Breast Cancer and HRT
Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France.
There is extensive epidemiological evidence that menopausal hormone therapy (MHT) increases breast cancer risk, particularly combinations of estrogen and progestagen (EP). We investigated the effects of the specific formulations and types of therapies used by French women. Progestagen constituents, regimen (continuous or sequential treatment by the progestagen), and time interval between onset of menopause and start of MHT were examined.
We conducted a population-based case-control study in France in 1555 menopausal women (739 cases and 816 controls). Detailed information on MHT use was obtained during in-person interviews. Odds ratios and 95% confidence interval adjusted for breast cancer risk factors were calculated.
We found that breast cancer risk differed by type of progestagen among current users of EP therapies. No increased risk was apparent among EP therapy users treated with natural micronized progesterone. Among users of EP therapy containing a synthetic progestin, the odds ratio was 1.57 (0.99-2.49) for progesterone-derived and 3.35 (1.07-10.4) for testosterone-derived progestagen. Women with continuous regimen were at greater risk than women treated sequentially, but regimen and type of progestagen could not be investigated independently, as almost all EP combinations containing a testosterone-derivative were administered continuously and vice-versa. Tibolone was also associated with an increased risk of breast cancer. Early users of MHT after onset of menopause were at greater risk than users who delayed treatment.
This study confirms differential effects on breast cancer risk of progestagens and regimens specifically used in France. Formulation of EP therapies containing natural progesterone, frequently prescribed in France, was not associated with increased risk of breast cancer but may poorly protect against endometrial cancer.
HRT in the menopause is very safe, in spite of the frequent scare campaigns in the press. More and more studies are proving the point. Most of these studies refer to the standard HRT. The natural HRT I use is even safer (see pages on BHRT and Evidence.) The latest very large study is available below:
From the Article by Prof. John Studd, one of the top hormone experts:
HRT is safe
In spite of the press reports stressing bad news, virtually all claims of major adverse effects from the WHI study have been reconsidered even by the investigators. It seems quite clear that the reported major side-effects of breast cancer, stroke and heart attacks occurred in women who started the wrong dose of HRT over the age of 60. In women who started below the age of 60 there were fewer heart attacks, fewer deaths, fewer osteoporotic fractures and even less breast cancer in this study. It is probable that the one residual side-effect is a small 1% extra lifetime risk of developing breast cancer, but this is no more than the breast cancer risk of being overweight, drinking wine, having no children or even taking statins.
- © 2010 The British Menopause Society
This appeared in the International Menopause Association recent update on HRT use (normal synthetic HRT):
Women should be reassured that the possible increased risks of breast cancer associated with HRT are small (less than 0.1% per annum, or an incidence of <1.0 per 1000 women per year of use), and less than the increased risks associated with common lifestyle factors such as obesity and alcohol consumption. Randomized controlled data from the WHI study demonstrated no increased risk in first-time users of HRT during the 5–7 years since initiation of treatment. The majority of subjects in the WHI study were overweight or obese, which may have affected their basal breast cancer risk.
Data from the WHI and the Nurses’ Health Study suggest that long-term, estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in North American women. Recent European observational studies suggest that the risk may increase after 5 years.
European observational studies suggest that a difference in risk between estrogen-only and combined estrogen– progestogen therapy is seen with some categories of progestogens but not with natural progesterone derivatives.
CLIMACTERIC 2011;14:302–320. Updated IMS recommendations on postmenopausal hormone therapy
Unopposed oestrogen and breast cancer.
British Med Journal Sept 2012
For the subgroup of women who had undergone hysterectomy and who received unopposed 17-β-estradiol/control we found a significant reduction in the combined endpoint of mortality or breast cancer in the treatment group.
This is in accordance with findings from the Women’s Health Initiative, where 10 739 women who had undergone hysterectomy were randomised to conjugated equine oestrogen or placebo 0.625 mg/day; all women (irrespective of age) in the conjugated equine oestrogen arm experienced a reduced risk of breast cancer (hazard ratio 0.77, 95% confidence interval 0.62 to 0.95).35 Furthermore, in the present study, there seemed to be a non-significant increase in breast cancer in the treatment arm after discontinuation of treatment (hazard ratio 0.58 after 10 years and 0.90 after 16 years) predominantly in the women aged more than 50, although none of these differences were statistically significant. Previously, starting hormone replacement therapy early has been considered unfavourable for breast cancer,36 37 and conclusions cannot be drawn from the presented data. A recent trial, the Kronos Early Estrogen Prevention Study,38 may reveal more on whether timing, type of oestrogen, and route of being administered can account for the differences across previous studies.
