January 16, 2012

expert reaction to critique of Million Women Study

The authors of an article published in the Journal of Family Planning and Reproductive Healthcare criticised the conclusions of the Million Women Study, in relation to the link between hormone replacement therapy (HRT) and breast cancer.

Valerie Beral, Professor of Epidemiology and Director of the Cancer Epidemiology Unit, University of Oxford, said:

“HRT is one of the most important causes of breast cancer in the world and women can easily change their risk by stopping.

“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.”

Richard Peto, Professor of Medical Statistics & Epidemiology University of Oxford, said:

“”A. 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.

“B. 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.”

Professor Rod Baber, President-Elect of the International Menopause Society, 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.”

Professor Anne Gompel, International Menopause Society Board member, 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.

“There are other studies which do show risks and benefits for HRT, so I believe that the take home message is that, for a given woman, the important evaluation is her own risk. Recent papers on breast density, alcohol, obesity and exercise suggest that taking all these factors into account should help to identify which patients are at risk. HRT does not carry the same risk and benefit for each woman; some women will have increased risks, some will have only benefits, and this also applies to breast cancer.”

‘Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies – Part 4. The Million Women Study’ by Samuel Shapiro et al. published in Journal of Family Planning and Reproductive Healthcare on Monday 16th January.