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Cancer risk after combined HRT

Wednesday 5 March 2008

A major study has found that “hormone replacement therapy patients face a higher cancer danger long after they have stopped taking the treatment”, the Daily Mail warns today.

The newspaper reports that the research was by the same team who carried out the Women’s Health Initiative study, which in 2002 reported that cancer risks were elevated while taking hormone replacement therapy (HRT). They say that the findings published today suggest that cancer risks continue to be raised, but that other risks associated with taking HRT, such as blood clots and strokes, return to normal after the pills are stopped.

The Times reports that three years after stopping treatment, the risk of breast cancer “remained 27 per cent higher while risks of any type of cancer were 24 per cent higher”. They also say that in order to maximise benefits and reduce the risks, “advice from drug regulators in Britain is that HRT should be used for the control of symptoms of the menopause at the minimum effective dose and for the shortest possible time”.

This was a good quality study but, as its authors acknowledge, the follow-up results may have been affected by differences in cancer screening between the groups once women who had been taking HRT were informed of their potentially increased cancer risk. It is also worth bearing in mind that the increase in risk of developing cancer is relatively small. Further follow-up from this trial will show us whether this difference in risk is maintained over the longer term, and whether it leads to more cancer fatalities.

Where did the story come from?

Dr Gerardo Heiss from the University of North Carolina School of Public Health and other Universities and research centres in the US carried out the research. The study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. The study was published in the peer-reviewed: Journal of the American Medical Association.

What kind of scientific study was this?

This was an analysis of outcomes of the Women’s Health Initiative (WHI) double blind randomised controlled trial three years after the end of the trial. The trial was stopped when the risks associated with combined HRT were found to exceed its benefits.

The WHI trial randomly allocated 16,608 postmenopausal women aged 50 to 70 to either receiving combined HRT (0.625mg conjugated equine oestrogen plus 2.5mg medroxyprogesterone acetate daily) or a placebo between 1993 and 1998. The researchers assessed the women twice a year in the clinic or through telephone interview. Their medical records were checked to confirm reported cancers, cardiovascular problems, or fractures, and their death certificates were checked to determine cause of death.

In 2002, the trial was stopped when women taking combined HRT for an average of 5.6 years were found to have a higher risk of breast cancer and certain cardiovascular events. The study also found that these women had lower risks of fracture and colorectal cancer.

After the trial ended, the women stopped taking study medications, but continued to be assessed twice a year and were given annual mammograms. The researchers were able to follow 95% of the participants (15,730 women) for an average of 2.4 years after the end of the trial. The risk of cancer, cardiovascular disease, and fractures in this period were compared between the combined HRT and placebo groups. The researchers also looked at how the risks had changed during this period compared with the trial period.

What were the results of the study?

For the period following the end of the trial, there was no difference in the risk of cardiovascular disease events (such as a stroke, heart attacks, or blood clots) between the combined HRT and placebo groups, with about two per cent of women experiencing an event each year in both groups.

However, the HRT groups overall risk of cancer remained significantly higher (about 24% higher) than the placebo groups. Each year, about 1.6% women in the HRT group developed cancer compared to about 1.3% of women in the placebo group. Although examining the rate of each individual type of cancer revealed that the combined HRT group had a slightly higher risk of invasive breast cancer and a slightly lower risk of endometrial cancer, neither of these differences were large enough to reach statistical significance.

There was still a slight reduction in the risk of fractures in the HRT group after the trial ended, however this difference was also not large enough to reach significance. There was no significant difference between groups in the risk of death in this period.

What interpretations did the researchers draw from these results?

The researchers concluded that three years after the termination of the WHI trial, there is no longer an increased risk of cardiovascular disease events or a decreased risk of fractures associated with combined HRT. However, the risk of cancer with combined HRT remains elevated, and therefore that the balance of benefits and risks with this treatment remain tipped towards greater risk.

What does the NHS Knowledge Service make of this study?

This was a good quality study, and its results continue to be of interest. Women who have taken combined HRT and now stopped can take comfort from the fact that the risk of having a cardiovascular event does not stay high after they have stopped taking the treatment. It is of concern that cancer risk remains elevated, but it is worth bearing in mind that the risk of developing cancer is relatively low, with about an extra three in 1,000 women developing some form of cancer a year in the three years after stopping combined HRT.

In addition, the authors of the study point out that the differences seen should be interpreted with caution, as they may have resulted from differences in health seeking behaviours in the two groups of women after the trial. Women who had been told that they had been taking combined HRT at the end of the trial and knew of the cancer risk may have been more likely to seek medical attention for any suspicious symptoms than women who knew they had only received placebo.

As there were small numbers of events in the post-treatment phase, the researchers acknowledge that “chance could have contributed to some” of their findings. Further follow up of the women from the WHI will tell us whether cancer risk remains elevated in the longer term. It is also important to note that the study did not find a significant increase in the risk of death in women who had taken HRT.

Other points to bear in mind are that the results of this study (largely in white American women) may not apply to groups of women with a different ethnic background. In addition, not all HRT is the same, with varying doses used, and some consisting solely of oestrogen, rather then oestrogen plus progestin (the form used in this trial). These results may not be directly applicable to other forms and doses of HRT.

Sir Muir Gray adds...

This is a good quality study that adds another note of caution, but all healthcare involves balancing two probabilities: the probability of being helped and the probability of being harmed.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Stopping HRT “increases cancer risk”.

The Daily Telegraph, 5 March 2008

Cancer risk goes on long after women stop HRT, say researchers

Daily Mail, 5 March 2008

Cancer risk continues even after women stop hormone treatment.

The Times, 5 March 2008

Links to the science

Lethaby A, Hogervorst E, Richards M, et al.

Hormone replacement therapy for cognitive function in postmenopausal women.

Cochrane Database Syst Rev 2008, Issue 1

Lethaby A, Suckling J, Barlow D, et al.

Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding.

Cochrane Database Syst Rev 2004, Issue 3

Gabriel-Sánchez R, Carmona L, Roque M, et al.

Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women.

Cochrane Database Syst Rev 2005, Issue 2

Heiss G, Wallace R, Anderson GL, et al.

Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin.

JAMA 2008; 299: 1036-1045