Carroll and his team uncovered a possible explanation for why women whose breast cancer cells carry two key molecules – called the oestrogen and progesterone receptors – do better than those whose cells only carry the oestrogen receptor. Even when they receive the same treatment.
They revealed that when signals were sent through the progesterone receptor it slowed down the growth of breast cancer cells. To find out if this had potential as a treatment, the researchers tested a new combination of hormone therapies and found it slowed down tumour growth in mice.
This was a really important study, but had only been carried out in mice, so it was too early to say whether it could help treat women with breast cancer.
Now, just 2 years after the discovery from Carroll’s team, 3 clinical trials are set to open that will test this new approach in people.
From lab beginnings
Carroll’s study was instrumental in understanding how the progesterone receptor works in breast cancer, and how it can act as a handbrake on cancer cells’ growth. The team’s results have now led to a possible new approach for stopping double positive breast cancer cells growing.
Normally, women whose breast cancer cells carry the oestrogen receptor (so-called ER positive) are treated with drugs that cut off oestrogen or directly block the oestrogen receptor. This will either be tamoxifen or aromatase inhibitors, depending on whether the woman is pre- or post-menopausal.
But Carroll’s results showed that treating mice with those oestrogen-blocking drugs and a dose of the hormone progesterone had an even bigger effect compared to the oestrogen-blocking drugs alone.
Progesterone changes the genes that oestrogen turns on and off by forcing the oestrogen receptor to sit in different positions in the genome, and according to Carroll this means the combined treatment offers a safety net.
“It’s like a double blow,” he says. “We cut off oestrogen, and as an insurance policy we use progesterone to pull the oestrogen receptor away from the genes that support cancer’s growth.”
This was the evidence that was needed to take the research into early clinical trials.
When the results were published, they caused quite a stir. Carroll says they challenged how people thought these different types of breast cancer worked at the time.
“For years there’d been a lot of confusion over whether progesterone encourages cancer to grow, and this has largely come from population studies looking into hormone replacement therapy (HRT),” he says
Some women choose to take HRT to ease symptoms caused by the menopause. There are different types, and the combined form contains a man-made version of progesterone called medroxyprogesterone acetate (or similar versions).
It’s this combined form of HRT in particular that is linked to an increased risk of developing breast cancer.
“This led to the popular belief that progesterone encourages breast cancer to grow,” says Carroll. “But it’s not that simple. Different versions of man-made progesterone seem to have different effects on cells compared to the natural hormone.
“Plus we were trying to understand what role progesterone plays after a breast cancer has developed, rather than looking at how it affects risk of cancer beginning in the first place.”
Into the clinic
Just 6 months after the findings were published, Carroll was approached by Dr Richard Baird, a clinical trials specialist based at our Cambridge Centre, to discuss possible trials.
Because the drugs we want to test have been used by doctors for years for a variety of reasons, we know they are safe and what doses to use them at. Plus they have the benefit of being cheap.
– Dr Jason Carroll
“A clinical trial from Brazil showed that around 40% of women whose cancer had stopped responding to standard oestrogen-blocking therapies, including tamoxifen and anastrozole, still responded to a man-made progesterone called megestrol acetate,” says Carroll.
Their idea was to try the combination of oestrogen-blocking drug and progesterone as the first therapy women receive. And setting up the trial was surprisingly simple.
“Because the drugs we want to test have been used by doctors for years for a variety of reasons, including in the treatment of late stage metastatic breast cancer, we know they are safe and what doses to use them at. Plus they have the benefit of being cheap,” says Carroll.
The Pioneer trial is being led by Carroll and Baird, and will start enrolling women with early stage breast cancer in June 2017.
Women joining the trial will still get the gold standard of care treatment that all women with early breast cancer receive, but the team will test the combination in a gap that exists between diagnosis and surgery.
“What happens is there’s normally a few weeks’ wait between a women having a biopsy and then having surgery to remove her tumour.
“In our trial, we’re going to ask women to take the combination of an oestrogen-blocking drug – in our case anastrozole – and the man-made progesterone (megestrol acetate) during this wait. Then we can study the biopsy sample and a sample of the tumour removed during surgery to see the effects of the combination treatment on the cancer cells.”
Not 1, but 3 trials
Carroll and Baird are focusing on post-menopausal women in their trial, but there are 2 other trials that have been set up in partnership that look at slightly different things.
One of the trials, led by Dr Carlo Palmieri at the University of Liverpool, is being funded by us. The approach is similar to that of Carroll and Baird, but Palmieri’s trial will involve pre-menopausal women who will be given a combination of tamoxifen and man-made progesterone instead.
The third trial will be opening in Australia, testing a combination of aromatase inhibitors and natural progesterone in post-menopausal women.
If the trials show that the combination treatment is effective by studying tumour samples, the next steps would be extending the studies into larger trials so women are given the combination after surgery too, to see if it improves survival and doesn’t cause any harms in the long-term.
Another interesting angle to the trials is finding out if adding progesterone to oestrogen-blocking drugs helps reduce the side effects of treatment.
“For the maximum effect, women should take oestrogen-blocking drugs for the recommended time period after surgery,” says Carroll. “But unpleasant side effects mean many women stop their treatment early, and this increases the risk of their cancer returning.
“As part of this trial, we’re also finding out if a lower dose of progesterone routinely used to alleviate menopausal symptoms works as well as the higher dose. This could make the side effects of hormone therapy more manageable and improve the fraction of women that stay on their standard treatments.”
The clinical trials are only just opening, so we’ll need to wait until they’ve got some results before knowing if this will benefit women with double positive breast cancer and could be made widely available.
But thanks to some excellent lab research by Carroll and his team, and our funding, the trials are up and running and we’re another step closer to an answer.