We found a borderline interaction with age and breast cancer suggesting that hormone replacement therapy reduces the risk of breast cancer in women aged less than 50 (or at least it was not harmful), but data were not consistent over time. We find it difficult to draw firm conclusions from these data.
Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: Part 4. The Million Women Study.
Visiting Professor of Epidemiology, Department of Epidemiology, University of Cape Town, Cape Town, South Africa.
Background Based principally on findings in three studies, the collaborative reanalysis (CR), the Women’s Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3). Objective To evaluate the evidence for causality in the MWS. Methods Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET. Results Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported. Conclusion HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.
Postmenopausal hormone therapy and the risk of breast cancer: a contrary thought.
Oregon Health & Science University, Portland, OR 97239, USA. firstname.lastname@example.org
The most important unanswered question regarding postmenopausal hormone therapy and the risk of breast cancer is whether hormone therapy initiates the growth of new breast cancers or whether the epidemiologic data reflect a hormonal impact on preexisting tumors. In this perspective I review the evidence favoring hormonal effects on preexisting tumors and suggest that exposure to combined estrogen and progestin is beneficial, causing greater differentiation and earlier detection of breast cancers.
A summary of the research;
HRT and breast cancer risk: a realistic perspective.
A new analysis from the Women’s Health Initiative included data on breast cancer incidence over a 11-year period from the randomized trial of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) and a subsequent observational follow-up. The conclusions were that CEE/MPA use was associated with an increase in both breast cancer incidence and mortality. We have concerns over the validity of their statistical analyses, as adjustments for baseline characteristics or for multiple comparisons demonstrate no significant differences in incidence between those allocated to CEE/MPA or placebo. We suspect that the apparent increase in mortality is the result of surveillance and detection bias rather than a true cause and effect. Even if such an effect were true, mortality from breast cancer would still be a very rare event. We also question the clinical relevance and applicability of their findings. The data over the 11 years show no increased risk of breast cancer with CEE/MPA in women who had not previously used hormone replacement therapy (HRT), and the vast majority of women on HRT would not be prior users at initiation. It should be remembered that women using CEE alone showed a significant decrease in breast cancer risk in the WHI trial and follow-up. Even if combined estrogen?progestogen HRT did cause an increase in breast cancer risk, and this is not proven, the magnitude of that risk is small, and less than that risk seen with many lifestyle factors. HRT is a benefit, not a risk, for those women requiring it.
- [PubMed – indexed for MEDLINE]
A study of women who took estrogen for about six years and then stopped has found they were less likely to develop breast cancer and die from the disease than those who never used hormone replacement therapy. The follow-up study of more 7,500 women from the Women’s Health Initiative trial found women…
A study of women who took estrogen for about six years and then stopped has found they were less likely to develop breast cancer and die from the disease than those who never used hormone replacement therapy.
The follow-up study of more 7,500 women from the Women’s Health Initiative trial found women who took the oral estrogen-only treatment were more than 20% less likely to develop breast cancer and remained significantly less likely to die from the disease almost five years after stopping treatment.
The results of the study have been published online in the journal The Lancet Oncology. They contradict the findings of a previous study that suggest there is a definitive link between hormone therapy and the risk of breast cancer.
Taking estrogen alone, however, still carries an increased risk of blood clots and stroke. And the decreased risk of breast cancer was not found among women with a family history of the disease, or with benign breast cancer.
“These latest results should provide reassurance about breast safety of estrogen use for durations of about five years for women with a hysterectomy seeking relief from postmenopausal symptoms,“ said lead author Garnet Anderson, from the Fred Hutchinson Cancer Research Center in Seattle.
In 1993, the Women’s Health Initiative trial of estrogen was established to investigate the effects of conjugated equine estrogen on chronic disease. Nearly 11,000 postmenopausal women aged 50 to 79 who had previously had a hysterectomy received estrogen or a placebo for almost seven years. The trial was stopped in 2004 – earlier than planned – because of an increased risk of stroke and blood clots.
In this new analysis, the researchers have reported the overall effects of estrogen use on breast cancer rates and mortality after an extended follow-up of 7,645 women (78% of the original surviving members), who were tracked from March 2005 until August 2009.
The researchers found there was a 23% reduction in the incidence of invasive breast cancer compared with women who took the placebo. Among women in the estrogen group who did develop breast cancer, there was a 63% reduction in deaths from the disease compared with those in the placebo group.
The lower risk of breast cancer was restricted to women without a history of benign breast disease or a strong family history of breast cancer.
The team cautioned: “Our data do not support the use of estrogen for breast cancer risk reduction in light of the lack of benefit noted in populations at higher risk (including those with a strong family history of breast cancer or benign breast disease) and the additional risk of stroke and blood clots.”
