HRT Risk Holds Steady Based on Updated Review - in OB/Gyn, HRT from MedPage Today

HRT Risk Holds Steady Based on Updated Review - in OB/Gyn, HRT from MedPage Today

Action Points

• A systematic review of papers published since 2002 (post-WHI study) found that the risks of hormone replacement therapy still outweighed any benefits in primary prevention of chronic conditions.
• Point out that both estrogen plus progestin and estrogen alone prevented fractures, but increased the risk of stroke, thromboembolic events, gallbladder disease, and urinary incontinence.

paywalled: 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 trial : The Lancet Oncology

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 trial : The Lancet Oncology

 Interpretation

Our 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.

Commentary: Oestrogen and breast cancer: results from the WHI trial : The Lancet Oncology

Oestrogen and breast cancer: results from the WHI trial : The Lancet Oncology

"In The Lancet Oncology, the Women's Health Initiative (WHI) investigators report1 that receipt of conjugated equine oestrogen for a median of 5·9 years reduced the risk of invasive breast cancer by 23% compared with placebo (151 cases in 5310 women who received oestrogen vs 199 cases in 5429 controls; p=0·02). Women who did develop breast cancer after receipt of oestrogen had significantly reduced breast cancer-specific mortality (six deaths in the oestrogen group vs 16 deaths in controls; p=0·03) and all-cause mortality (30 deaths vs 50 deaths; p=0·04). This preventive effect occurred at all ages and continued beyond the period of oestrogen use, a carryover effect also noted in prevention trials of tamoxifen.2 ....Although modest, the WHI results are significant and raise important questions about their disparity with many observational studies and the mechanism of reported benefit with oestrogen therapy......

abstract: Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression

 http://cancerres.aacrjournals.org/content/early/2012/04/17/0008-5472.CAN-11-2619.abstract
  
Abstract

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell cycle regulators. However, epidemiologic studies evaluating hormone therapy (HT) use and colorectal cancer risk by the status of cell cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between HT use and colorectal cancer risk differs by the molecular pathological status of microsatellite instability (MSI) and expression of cell cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between HT use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105520 postmenopausal women. We found a difference between HT use and colorectal cancer risk according to CDKN1A expression (p-value for heterogeneity=0.01). Current HT use was associated with a reduced risk for CDKN1A-nonexpressed (multivariate relative risk (RR)=0.61, 95% confidence interval (CI), 0.46-0.82), but not for CDKN1A-expressed (RR=1.32, 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed, but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between HT use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular epidemiology findings suggest a preventive effect of HT against colorectal carcinogenesis which depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.

abstract: Hormone Therapy and Different Ovarian Cancers: A National Cohort Study (postmenopausal women/does not include reference to clear cell ovarian)

 Blogger's Note: the abstract makes no reference to clear cell ovarian, given the number of women followed this omission (in the abstract) is curious


Hormone Therapy and Different Ovarian Cancers: A National Cohort Study

Abstract

Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. 

Using Danish national registers, the authors identified 909,946 women who were followed from 1995–2005. The women were 50–79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. 

Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers, including information about tumor histology......... In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. 

Compared with never users, women taking unopposed oral estrogen therapy had increased risks of both serous tumors and endometrioid tumors but decreased risk of mucinous tumors. Similar increased risks of serous and endometrioid tumors were found with estrogen/progestin therapy, whereas no association was found with mucinous tumors. 

Consistent with results from recent cohort studies, the authors found that ovarian cancer risk varied according to tumor histology. The types of ovarian tumors should be given attention in future studies.

Postmenopausal hormone therapy and ductal carcinoma in situ: A population-based case–control study

Postmenopausal hormone therapy and ductal carcinoma in situ: A population-based case–control study: Publication year: 2012

Source:Cancer Epidemiology

Background and aim:

The relationship between hormone therapy (HT) and invasive breast cancer has been extensively investigated, but the relationship between HT and in situ breast cancer has received relatively little attention. We examined the relationship between HT and ductal carcinoma in situ (DCIS) among postmenopausal women who participated in a population-based case–control study in Connecticut, USA.

