A new review has cast doubt on the findings of a large study which identified a link between hormone replacement therapy and breast cancer, but experts are treating the conclusions of both pieces of research with caution.
In the ongoing debate over the benefits and harms of hormone replacement therapy, an international team of researchers has suggested that findings from the Million Women Study, which were used to establish that hormone replacement therapy (HRT) causes breast cancer, do not in fact prove a causal link.
The Million Women Study (MWS) is the largest study of its kind on the topic and has produced four reports (2003, 2004, 2006 and 2011). It was one of three major pieces of research that prompted a rethink of the long-term safety of HRT and its proponents state the findings have been replicated in many other studies.
A new review, published today in the Journal of Family Planning and Reproductive Health Care, highlights several design flaws that may have skewed the findings in the Million Women Study and argues that the sheer scale of the study alone should not considered a source reliability in itself.
“The name ‘Million Women Study’ implies an authority beyond criticism or refutation. Many commentators, and the investigators, have repeatedly stressed that it was the largest study of HRT and breast cancer ever conducted,” write the authors.
“Yet the validity of any study is dependent on the quality of its design, execution, analysis and interpretation. Size alone does not guarantee that the findings are reliable,” they continue.
Our colleagues at the Australian and UK SMCs collected the expert responses below.
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Dr Andrew Penman, Chief Executive Officer of Cancer Council, NSW, Australia comments:
“This research review offers no new conclusions when it comes to assessing the well-established link between hormonal replacement therapy (HRT) and breast cancer.
“The reality is that the overwhelming body of global evidence confirms a link between HRT and breast cancer. Cancer Council NSW research conducted in 2008 added to this evidence with our study showing that Australian women lowered their use of hormone replacement therapy (HRT) by more than half since 2001, and this resulted in sustained reductions in the number of women developing breast cancer.
“Our research reveals that HRT use dropped 55 per cent between 2001 and 2005. During the same period there was also a nine per cent drop in breast cancer rates among women aged 50 years and older, which is the equivalent of 800 fewer cases. No changes were seen in breast cancer rates in women aged under 50 years, who do not usually use HRT.
“These results are consistent with other evidence that women can reduce their risk of breast cancer quickly by stopping or reducing use of HRT. So, by reducing their use of HRT, women and their doctors have had a very positive impact on breast cancer in Australia.”
Prof Ian Fraser, Professor in Reproductive Medicine at the University of Sydney, comments:
“These authors rightly draw attention to the problems inherent in the so-called “Million Women Study”. For reasons well addressed by these authors the title of the study has inappropriately given the MWS analysis a measure of authority which size alone does not justify.
“Tiny statistical differences, as promoted by the Million Women Study, cannot be convincingly demonstrated by the techniques used, even though the authors attempted to ‘control’ for some of the recognized biases. It is not possible to control for all known and unknown biases in such studies, and this is well demonstrated by the authors of this latest article in the Journal of Family Planning and Reproductive Health Care. Sadly, the Million Women study did not add anything valid to the debate on HRT existing at the time it was published.
“The present authors are very well respected endocrinologists and epidemiologists who have undertaken a new and critical analysis of the data presented in ‘Million Women’ and have clearly demonstrated biases, which could not be allowed for in making the conclusions which ‘Million Women’ published.
“Any statistical analysis is only as good as the quality of the data analysed. Breast cancer epidemiology is so complex, and so many factors have been shown or suspected to influence incidence rates, that data analyses have to be extraordinarily comprehensive to allow for all relevant and known factors (and, when statistical differences are tiny, they must also take into account possible unknown confounding factors). The current authors have highlighted this fallacy clearly.
“This detailed critique is long overdue, and is an important contribution to the ongoing debate on the well-recognized benefits of hormone replacement therapy contrasted with a small number of uncertain disadvantages. The debate raised by the Million Women study merely frightened women without giving them a clear view of the potentially valuable benefits balanced against a theoretical risk. Women need clear, balanced, accurate and unemotional information about the quality of published scientific recommendations. The Million Women study failed to do this, and the current article goes a long way to remedying this.”
From the UK SMC
Comments from Valerie Beral, Professor of Epidemiology and Director of the Cancer Epidemiology Unit, University of Oxford, and Richard Peto, Professor of Medical Statistics & Epidemiology University of Oxford:
“HRT is one of the most important causes of breast cancer in the world and women can easily change their risk by stopping.”
Prof Dame Valerie Beral comments:
“This paper is a re-statement of views held by many consultants to HRT manufacturers (as these authors are) attempting to dispute evidence about the adverse effects of HRT. The issues raised are not new and have been refuted previously.
