Articles disputing link between HRT and breast cancer are “ridiculous”BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e513 (Published 19 January 2012) Cite this as: BMJ 2012;344:e513
All rapid responses
I was surprised to read the emotional response in the BMJ by a renowned epidemiologist (Ref Kmietowicz) to the recent publication in the Journal of Family Planning and Reproductive Health Care of an article by Shapiro and colleagues (Ref Shapiro et al). This was a reanalysis of data from the so-called ‘Million Women’ study (Ref MWS), which raises important clinical concerns about the originally strongly stated conclusions of that study. I think it is essential that we see continuing debate about these complex epidemiological studies, where results conclusions are open to different interpretations.
Putting emotions aside, there are some problems with the original analysis of the Million Women study. This is not the absolutely perfect study that has predicted precisely all possible biases, although the authors made extensive attempts to address such biases. This type of study cannot make allowances for every possible bias, and as we are all aware ‘big is not necessarily better’ when biases are present. The statistically significant differences seen in the findings of MWS are still very small, and it does not take much erroneous consideration for some potential biases to considerably change the final statistics.
It is the traditional scientific way to have debate about the findings of controversial studies, and, to me, it seems appropriate that the epidemiologists should set aside emotion and address the legitimate questions and criticisms of other scientists in the original journal to which the article was submitted
The epidemiologists have managed to raise fear among women in the general community about use of hormone replacement preparations, yet these therapies have an enormous impact on many aspects of wellbeing, such that the benefit-risk ratio for most individual women is very positive. I would really like to show the epidemiologists I know (who do not see any patients) the dramatic impact which this therapy can have on the quality of the lives of many menopausal women.
We should not forget that the much vaunted and highly criticized Women’s Health Initiative study showed a significant reduction in risk of breast cancer for women using oestrogen-alone hormone replacement therapy (ref WHI). I do not hear the epidemiologists trumpeting this!
Everything we do in this life carries risk. Please can we look realistically at what are the many potential benefits of HRT, and put them in perspective with individual risk. Let the debate continue – without emotion!
Ian S. Fraser
Professor in Reproductive Medicine
University of Sydney
Shapiro S, Farmer RDT, Stevenson JC, Burger HG, Mueck AO. J Fam Plann Reprod Health Care 2011. doi: 1136/jfprhc-2011-100229
Kmietowicz Z. Articles disputing link between HRT and breast cancer are “ridiculous” BMJ 2012;344:e513
Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003;362:419–427.
The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701–1712.
Competing interests: No competing interests
What really matters is the menopausal woman!
Yet again scientists and epidemiologists are publicly debating the controversies around the previously reported risks of HRT. Is this further publicity deserved? The impact of studies such as the Million Women Study1 and Women’s Health Initiative2 has been profound leading to significant reductions in the use of HRT. This has understandably affected millions of menopausal women globally who deserve to be fully informed of any doubts that may exist concerning the studies and should be aware of the debate.3-4
Ever since these publications were published the headlines in the popular press have been biased towards the ‘bad news’ messages, resulting in our patients feeling confused and under pressure to stop HRT. Following a recent web based survey 70% of women who came off their HRT were below the age of 50. More importantly had these women known what we know today, 45% would have stayed on treatment.5 We believe that the risk, if any is small and it is the view of the British Menopause Society that, when used appropriately, any risks are outweighed by the benefits for the majority of women.
We must not forget that at the centre of the current published arguments there are millions of women who want to be properly informed about whether they should be taking HRT. Further, there are likely to be thousands of doctors and nurses who want to be more knowledgeable and confident about prescribing HRT.