Jane Elliott, president of the Australasian Menopause Society (AMS) and a lecturer in obstetrics and gynaecology at the University of Adelaide, said the results were reassuring for Australian women, many of whom use hormone replacement therapy for up to five years.
“It is also encouraging that the study found the protective effect of the therapy extended for years after women stopped taking it,“ Dr Elliott said. “But we note that the lower risk of breast cancer was restricted to women without a history of benign breast disease or a strong family history of breast cancer, and the study used one particular oral form of estrogen.
“Findings only apply to women with a hysterectomy as those without a hysterectomy are not usually prescribed estrogen-only treatment; instead progesterone is added to the estrogen to prevent womb cancer.
It was disappointing, however, that the report came amid a sharp reduction in the number of hormone replacement therapy options for Australian women, she said. Last month, 12 current and past presidents of the AMS wrote to Catherine King, the Parliamentary Secretary for Health and Ageing, to express concern about the limited options for women suffering from disabling symptoms.
The letter warned that some women were resorting to untested medicines because they could not get proven products at an affordable price.
“Estrogen implants are no longer on the market and an Australian-developed estradiol transdermal spray has been approved by the [Food and Drug Administration] in America but is not approved for use here,” Dr Elliott said.
Hormone replacement therapy and cancer? Let’s get the facts straight.
Dr Henry Burger, endocrinologist & Emeritus Director Prince Henry Institute.
- The authors of the 2003 Million Women Study were wrong to conclude their investigation proved that hormone replacement therapy caused cancer, according to a series of articles published this week in the Journal of Family Planning and Reproductive Health.Endocrinologist and paper co-author Professor Henry Burger explains that there may be a modest increase in cancer risk for some hormone therapy users but it’s important menopausal women get clear and accurate information about the risks and benefits of this therapy:
- During menopause, the ovaries effectively stop making estrogen. Over the two to three year lead-up to a woman’s final spontaneous menstrual period, the estrogen levels in her blood have dropped by around 90%. Around one in five women don’t experience any symptoms. But the same proportion suffers from severe symptoms such as hot flushes, night sweats (which destroy the quality of her sleep) and vaginal dryness (which makes intercourse uncomfortable). Hormone replacement therapy aims to give back some estrogen to prevent or relieve these symptoms. It’s 90 to 95% effective, which is far greater than other treatments.
- What did the 2003 Million Women Study claim about the link between the use of hormone replacement therapy and cancer?
- This study of one million women who presented for routine mammograms in the United Kingdom asked participants to complete a questionnaire about hormone therapy and the risk of breast cancer. The researchers looked at the rate at which breast cancer was diagnosed in these women and their history of using hormone replacement therapy.The authors claimed the study definitively proved hormone therapy caused breast cancer. And this is the focus of the papers we released this week, led by Professor Samuel Shapiro(I was a co-author). We asked whether the Million Women Study authors came to a valid conclusion.Our analysis found it did not meet a number of requirements for a valid epidemiological study and therefore the authors were not justified in claiming this was the final proof that hormone therapy caused breast cancer.It’s important to be clear that we’re not disputing the possibility of a link between hormone therapy and breast cancer. What we’re disputing is the use of the Million Women Study data to prove that link. The Million Women Study is what’s called an observational study, which cannot prove causality – it can only prove association.
- What impact did the 2003 study have on the use of hormone therapy?
- It’s difficult to say because not long before that, the Women’s Health Initiative (WHI) published a randomised control trial of hormone therapy, which resulted in a profound drop in the use of this therapy – around 80% in the United States.
- There’s no doubt the Million Women Study added to the fear and anxiety generated by the American WHI study.What is known about the actual links between hormone therapy and cancer?It’s important to put any risk on the context of the overall analysis of benefit and risk.If you’re looking at the benefits, hormone therapy can relieve or cure the symptoms of menopause in the 20% of women who have severe symptoms. It’s also suitable for women who have moderate symptoms and would rather have them treated. So 30 to 40% of menopausal women could benefit from the therapy.The second benefit it a reduction in the risk ofosteoporotic fracture. Around the time of menopause, with the fall in estrogen, there’s a loss of bone tissue, which increases the risk of fracture. Hormone therapy has been shown to prevent or substantially reduce that loss of bone and therefore reduce the risk of fracture.A third demonstrated benefit is that oral therapy reduces the risk of colorectal cancer. It actually reduced the number of colorectal cancers in theWHI study by almost the same number as the increase in breast cancers.TheWHI study also showed there was a reduction in the incidence of diabetes. And there’s also growing evidence to show it may reduce her risk of dementia and heart disease.What are the risks of hormone therapy?
