abstract: Hormone replacement therapy and breast cancer

Hormone replacement therapy and breast cancer.

Howell A, Evans GD.

Genesis Prevention Centre, University Hospital of South Manchester, Manchester, M23 9LT, UK, anthony.howell@christie.nhs.uk.

Abstract

There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT.It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies. Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women.

Second Look at Estrogen in Breast Cancer Protection - NYTimes.com (re: WHI)

Blogger's Note: a similar issue was reported and largely ignored regarding colorectal cancer

“The data were absolutely missed. They weren’t emphasized, and they weren’t brought to the attention of oncologists,”...

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement - multinational/abstract/eletters/response

This version published online on June 21, 2010
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-2509

Submitted on November 24, 2009
Accepted on April 21, 2010

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement

Richard J. Santen^*, D. Craig Allred, Stacy P. Ardoin, David F. Archer, Norman Boyd, Glenn D. Braunstein, Henry G. Burger, Graham A. Colditz, Susan R. Davis, Marco Gambacciani, Barbara A. Gower, Victor W. Henderson, Wael N. Jarjour, Richard H. Karas, Michael Kleerekoper, Roger A. Lobo, JoAnn E. Manson, Jo Marsden, Kathryn A. Martin, Lisa Martin, JoAnn V. Pinkerton, David R. Rubinow, Helena Teede, Diane M. Thiboutot, and Wulf H. Utian
Division of Endocrinology and Metabolism (R.J.S.), Department of Obstetrics and Gynecology (J.V.P.), University of Virginia, Charlottesville, Virginia 22908; Tufts University School of Medicine (R.H.K.), Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Jean Hailes Research Centre (H.T.), School of Public Health, Melbourne, Australia 3168; Prince Henry's Institute of Medical Research (H.G.B.), Monash Medical Centre, Melbourne, Australia 3168; Department of Medicine/Women's Health Program (S.R.D.), Monash University, Melbourne, Australia 3181; Departments of Health Research and Policy (Epidemiology) and of Neurology and Neurological Sciences (V.W.H.), Stanford University, Stanford, California 94305; Departments of Pathology and Immunology (D.C.A.) and Surgery (G.A.C.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Nutrition Sciences (B.A.G.), University of Alabama at Birmingham, Birmingham, Alabama 35294; St. Joseph Hospital (M.K.), Internal Medicine, Reichert Health Center, Ypsilanti, Michigan 48197; Division of Immunology and Rheumatology, Ohio State University School of Medicine (W.N.J., S.P.A.), Columbus, Ohio 43219; University of Pisa (M.G.), Department of Obstetrics and Gynecology, Pisa I-56100, Italy; University of Toronto (N.B., L.M.), Department of Nutritional Sciences, Department of Medicine, Toronto, Ontario, Canada M5G 2C1; Cedars-Sinai Medical Center (G.D.B.), Department of Medicine, Los Angeles, California 90048; Columbia University Medical Center (R.A.L.), Department of Obstetrics and Gynecology, New York, New York 10037; Eastern Virginia Medical School (D.F.A.), Clinical Research Center, Norfolk, Virginia 23507; North American Menopause Society (W.H.U.), Mayfield Heights, Ohio 44124; Massachusetts General Hospital (K.A.M.), UptoDate, Waltham, Massachusetts 02453; University of North Carolina at Chapel Hill (D.R.R.), Chapel Hill, North Carolina 27516; Section of Dermatology (D.M.T.), Hershey Medical Center, Pennsylvania State University School of Medicine, Hershey, Pennsylvania 17033; King's Breast Care (J.M.), King's College Hospital, London SE5 9RS, United Kingdom; and Harvard Medical School (J.E.M.), Brigham and Women's Hospital, Boston, Massachusetts 02215


Objective: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint.
Participants in Development of Scientific Statement: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.
Evidence: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.
Consensus Process: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.
Conclusions: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

eLetters:
Read all eLetters

Statistical Analysis in the Postmenopausal Hormone Therapy

Joseph W. Goldzieher

JCEM Online, 17 Aug 2010 [Full text]
"It is to be hoped that this monumental, desperately needed report will help to counter the persistent damaging effect of the 2002 WHI publication, and have an influence that ranges from generators of policy and guidelines to the most remote doctor/patient interaction...."

The breast cancer “plunge” after initial publication of the WHI results: An alternative explanation

Abstract 

From 2002 to 2003, the breast cancer incidence in the United States, as reported by the National Cancer Institute's Surveillance Epidemiology and End Results (SEER 9) database, appeared to decrease by 6.7%. This phenomenon has been attributed to a reduction in the use of menopausal hormone therapies after the initial publication of the Women's Health Initiative (WHI) study results in July of 2002. 

However, attempts to draw a causal association between the use of menopausal hormone therapies and the incidence of breast cancer have not accounted for the facts that prescriptions of estrogen-plus-progestin menopausal therapies, which are associated with increased rates of breast cancer, fell by 53% from 2002 to 2003, while prescriptions of estrogen-only therapies fell by only 27%. To address this issue,...

Disruptive Women in Health Care » Blog » “News (Hot) Flash: Sex, Drugs and Menopause” Recap – 2010 Breakfast Series

Blog Note: at the time of the WHI publications, both clinical and media, this blogger attended several debates/seminars on the WHI.  Along with others, we have finally been redeemed via this statement, albeit few listened.

"....Phyllis Greenberger, President and CEO of the Society for Women’s Health Research, started off speaking about the Women’s Health Initiative. “There was a lot of misinterpretation, some of the results reported were incorrect,” she said. She quickly explained what they did, what was wrong, and what’s true today...."