New research led by Dr Andrew Sims, Professor Mike Dixon and Dr Arran Turnbull at our research unit in Edinburgh shows how a test of four genes can accurately identify women for a particular treatment.
This test makes a significant contribution to our advances in personalised medicine. In this blog post we explore this research and the impact it could have on patients.
Conception of a wonder drug
In 1962, a revolutionary discovery set off a chain of events that would lead to one of the most important advances in oncology. Dora Richardson, a chemist at Imperial Chemical Industries (ICI), was put in charge of designing a ‘morning after’ pill – work which resulted in her synthesising the compound tamoxifen.
Although the drug failed as a contraceptive, the 1970s and 1980s saw tamoxifen being trialled for other uses, including some types of breast cancer. By the end of the 1980s it was becoming increasingly clear that tamoxifen was extremely effective at treating oestrogen receptor (ER) positive breast cancer. Tamoxifen eventually became the number one treatment choice for these patients and its impact is immortalised in the abrupt decline in breast cancer deaths in the 1990s.
Rise in targeted treatments
Further advances in the treatment of ER-positive breast cancer led to the discovery of other targeted drugs, such as aromatase inhibitors, which have established themselves in mainstream treatment. But cancer isn’t that easy to conquer. Many patients for whom these drugs are designed don’t benefit from them because their tumours are resistant or become resistant over time. To deal with this problem we need to be able to identify the patients who aren’t going to respond to a particular treatment.
New research published this week by our research team in Edinburgh has taken a significant step towards an accurate test capable of doing just that. Importantly, their test can pick out these patients just two weeks into the start of treatment so that they can be moved onto more suitable treatment as quickly as possible.
The backbone of this study is analysis of the genetics of tumour samples, taken at different time-points, from patients with ER-positive breast cancer who had been treated with letrozole (an aromatase inhibitor). Biopsies were taken from 89 patients before treatment began, two weeks into their treatment and then again at three months.
During their treatment patients were grouped depending on how well they were responding to letrozole by looking for reduction in the size and volume of their tumour. When the team looked deeply into the genetic profiles of these tumours, they found 200 genes which varied in expression (how much they are switched on or off) between patients that responded well and those that didn’t. Of these genes, 82 were found to be different before treatment even began, another 82 were different two weeks into treatment and a set of 36 genes were different in tumour samples taken three months into treatment.
Four genes, one test
Trying to make a feasible genetic test out of 200 genes is never going to be easy. But by using some clever statistical analyses, and the gift of computer technology, the researchers were able to whittle this number down from 200 to just four. Four genes that produce the optimal model for predicting response to letrozole.
And it’s not surprising that the four genes pulled out are responsible for cellular functions relevant to cancer. One of the genes, called IL6ST, is involved in activating the immune response – a reaction known to help repress cancer. A second gene, called NGFRAP1, helps to kick-start a suicide programme in cells. The other two genes, called ASPM and MCM4, regulate cell division – a process that is out of control in cancer.
So how does this test work? Firstly, it involves taking a tumour biopsy from the patient before they start treatment. The genetics of the tumour are then analysed to look at the expression of the first two genes (IL6ST and NGFRAP1). Two weeks into treatment a second biopsy is taken and the genetics re-analysed – this time looking for the expression of the other two genes (ASPM and MCM4). Patients that are found to have high expression of the first two genes before treatment begins, and low expression of the second set of genes two weeks later, are likely to respond to well to treatment with letrozole.
This four gene test offers a new way to quickly and easily identify patients that won’t benefit from letrozole. This is crucially important because patients that don’t respond can be moved on to a more effective treatment from as early as two weeks. On the flip side, those patients that fall into the ‘responder’ group will be able to continue on their treatment course knowing that they are very likely to continue receiving benefit from the drug.
A big step in the right direction
Most patients already have a delay of about two weeks between their first biopsy and surgery, so there is a great window of opportunity to start treating all ER-positive breast cancer patients with drugs like letrozole from day one, and then individualising their treatment post-surgery. This study also demonstrated that the four genes could be detected with two methods commonly used in hospitals – highlighting the huge clinical benefit this test has to offer.
We have come a long way since Dora unlocked the secret of tamoxifen in her lab at ICI. Since then our ideas about breast cancer and how to treat it have become more complex and ever more refined. But this kind of research is taking us in the right direction. We hope that soon we will see tests like this in the clinic - being used routinely to make sure that the right treatment is selected for every patient.
Dr Matthew Lam – Senior Research Communications Officer