“The authors omit to say that Million Women Study findings, of an increased risk of breast cancer in users of HRT, especially of oestrogen-progestagen combinations, have been replicated in over 20 other studies. The totality of the worldwide evidence is now overwhelming.
“In line with the findings from these studies, the recent large decrease in HRT use has been followed in many countries by a nationwide decline in the incidence of breast cancer.”
Prof Sir Richard Peto comments:
“Changes in hormonal stimulation of invisibly small clumps of hormone-sensitive breast cancer cells can have a BIG effect on cancer rates within just ONE OR TWO years. Ordinary breast cells can be stimulated to divide by the female hormone, estrogen. Even when one cell from the breast has gone wrong and has turned into the seed of a growing cancer, that cancer can still be dependent on the continued stimulation by the body’s own oestrogen. Hormone-sensitive breast cancers can, however, be shrunk (and sometimes cured completely) by drugs such as tamoxifen, which block the action of oestrogen on the breast cancer cells.
“In women who have had a hormone-sensitive breast cancer apparently completely removed from their breast, invisibly small deposits of cancer cells may remain either nearby or in distant parts of the body that, without drug treatment, would cause breast cancer recurrence and eventually death.
“Our review of the randomized trials of daily tamoxifen vs no tamoxifen (Lancet 2011, 378: 771-84) showed that daily tamoxifen halves breast cancer recurrence rate during the first year or two, and that these rapid gains persist. These trials also showed that tamoxifen prevents one-third of the deaths from breast cancer. A few breast cancers are not hormone sensitive, and tamoxifen does not help patients with this type of cancer.
“Hormone replacement therapy (HRT) was supposed to replace the body’s own oestrogen after the menopause, and many non-randomized studies have produced strong evidence that it can cause a substantial risk of breast cancer.
“The Million Women Study has shown that oestrogen-progestagen HRT, the type most commonly used in the UK, substantially increases the risk of developing a hormone-sensitive breast cancer. As is biologically plausible, in view of the rapidity of the benefit from tamoxifen, the HRT-associated risks fall rapidly after use stops.
“In the Million Women Study participants were recruited just before they attended a breast screening clinic, at which some cancers were detected. But, even if attention is restricted to cancers that were detected only later, hormone-sensitive cancers are still three times as common in HRT users as in non-users or ex-users.
“Thus, the Million Women Study provides strong, biologically plausible evidence of causality, i.e. of an increased probability of getting breast cancer among otherwise similar women (and a rapid decrease after they stop).”
Hazel Nunn, Head of Health Information at Cancer Research UK, said:
“Women shouldn’t be unduly worried by this latest review of HRT and breast cancer risk. HRT can be an effective short-term treatment for menopausal symptoms – women taking it should try and use the lowest dose possible for as short a time as they need it.
“If you are considering starting or stopping HRT, or using it for a long time, you should discuss it with your doctor. The issues are different for every woman and your doctor will be able to help you weigh up the benefits and risks of different types of HRT and make the right choice based on your own circumstances.
“In the UK, HRT use has been falling since the start of the Millennium. Studies suggest that in 2005 there were 1,400 fewer cases of breast cancer in the UK among women aged 50-59 than would have been if there had been no drop in HRT use.”
President-Elect of the International Menopause Society, Professor Rod Baber (Sydney) said:
“This review of The Million Women Study (MWS) highlights the problems associated with any observational study regardless of size. Potential biases inherent in any observational study make it difficult for such studies to accurately comment on relative risks of less than 2 and this paper identifies them in a clear concise manner. In the MWS identified biases including time order, information and detection bias, confounding, internal and external consistency may all have contributed to the excess risk of breast cancer with HRT use found in this study. HRT may contribute to increased breast cancer risk but the evidence from this study is flawed and does not assist in the decision making process.
“Every woman has individual risk factors for breast cancer, a number of which are modifiable and she should discuss these with her physician when considering whether or not to use hormone replacement therapy so that an accurate assessment of risks and benefits may be made”
International Menopause Society Board member, Professor Anne Gompel (Paris) said:
“This paper is a meaningful analysis of the MWS by an expert in Epidemiology, and puts forward the fact that the numbers of patients included in a study does not guarantee the accuracy of results. I would advise everyone to read this paper closely, since it highlights some of the important requirements of a good quality epidemiological study. For example, Professor Shapiro shows that the real relative risk is actually difficult to evaluate when it is under 2.