Longer use of tamoxifen improves breast cancer survival

The findings – for women with oestrogen receptor positive (ER-positive) breast cancer – come from the long-running ATLAS trial led by Oxford University's Clinical Trial Service Unit (CTSU).

A majority of breast cancers are ER-positive and the results will help guide future treatment recommendations for women with this type of cancer.

The results are published online in the medical journal The Lancet, timed to coincide with a major presentation at the 2012 San Antonio Breast Cancer Symposium.

'Five years of adjuvant tamoxifen is already an excellent treatment that substantially reduces the 15-year risk for recurrence and death from ER-positive breast cancer, but ATLAS now shows that 10 years of tamoxifen is even more effective,' says Dr Christina Davies of Oxford University, the principal investigator of the study.

ER-positive breast cancer is driven by the female sex hormone oestrogen, and tamoxifen blocks the hormone’s effect.

The drug is widely used for treating ER-positive breast cancer, and is usually given daily for five years after the cancer has been removed surgically. This substantially reduces the chances of the cancer coming back and significantly lowers the breast cancer mortality rate – not only while treatment continues, but throughout the first 15 years after diagnosis.

Dr Davies explains that many women with ER-positive breast cancer take tamoxifen, or a similar treatment, but the current recommendation is to stop after five years.

'ATLAS showed that protection against breast cancer recurrence and death is greater with 10 years than with five years of tamoxifen use,' she says. 'Women and their doctors should be aware of this evidence when deciding how long to continue tamoxifen, or any other endocrine treatment.'

In the ATLAS trial, an international group of researchers examined whether continuing treatment with tamoxifen for ten years resulted in any further reduction in breast cancer deaths. They also assessed the additional side-effects resulting from longer use of tamoxifen.

The decrease in breast cancer mortality was 30 times as great as the relatively small increase in mortality from side-effects such as a blood clot in the lungs or cancer of the womb, the researchers found.

6,846 women with ER-positive breast cancer were enrolled on the study between 1996 and 2005. All the women had been using tamoxifen for five years, and the researchers randomly assigned them to continue treatment for another five years or to stop tamoxifen immediately.

After about eight years of follow-up, 1,328 women had had a recurrence of their breast cancer, of whom 728 had died.

Dr Davies' colleagues, including Dr Hongchao Pan, Sir Richard Peto, Sir Rory Collins and others at CTSU, found that continuing tamoxifen for ten years rather than stopping at five years reduced rates of recurrence and breast cancer mortality. However, the additional benefits took some years to emerge.

There was little effect on recurrence rates or death rates during the period five to nine years after breast cancer diagnosis. However, during the second decade after diagnosis, the clear benefit became apparent. The breast cancer mortality rate of women who continued tamoxifen treatment was about one quarter less than those who stopped after five years.

The risk of death from breast cancer 10 to 15 years after diagnosis was 6.4% among those who continued to use tamoxifen for 10 years. It was 9.0% among those who stopped after 5 years – an absolute difference of 2.6 percentage points.

'The main additional benefit from continuing tamoxifen treatment is to reduce breast cancer mortality during the second decade after diagnosis,' Dr Davies says. 'We already knew that five years of tamoxifen reduces breast cancer mortality in this late period by about a third in comparison with no tamoxifen. We now know that 10 years of tamoxifen is even better, approximately halving breast cancer mortality during the second decade after diagnosis.'

Continuing tamoxifen use for 10 years can increase the side-effects women experience, but the ATLAS study found their overall effect on survival was small relative to the benefits of longer treatment.

The most significant side effect was an increased risk among post-menopausal women of developing endometrial cancer (cancer of the lining of the womb). However, this type of cancer is generally curable, say the researchers, and the risk is heavily outweighed by the reduction in breast cancer deaths. In premenopausal women, there was no apparent excess of endometrial cancer.

'While our results show a small increase in life-threatening side-effects for women who take tamoxifen for ten years rather than five, this increase is greatly outweighed by the reduction in breast cancer mortality,' explains Dr Davies. 'Moreover, these side-effects cause little or no risk in pre-menopausal women with ER-positive disease, and if tamoxifen prevents the death of a pre-menopausal woman, then she could well gain several decades of life expectancy.'

The researchers found no evidence for an increased risk of stroke during treatment with tamoxifen, though the US Food and Drug Administration (FDA) lists this as a possible side-effect of the drug.

Professor Trevor Powles of Cancer Centre London, who was not involved in the study, suggests: 'If, as seems likely, the ATLAS findings will be reinforced next year, this should herald a change of practice, with the standard of care revised to 10 years rather than 5 years of treatment in patients for whom tamoxifen is indicated.'

The study was funded by Cancer Research UK, the UK Medical Research Council, AstraZeneca UK, the United States Army and the European Union.