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......

Does Estrogen-Only HRT Decrease Breast Cancer Risk? Nationally Recognized Endocrinologist Dr. Marina Johnson Weighs In

Does Estrogen-Only HRT Decrease Breast Cancer Risk? Nationally Recognized Endocrinologist Dr. Marina Johnson Weighs In

"....So here's Dr. Johnson's take-home message: "You don't need to delay starting HRT if you choose natural estradiol and progesterone over synthetic estrogens and progestins. Don't endure symptoms like hot flashes, insomnia, anxiety, depression, sexual dysfunction, mental confusion, and weight gain. Start HRT within 10 years of menopause for the most protection against Heart Disease, Alzheimer's and Osteoporosis.
"Avoid the increased heart attacks and strokes seen in WHI by choosing topical estrogen in the form of patches, gels, creams and mists that are available at any drug store. Pharmaceutical natural hormones (also called bioidentical hormones) are superior to compounded bioidentical hormones because they are required to meet higher standards for quality control and efficacy."

Read more in Dr. Johnson's book, "Outliving Your Ovaries: An Endocrinologist Weighs The Risks And Rewards Of Treating Menopause With Hormone Replacement Therapy" (http://www.outlivingyourovaries.com) (Eyesong Publishing, February 2011), which is available in paperback, e-book and can be shipped internationally. Use coupon code BZCWJDM5 for $5 off of the retail price with purchase at http://www.buydrmarinajohnsonbook.com.
Dr. Marina Johnson, a pharmacist and UCLA/USC-trained physician, is board-certified in Endocrinology and Internal Medicine.

Long-term Use of Estrogen Hormone Therapy Linked to Higher Risk for Breast Cancer « AACR News

Long-term Use of Estrogen Hormone Therapy Linked to Higher Risk for Breast Cancer « AACR News

• Risk increased as the duration of hormone therapy use increased.
• Death rate from breast cancer did not increase with hormone therapy use.

Clinical Oncology News - Zoledronic Acid Debate in Breast Cancer Continues

Clinical Oncology News - Zoledronic Acid Debate in Breast Cancer Continues

San Antonio—Long-term results of the ABCSG-12 trial and subanalyses of two recently presented Phase III trials provide further evidence that bisphosphonates can improve survival in breast cancer patients with low estrogen levels. The results of the studies, presented at the recent San Antonio Breast Cancer Symposium (SABCS), have convinced some doctors of the low estrogen hypothesis, but for others the water is still very murky.....


Weighing the Evidence
In recent years, some oncologists have been prescribing bisphosphonates off-label to treat breast cancer, and the new studies may sway more doctors to do so.
“The anticancer effects of adjuvant zoledronic acid are now well established in endocrine-responsive patients,” said Dr. Gnant.
Dr. Paterson added that “inhibition of osteoclast function with bisphosphonates has an effect on cancer growth in older women, and little effect in premenopausal women.”
For other doctors, however, the jury is still out. “Subanalyses are suspect,” said Dr. Vogl. “This is interesting, but we need to study it some more. But if they study it some more, Novartis will have lost its patent protection by the time that study comes out. Novartis has some interest in it [being approved] now.”

Dr. Paterson is a consultant for GlaxoSmithKline, Amgen, Roche and Nicomed and has received a grant for a clinical trial involving denosumab. Dr. Gnant disclosed relationships with AstraZeneca, Novartis, Pfizer, Sanofi, Roche, Schering and Amgen. Dr. Möbus disclosed relationships with Amgen, Novartis and Roche. Dr. de Boer disclosed a relationship with Novartis. Drs. Ingle and Dr. Vogl have no relevant disclosures.

Estrogen-Only Therapy May Reduce Breast Cancer Risk --Doctors Lounge

Medpage: LaCroix A, et al "Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial" JAMA 2011; 305: 1305-1314.

Blogger's Note: also see website for video

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New WHI Estrogen Analysis Shows Lower Breast Ca Risk

By John Gever, Senior Editor, MedPage Today

Published: April 05, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

• Explain that post-intervention follow-up of the WHI Estrogen-Alone Trial showed that both risks and benefits of unopposed estrogen largely disappeared after therapy stopped.
• Note that while the risk of breast cancer remained decreased for the intervention and post-intervention period combined, the decreased risk during the post-intervention period itself was not statistically significant.

In contrast to other studies of unopposed postmenopausal estrogen therapy, long-term follow-up of Women's Health Initiative (WHI) Estrogen-Alone Trial participants showed a persistent reduction in breast cancer risk, researchers said.

But other benefits and risks associated with use of conjugated equine estrogens (CEE) quickly dissipated after the therapy was stopped, according to Andrea Z. LaCroix, PhD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

"Considering the entire follow-up period, rates of total mortality and the global index of chronic diseases were essentially the same in the conjugated equine estrogen and placebo groups," LaCroix and co-authors wrote in the April 6 issue of the Journal of the American Medical Association.
"Statistically significant age interactions for conjugated equine estrogen use, suggesting greater safety and possible benefit among women in their 50s and potential harm among older women, were observed for coronary heart disease, total MI, colorectal cancer, total mortality, and the global index of chronic diseases," they added.

An editorial in the same issue suggested more caution in interpreting the breast cancer results.

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.

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.

Hot flash remedies: Estrogen may be the best answer - Health News Review

Hot flash remedies: Estrogen may be the best answer

Reviewed by Christine Norton, MA; Karen Carlson, MD; and Gary Schwitzer

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...."

extract: Estrogen's Dual Nature? Studies Highlight Effects on Breast Cancer

Note: to read full text $$$ (requires subscription)

abstract: The effect of estrogen vs. combined estrogen-progestogen therapy on the risk of colorectal cancer

"While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk."

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. 

Revisiting the Women’s Health Initiative Estrogen-Alone Trial - hcp.obgyn.net

Note: scroll to bottom for addition references

Lengthened WHI Follow-Up: Postmenopausal Estrogen Therapy - Women's Health Journal Watch

Editorial (excerpt) Short-term Use of Unopposed Estrogen, April 6, 2011

Note: Editorial is $$$ (requires payment)

JAMA full free access: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy-randomized control trial

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

(timeline) Landmarks From Two Decades of Study - NYTimes.com

By THE NEW YORK TIMES

Published: April 9, 2011

1991 National Institutes of Health embarks on a study of menopause hormones after observational data suggest that women who use hormones have lower rates of heart disease.

Related

• The Women’s Health Initiative and the Body Politic (April 10, 2011)

2002 Part of the Women's Health Initiative is stopped after women in the study taking estrogen plus progestin (E+P) show higher rates of heart attack, stroke and breast cancer. Millions of women abandon hormones overnight.
2003 Women taking E+P are not protected from mild memory loss; they are found to be at increased risk for developing dementia.
2004 The second W.H.I. hormone study is stopped one year early because women taking estrogen only show a small increased risk of stroke.
2006 An updated analysis of the estrogen-only trial shows hormone therapy does not increase the risk of breast cancer in postmenopausal women.
2007 Combined data from both hormone trials suggest that timing of therapy may affect risk; hormones may reduce heart disease in women who start therapy closer to menopause.
2009 Women using E+P for more than about five years double their annual risk of breast cancer. That risk is higher than previously thought.
2011 Follow-up of women in the estrogen-only study shows those who took just estrogen had 23 percent fewer breast cancers; younger estrogen users had 46 percent fewer heart attacks.
Sources: Women’s Health Initiative; New York Times reports