Hormone replacement therapy (HRT) “could increase the risk of developing early signs of breast cancer after only one year”, The Daily Telegraph reports today. One of the largest studies of its kind has shown that “the group taking the hormones had a 4% greater risk of having an abnormal mammogram, or breast X-ray, than those taking the placebo”, the newspaper said.
There has been ongoing debate about the risks and benefits associated with HRT. It is known to cause a slight increase in the risk of breast cancer if taken for longer than five years. This news report will no doubt raise concerns among many women taking, or considering taking, HRT.
The report is based on data from a large Women’s Health Initiative (WHI) study in the US. However, the study was not directly investigating any link between breast cancer and HRT. Instead it looked at whether HRT increased the chances of detecting an abnormality on a mammogram that then required a biopsy for further investigation; this would not necessarily involve a diagnosis of breast cancer. The study’s authors say that HRT seemed to increase the chances of having to undergo further investigation after a mammogram and reduced the ability of the mammogram to detect breast cancer accurately. They advise that these issues should be considered when doctors are discussing the risks and benefits of HRT with women, and this seems to be sensible advice.
Where did the story come from?
This research was carried out by Dr Rowan Chlebowski and other investigators for the WHI in the US. The WHI is funded by the US Department of Health and Human Services’ National Heart, Lung and Blood Institute. It was published in peer-reviewed medical journal Archives of Internal Medicine .
What kind of scientific study was this?
This study reports an analysis of data from a large randomised controlled trial in which the researchers aimed to clarify the effect of combined HRT (oestrogen and progestogen) on breast cancer detection.
The WHI researchers enrolled 16,608 postmenopausal women (aged 50 to 79 years) from 40 clinics in the US between October 1993 and December 1998. The women received either a combination of oestrogen and medroxyprogesterone in a single daily tablet (HRT) or a placebo tablet. Women were not included in the trial if they had a family history of breast cancer, had any other cancer within the past 10 years, or another medical condition that meant they could die within three years of the start of the study. All participants had a normal mammogram and breast examination at the start of the trial. Researchers also collected participants’ personal information, including details of health, lifestyle and previous use of HRT.
The women were followed up six weeks after starting the tablets to check they were taking the medication as directed and to monitor any symptoms. They had a clinical assessment every six months and a yearly breast examination and mammogram. Any mammograms that were suggestive of abnormalities or possible cancer were referred to a doctor who decided whether further investigation was needed.
In their analysis the researchers looked at the mammograms of the women who received HRT and those who received the placebo. They monitored two factors: specificity, which refers to the proportion of women without breast cancer whose mammogram was, correctly, free from abnormalities; and sensitivity, which refers to the proportion of women with breast cancer whose mammogram correctly showed the abnormality. They also looked at the rates of false-positive and false-negative test results. They carried out this analysis after the women had been taking the medications for three periods of time: one to two years; three to four years; and five or more years. Non-adherence to study medications was taken into account when conducting the analyses.
Researchers report that medications in all women were discontinued when it was considered that the risks of combined HRT therapy outweighed any benefits. Women were advised to continue with follow up assessments every six months and yearly mammograms. The researchers used this later data to assess the accuracy of mammograms for correctly detecting breast cancers 2.4 years after the women finished taking the study medication.
What were the results of the study?
The average age of women in this study was 63 years. There were no differences in demographics, lifestyle or relevant medical factors between the HRT and placebo groups. During the course of the study, breast cancers were diagnosed in 199 of the HRT group and 150 of the placebo group (giving a small increase in the risk of breast cancer in the HRT group). When breast cancer was diagnosed in the HRT group, it was generally at a later stage. These results have already been published.
The frequency of detecting an abnormality on a mammogram was higher in the HRT group (35% compared with 23% for the placebo group) with a corresponding increase in the number of biopsies that needed to be carried out. The increase in the chances of having an abnormal scan with HRT compared with placebo increased during the time HRT was taken (4% increase with one year of HRT, rising to an 11% increase with five years of HRT).
The researchers found that the specificity of mammograms was very similar in the HRT and placebo groups. However, the sensitivity of mammograms for correctly identifying women with breast cancer was reduced with HRT. Of all the women who went on to have a biopsy after a mammogram, fewer in the HRT group demonstrated actual breast cancer (14.8%) than those in the placebo group (19.6%).
For 12 months after the participants stopped taking HRT, the effects upon abnormality detection at mammography remained significant; however, they decreased after this time.
What interpretations did the researchers draw from these results?
The researchers concluded that the use of combined oestrogen and medroxyprogesterone HRT increased the rates of finding any abnormality on a mammogram and of needing to have a biopsy investigation, while “compromising the diagnostic performance of both”. This, they say, results in “one in 10 and one in 25 women having otherwise avoidable mammogram abnormalities and breast biopsies, respectively”.
What does the NHS Knowledge Service make of this study?
This was a complex and well-conducted study in which the WHI researchers attempted to clarify how HRT affects the risks of having an abnormal mammogram test. This follows on from the earlier findings of this study that use of HRT for over five years increases the risk of developing breast cancer. Being a large study, it offers valuable information; however, there are still points that should be taken into account:
- The newspaper headline in The Daily Telegraph that “HRT could increase breast cancer risk” is a slight oversimplification of the study’s findings. The actual increase in the number of cases of breast cancer in the HRT group compared with the placebo group was relatively small, and was not the focus of this investigation. The main finding of the study was that the diagnostic accuracy of mammography was decreased in women who had taken combination HRT.
- This study only investigated one type and one dosage of combination HRT. The findings may not be the same with other drug combinations or for oestrogen therapy alone in women who have undergone a hysterectomy. The effects upon women with a family history of breast cancer are also unclear.
- This study was conducted in the US. Findings may be similar in other countries, but care should be taken when applying the results to the UK or elsewhere because the sensitivity of detection of abnormalities on mammograms may be slightly different.
- The researchers suggest that the decrease in diagnostic accuracy of the mammograms may be due to the increase in breast density that occurs because of hormone therapy. This was not assessed by the study, the researchers explain, so the precise role of this factor remains unknown.
The authors say that the emotional and economic costs for women who have an abnormal mammogram and need further investigation may be significant. They therefore advise that these issues are considered when doctors are discussing the risks and benefits of HRT with women. At the current time, this seems to be sensible advice.
Sir Muir Gray adds...
One of the reasons that breast screening shows less benefit in women under the age of fifty is that the breast tissue is denser before the menopause. It is therefore not surprising that HRT makes mammograms more difficult to read.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
The Daily Telegraph, 26 February 2008
Links to the science
Arch Intern Med 2008; 168:370–377