestane – are the gold standard treatment for postmenopausal women with ER positive breast cancer. Each year these drugs help thousands of women across the world survive their disease.

Professor Arnie Puroshotham, consultant surgeon at Guy’s and St. Thomas trust agrees. “Three decades after the introduction of tamoxifen into the clinical care of breast cancer patients, aromatase inhibitors have revolutionised breast cancer treatment in postmenopausal women following the breakthrough results of the ATAC trial. This has resulted in improved treatment with fewer side effects for many thousands of women”.

And none of this would have been possible without either early trials into aromatase inhibitors like the 4-OHA trial, and later larger trials like ATAC – trials we’re proud to have supported.

But of course, there’s still more work to do. There are more than 11,000 deaths from breast cancer in the UK each year. That’s why we continue to fund research into every aspect of the disease – from understanding its causes and how to prevent it, to finding better ways to diagnose and treat it. Together, we will beat breast cancer sooner.

– Áine