Methods: 

This analysis included 1179 post-menopausal women (603 controls and 576 cases), who comprised a subset of a population-based case–control study that included all incident cases of breast carcinoma in situ (BCIS) in Connecticut and frequency-matched controls by 5-year age intervals.

Results: 

We found no association between DCIS and ever use of any HT (adjusted odds ratio (OR)=0.85, 95% confidence interval (CI): 0.65–1.11); of estrogen alone (adjusted OR=0.93; 95% CI: 0.68–1.29) or of estrogen and progesterone (adjusted OR=0.75; 95% CI: 0.52–1.08). There was also no association between DCIS and current use of these hormones. In addition, estimated risk of DCIS did not increase with duration of use of these preparations. Conclusions: These results add to a small literature that remains inconclusive. To determine whether HT poses risk of in situ breast cancer, larger studies with greater power and precise control of important covariates (e.g., mammography screening) are needed, as are meta-analyses of available data.

Medical News:Estrogen Benefit in Breast Cancer Affirmed - in Oncology/Hematology, Breast Cancer from MedPage Today

Medical News:Estrogen Benefit in Breast Cancer Affirmed - in Oncology/Hematology, Breast Cancer from MedPage Today

Action Points

• Explain that reduced breast cancer risk with use of estrogen-only hormone therapy after hysterectomy persists long term.
• Point out that the benefit was concentrated largely among low-risk groups, such as those without benign breast disease or a family history of breast cancer.

The Lancet Oncology: 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 trial

The Lancet Oncology, Early Online Publication,  

7 March 2012

doi:10.1016/S1470-2045(12)70075-XCite or Link Using DOI

 Feature

The Women's Health Initiative

Women who use the oestrogen-only form of hormone replacement therapy (HRT) appear less likely to develop breast cancer in the longer term, according to new research published in The Lancet Oncology. A follow-up study of over 7500 women from the Women's Health Initiative trial who took oestrogen for about 6 years and then stopped has found that they are over 20% less likely to develop breast cancer and remain significantly less likely to die from the disease than those who never used HRT, a period of nearly 5 years after stopping treatment. The findings are discussed further in a Comment.

 Summary

Background

By 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.

Methods

Between 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.

Findings

After 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).

Interpretation

Our 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.

2012 Hormone Therapy Position Statement of the North American Menopause Society (PDF/repost)

POSITION STATEMENT The 2012 Hormone Therapy Position Statement of The North American Menopause Society

abstract: Unopposed estrogen and estrogen plus progestin menopausal hormone therapy and lung cancer risk in the NIH-AARP Diet and Health Study Cohort

Abstract

PURPOSE:

Previous studies have reported that lung cancer risk may be decreased, increased, or unaffected by prior use of menopausal hormone therapy (MHT).

CONCLUSIONS:

Our results failed to support any substantial alterations in lung cancer risk associated with use of either unopposed estrogen or estrogen plus progestin MHT, even when detailed exposure measures and other risk predictors were considered.

abstract: Screening Mammography Use among Current, Former, and Never Hormone Therapy Users May Not Explain Recent Declines in Breast Cancer Incidence

Conclusions:
Differential screening mammography rates by HT use do not explain invasive breast cancer incidence declines. Our data suggest discontinuing HT has an immediate effect on breast cancer rates, lending support to the mechanism that cessation leads to tumor regression.

Impact:
Studies examining the influence of a changing exposure in relation to outcomes should account for varying exposures, individuals' characteristics, as well as screening methods and frequency.

ecancernews: Researchers defend HRT breast cancer (The Million Women Study)study

Million Women Study Wrong, Group Says - in Endocrinology, Menopause from MedPage Today

"A study long used to establish causal links between hormone replacement therapy (HRT) and breast cancer is severely flawed, a group of epidemiologists have charged. The observational Million Women Study (MWS), conducted in the U.K., doesn't adequately satisfy several criteria for causality -- including information bias, detection bias, and biological plausibility -- and thus can't be used to conclude that HRT causes breast cancer, according to Samuel Shapiro, PhD, of the University of Cape Town in South Africa, and colleagues.
"HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does," they wrote in the Journal of Family Planning and Reproductive Healthcare.
Several experts not involved in the study, however, have emphasized that they're well aware of the limitations of observational studies such as the MWS, and that the totality of evidence thus far has shown a strong association between HRT and breast cancer....."