In recognition of the menopause having diverse consequences and in an attempt to improve the provision of essential information for women, the British Menopause Society has recently submitted recommendations to the Department of Health. The key recommendation is that women should, around the time of the menopause transition, have a formal assessment of their needs, including advice concerning lifestyle, diet and individualised discussion of the risks and benefits of any suitable hormonal therapies. The British Menopause Society advise that whilst this would require additional resources, the potential long term health gains would make this consultation highly cost effective in disease prevention terms.6
There two key areas that require addressing urgently are:
1) A robust understanding of the benefits and risks of HRT for patients and carers
Most women who have been taking HRT since the publication of WHI and MWS will have been doing so having weighed up the pros and cons of treatment. Many women, even if there were genuinely a small increased risk of breast cancer, would accept this, if they could have a good quality of life through relief of the debilitating symptoms that invariably affect personal, social and wider quality of life.
The clear benefits in osteoporosis treatment and prevention have recently been included in a recommendation from the National Osteoporosis Society that HRT can be used as a first line agent for the treatment and prevention of osteoporosis in women under 60. 7
2) HRT is not a single drug as the press and our patients seem to have derived from the publicity.
HRT is a comprehensive suite of preparations and delivery routes produced by the pharmaceutical industry in response to women’s needs over more than 40 years of development, refinement and research. This research continues, even though research funding is a fraction of what it once was.8
Recently completed trials not only suggest that natural progesterone may not affect the risk of breast cancer and have a neutral effect,9 but also that soon to be released small studies of lower dose, endogenous-type hormone treatments given to recently menopausal women show great promise.10
The British Menopause Society feels that the research must continue. As the female population lives longer after the menopause we need to establish safe ways to prevent disease and maintain a high quality of life. This requires a trial to establish definitively the correct indications, patients and hormones for optimal postmenopausal health. 11 We should harness the wealth of knowledge from the debates around WHI and MWS to design this study rather than watch the arguments from the sidelines.
Nick Panay, Chairman of the British Menopause Society
Consultant Gynaecologist, Queen Charlotte's & Chelsea and Chelsea & Westminster Hospitals
Honorary Senior Lecturer, Imperial College London
Heather Currie, MAC member, British Menopause Society
Associate Specialist Gynaecologist, Dumfries and Galloway Royal Infirmary,
Edward Morris, MAC member, British Menopause Society
Consultant, Obstetrics & Gynaecology, Norfolk & Norwich University Hospital
1) Million Women Study Collaborators. Breast cancer and HRT in the Million Women Study. Lancet 2003; 362: 419-427.
2) Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s health initiative randomised controlled trial JAMA 2002; 288(3): 321-33.
3) Shapiro S, Farmer RD, Stevenson JC, Burger H, Mueck AO Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies Part 4: The Million Women Study Family Planning 2012. Jan 16 Ahead of Print
4) Shapiro S, Farmer RD, Mueck AO, Seaman H, Stevenson JC. Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 2. The Women's Health Initiative: estrogen plus progestogen. Fam Plann Reprod Health Care. 2011 Jul;37(3):165-72.
5)Cumming GP, Currie HD, Panay N, Moncur R, Lee AJ. Stopping hormone replacement
therapy: were women ill advised? Menopause Int. 2011; 17(3): 82-7.
6)British Menopause Society Council. Modernizing the NHS: observations and recommendations from the British Menopause Society. Menopause Int. 2011 Jun;17(2):41-3.
7)Bowring CE, Francis RM. National Osteoporosis Society’s Position Statement on hormone replacement therapy in the prevention and treatment of osteoporosis. Menopause International 2011; 17: 63-65.
8) Panay N, Ylikorkala O, Archer DF, Rakov V, Gut R, Lang E. Ultra low-dose estradiol and norethisterone acetate: Effective menopausal symptom relief. Climacteric 2007; 10(2): 120 131.
9) Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol. 2008; 26(8):1260-8.
10) Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N. KEEPS: The Kronos Early Estrogen Prevention Study. Climacteric. 2005; 8(1): 3-12.
11)Panay N, Fenton A. Has the time for the definitive, randomized, placebo-controlled HRT trial arrived? Climacteric. 2011 Apr;14(2):195-6.
Competing interests: Nick Panay (NP), Eddie Morris (EM) and Heather Currie (HC) have received sponsorship for lectures and advisory work performed for pharma companies. NP and HC have received educational grants for meetings and NP has received funding for pharmaceutical trials.
