New breast cancer test could predict response to tamoxifen and anastrozole

Scientists have developed a new high-tech test with the potential to accurately predict whether breast cancer patients will benefit from anti-hormonal treatments such as tamoxifen and anastrozole.

Thirty per cent of women who currently receive tamoxifen do not benefit from it and would do better with other treatments. But current pre-treatment testing procedures only give doctors a rough indication of whether it or other anti-hormonal drugs are likely to work.

The new research, funded by Cancer Research UK and the Breast Cancer Research Trust, is reported in the latest edition of the International Journal of Cancer¹. In addition to predicting a woman’s likely response to anti-hormonal drugs, the patented test could also be used to monitor patients over the course of hormone treatment, acting as an early warning system if a tumour becomes resistant to drugs.

Both anastrozole and tamoxifen work by interfering with the female hormone oestrogen, which is known to be the most important factor in the development of breast cancer.

Tamoxifen prevents the growth-promoting action of oestrogen on the cells of the breast, blocking a molecule called the oestrogen receptor (ER). A newer drug called anastrozole actually shuts down the production of oestrogen, and appears to be more effective and to lead to fewer side effects than tamoxifen in post-menopausal patients given the drug.

Both drugs are only effective in women whose breast cancers are reliant on ER for their growth.

Currently, doctors decide who to treat with tamoxifen or anastrozole by selecting patients who have high levels of ER within their tumours. But many of these women do not respond to the treatment, because although their tumours have large amounts of ER it is not properly active and not important for the growth of their cancers.

Professor Charles Coombes, Professor Brian Foxwell and their team² at Imperial College London and the Kennedy Institute of Rheumatology³ found that assessing the activity of ER, rather than simply its quantity, is a much better way of predicting whether treatment would work.

Professor Coombes, one of Cancer Research UK’s leading clinical researchers, explains: “Tamoxifen and anastrozole effectively knock out the influence of oestrogen on breast cancer growth. There’s no point in doing that in patients where ER doesn’t work properly, since in these cases the tumour will have learned to live without the hormone.

“Our new test will, for the first time, allow doctors to assess directly the importance of the ER molecule for the growth of a particular tumour, which means they’ll know much more accurately whether or not tamoxifen or other anti-hormonal drugs are likely to work.”

Previous work by the team had already developed a new way to purify breast cancer cells taken from patients. They infected these cells with a specially modified virus carrying the test gene and so were able to measure ER activity.

ER affects cell growth by flicking the on-switches of several genes. Researchers wired one of these on-switches to a special test gene, which when turned on produces a bright yellow colour. By measuring the intensity of the yellow colour, they were able to assess the switching-on activity of ER.

Usually women with high amounts of ER also had high ER activity, but in about one in five cases ER activity was low, even though levels of the molecule were high.

These are the women who would be most likely to benefit from the new test, because although they might currently be treated with tamoxifen or anastrozole, the new test shows that they would be unlikely to respond to those drugs. Such women would get greater benefit from being given conventional chemotherapy instead.

The test can also tell doctors which of the anti-hormonal drugs a tumour is most likely to respond to. By taking cells from the tumour and testing how each drug affects ER activity, doctors could predict which drug is most potent against an individual tumour.

Scientists also believe the test could be useful for monitoring women over a course of treatment. Standard treatment with tamoxifen runs for five years. The researchers found the activity of ER dropped in women whose cancers developed resistance to tamoxifen during treatment, so the test could offer a valuable early warning sign to doctors that it is time to switch to other drugs.

The test will shortly enter a second phase patient trial, to determine its accuracy and potential for clinical use⁴.

Professor Robert Souhami, Director of Clinical Research at Cancer Research UK, says: “Tamoxifen has proved an incredibly useful drug, but it doesn’t benefit all women. This test could give us much more reliable information about whether or not tamoxifen or other anti-hormonal drugs should be used, or whether chemotherapy should be used instead.

“Sometimes women are treated with tamoxifen over the course of several years. Many of these patients will be successfully treated with the drug, but others will eventually relapse because their tumours develop drug resistance. Monitoring women using this test could identify women who are on the brink of relapse, allowing doctors to pursue other lines of attack.”

ENDS

1. International Journal of Cancer107 pp.700 – 706
2. Primarily Anjana Singh and Simak Ali
3. The Kennedy Institute of Rheumatology is funded by the Arthritis and Rheumatism Council.
4. The Phase II clinical trial will take place at Charing Cross Hospital, London, commencing in early 2004.