There is a small increase in the risk of Venous thromboembolism, if the hormone is given orally. This isn’t present if it’s given through the skin via an estrogen patch.
There’s also a small increase in the risk of breast cancer. That risk varies depending on the duration of the therapy, the type of therapy and her other risk factors.
As an endocrinologist, how do you tackle this issue of balancing risk and benefits with your patients?
When I see patients with severe symptoms of menopause, I describe the benefits and the risks. I tell her there is a lot of evidence to suggest hormone therapy increases the risk of breast cancer, then we’ll look at her individual risk. If she’s a very slim lady, then her risks are probably a bit higher. Likewise, if she has a family history of breast cancer, her baseline risk will be slightly higher.
I’ll tell her it’s unlikely that hormone therapy will increase her risk of breast cancer if she uses it for less than five years.
I also tell her that in order to put that risk in perspective we can look at other things that increase her risk of breast cancer – being overweight or obese confers a higher risk of breast cancer than hormone therapy. As does an early first period (before 12 years), a late menopause, and childlessness. Hormone therapy falls into the lower end of a series of risk factors, which can increase a woman’s risk of breast cancer.
I tell her she has to weigh all of this up for herself in terms of her perception of how bad her symptoms are versus how much that risk is. And most women will say this isn’t a risk that worries them and they’re happy to take it.
What advice would you give to regulatory authorities about revising their clinical guidelines for prescribing hormone therapy?
Regulatory authorities in Australia and around the world used the WHI and the Million Women Study to formulate their policies and advise clinicians and women about the use and duration of hormone therapy. The conclusions of these studies aren’t valid so the regulatory authorities must acknowledge this and adjust their advice accordingly.
Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase.
Hôpital Saint-Louis, Paris, France.
The MISSION Study (Menopause: Risk of Breast Cancer, Morbidity and Prevalence) is a historical-prospective study with random patient selection to determine breast cancer incidence in postmenopausal women with or without hormone replacement therapy (HRT). The first prospective follow-up phase started on 5 January 2004 and the cut-off date for data collection was 30 June 2006.
Patients were divided into two groups: an ‘exposed group’ of women on HRT regimens commonly prescribed in France or who had stopped < or =5 years previously; and an ‘unexposed group’ of women who had never received HRT or stopped >5 years previously. In total 6755 patients were included; and prospective data were available for 4949 patients: 2693 in the exposed group and 2256 in the unexposed group. Women in the exposed group were younger, less overweight, and had fewer first-degree family histories of breast cancer than women of the unexposed group. Mean duration of HRT exposure was 8.3 years, with 31% being exposed for > or =10 years.
The incidence of new breast cancer cases was 0.64% in the exposed group and 0.70% in the unexposed group (relative risk RR(exposed/unexposed) = 0.914, 95% confidence interval = 0.449-1.858; not modified when adjusted for age). Mean age at breast cancer diagnosis was similar in both groups. Breast cancer incidence in the exposed group was not significantly affected by the route of estradiol administration (cutaneous 0.69%; oral 0.52%) or HRT type (estradiol alone 0.28%; estradiol + progesterone 0.40%; estradiol + synthetic progestin 0.94%).
No evidence was found for an increased risk of breast cancer in women exposed to HRT compared with non-exposed women.
- [PubMed – indexed for MEDLINE]
J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108.
Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.
Unit of Endocrinological Gynecology, Sant’Anna Gynecological Hospital, Corso Spezia 60, 10126 Torino, Italy. email@example.com
Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.
====================================================================================Published Online: 07 March 2012
Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trialProf Garnet L Anderson PhD a , Prof Rowan T Chlebowski MD b, Aaron K Aragaki MS a, Prof Lewis H Kuller MD c, Prof JoAnn E Manson MD d, Prof Margery Gass MD e, Elizabeth Bluhm MD f, Prof Stephanie Connelly MD g, Prof F Allan Hubbell MD h, Prof Dorothy Lane MD i, Lisa Martin MD j, Prof Judith Ockene PhD k, Prof Thomas Rohan MBBS l, Prof Robert Schenken MD m, Prof Jean Wactawski-Wende PhD n
BackgroundBy contrast with many observational studies, women in the Women’s Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort.
MethodsBetween 1993 and 1998, the WHI enrolled 10 739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50—79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611.
FindingsAfter a median follow-up of 11·8 years (IQR 9·1—12·9), the use of oestrogen for a median of 5·9 years (2·5—7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62—0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61—1·02) and post-intervention phase effects (0·75, 0·51—1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13—0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39—0·97; p=0·04).
InterpretationOur findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer.
US National Heart, Lung, and Blood Institute; Wyeth