"The analysis of the Million Women Study is the latest in a series of four papers by the Shapiro group exploring the credibility of three studies -- the MWS, the Women's Health Initiative (WHI), and the collaborative reanalysis (CR) -- that causally linking HRT, particularly estrogen plus progestogen therapy, with breast cancer.
The earlier papers similarly found that neither the CR nor the WHI could satisfy criteria for establishing causality...."

published Oct 2011 - full free access: The Role of Hormonal Therapy in Gynecological Cancers-Curren... : International Journal of Gynecological Cancer

Abstract (and full free access to full paper)

Many gynecological cancers, including epithelial and stromal ovarian cancers; endometrial carcinomas; and some gynecological sarcomas, in particular endometrial stromal sarcomas, express estrogen and/ or progesterone receptors. Hormonal therapy, typically progestogens or tamoxifen, is commonly prescribed to patients with potentially hormone-sensitive recurrent or metastatic gynecological cancers with very variable response rates and clinical benefit reported. Aromatase inhibitors are now widely used to treat postmenopausal women with hormone receptor-positive breast cancers as they have greater activity than tamoxifen and are generally better tolerated. The role of aromatase inhibitors in gynecological cancers is uncertain and has not been well studied, although they do appear to be active. The current evidence to support the use of hormonal therapies including aromatase inhibitors in gynecological cancers is reviewed, and the gaps in our knowledge highlighted.

Bioidentical hormone therapy: Clarifying the misconceptions

abstract #1501: Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer? | 2011 ASCO Annual Meeting Abstracts

abstract: UK - Hormone replacement therapy and women with premature menopause - A cancer survivorship issue.

Abstract

The importance of addressing survivorship issues has been emphasised in recent years. As cancer therapies improve there is a growing population of cancer survivors, which includes many women with premature menopause. Women who are premenopausal at the time of their cancer diagnosis may have specific survivorship issues to be addressed, including infertility, early menopause and sexual dysfunction. These factors can continue have a significant impact on the quality of life of these patients at long term follow up. Data for this Review were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms 'HRT', 'women/female cancer/tumour', 'menopause' and 'survivorship'. Abstracts and reports from meetings were excluded. Only papers published in English between 1980 and 2010 were included.

The aims of this review are to: • Address the hormonal factors which impact on cancer survivorship for premenopausal women • Review the debate for the role of hormone replacement therapy (HRT) in cancer survivors • Provide information for physicians and patients regarding the management of hormonally driven survivorship issues (for different tumour types), based on current evidence

The recommendations for practice are that HRT may be offered for the alleviation of vasomotor symptoms in cancer survivors who undergo premature menopause up to the age of natural menopause (51years in the UK).

HRT (including vaginal oestrogen preparations) is contraindicated in survivors of oestrogen receptor positive breast cancer and low grade endometrial leiomyosarcoma, where non-HRT alternatives should be considered to alleviate symptoms.

abstract: he impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation

Blogger's Note: this study would apply to all those who experience surgical menopause including those eg. Lynch Syndrome/other Syndromes - women at risk, it is unfortunate that all women undergoing cancer surgery - those affected by surgical menopause were not included in this study

 

CONCLUSIONS:

Women who undergo prophylactic salpingo-oophorectomy prior to menopause experience an increase in vasomotor symptoms and a decrease in sexual functioning. These symptoms are improved by HRT, but not to pre-surgical levels

abstract: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy — JAMA

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy

A Randomized Controlled Trial

Abstract

Context 

The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. 

Objective 

To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. 

Design, Setting, and Participants 

The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. 

Main Outcome Measures 

The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. 

Results 

The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). 

Conclusions 

Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. 

A decreased risk of breast cancer persisted. 

abstract: Differences in regional brain metabolism associated with specific formulations of hormone therapy in postmenopausal women at risk for AD (Alzheimer's disease)

"In conclusion, particular areas of relatively preserved metabolism were seen in women with more years of endogenous estrogen exposure, as well as in women taking estradiol-based formulations or estrogen therapies unopposed by progesterone, together suggesting regionally specific neuroprotective estrogenic effects."