The validity of many associations from observational studies is often questioned. We know from the history of postulated associations between HRT and coronary heart disease and CRP and cardio vascular diseases, just two examples out of many, where the scientific community, at one point in time, came to what was probably an incorrect conjecture. This has happened in the past and will undoubtedly happen in the future. It is completely nonsensical not to recognise this.
As scientists we must accept there is uncertainty. Scientific integrity is questioned by the public for good reason. Not only for the fact that they have been mislead by spurious associations. But, probably more so because uncertainty is rarely acknowledged. Practicing clinicians are moving away from paternalist care, isn’t it time that scientists did this too?
So, when Klim McPherson, visiting professor of public health epidemiology at the Nuffield Department of Obstetrics and Gynaecology at the University of Oxford, stated regarding a re-analysis of data on the association between HRT and breast cancer:
“If the scientific consensus can incorporate uncertainty about this relationship then people can market and prescribe HRT and downplay its importance”
Without even reading the re-analysis, I wonder why the scientific community is being told to suppress any concerns over uncertainty. Why, is this particular association immune to the uncertainties and biases that are inherent in observational studies? Surely, this association is not proven without any doubt; where there is any (however small) possibility for uncertainty, well conducted scrutiny must be allowed and encouraged.
If uncertainties, however small, are covered up and not relayed to the public, then mistrust can only increase. Honesty is the best option.
Competing interests: No competing interests
Yes, it is a disgrace that some individuals keep on re-analysing old data in the vain attempt to prove their own theories in the face of over whelming evidence that use of progestogens and oestrogens increases breast cancer.1 Professor Klim McPherson is absolutely right - it is ridiculous, but it is the same situation for the contraceptive pill. How can doctors be unaware that use of these hormones, whether for contraception or HRT, has caused epidemics of cancers? Breast and cervical screening were introduced as a consequence.
The percentage increases in breast cancer registration rates in England and Wales has matched increases in hormone use since 1962 for each 10 year age group for women aged 25 to 65. There were some decreases in both in the 1970s due to awareness of increased risk of vascular diseases and again in the late 1990s due to increased risk of venous thrombosis from newer progestogens. The largest increases have been in the age groups currently taking hormones, especially in women likely to have taken both OCs and HRT with a peak in the older women when mass screening was first introduced.
Johnson and colleagues found that the average doubling time of breast cancers is about one month but occasionally some really rapid tumours double within one week.2 Chlebowski and his WHI co-authors found that relatively short-term progestogen/oestrogen use increased incident breast cancers, which were diagnosed at a more advanced stage compared with placebo use, and increased abnormal mammograms.3 The increased risk of breast cancer declined markedly soon after discontinuation of the combined hormones and was unrelated to changes in frequency of mammography.4 Also deaths from both breast and lung cancers doubled in progestogen/oestrogen users.5
If randomised studies have faults, it is of underestimating risks because of lack of never users as most women used hormones before randomisation. This leaves few genuine never users as reference controls. How can anyone think it is more important to suppress symptoms (which are easily treated by safe, simple and physiological means in my experience) than to prevent morbidity and death from increases in cancers, and vascular and mental illnesses? Is the aim of the well-oiled pro-hormone publicity machine to increase breast cancer deaths again?
1 Kmietowicz Z. Articles disputing link between HRT and breast cancer are “ridiculous”. BMJ 2012; 344:e513.
2 Johnson AE, Bennett MH, Cheung CWD, et al. The management of individual breast cancers. The Breast 1995; 4: 100-111. p3
3 Chlebowski RT, Hendrix SL, Langer RD, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2003;289:3243-53.
4 Chlebowski RT, Kuller LH, Prentice RL, et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. JAMA 2010;304:1684-92
5 Chlebowski RT, Schwartz AG, Wakelee H, et al ; Women's Health Initiative Investigators. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243-51.
Competing interests: No competing interests