Gerald Hurowitz, M.D.·Published 8 March 2012·9 min read
Key points
Reduced breast cancer risk with use of estrogen-only hormone therapy after hysterectomy persists long term, researchers affirmed in an analysis of the Women's Health Initiative (WHI) trial.
The BCERF Fact Sheet #09, Estrogen and Breast Cancer Risk: What is the Relationship?, explores how estrogen works and how it might affect the development of breast cancer in greater detail.
Being overweight or obese has been found to increase breast cancer risk, especially for women after menopause.
Simply being a woman is the main risk factor for developing breast cancer.
Reduced breast cancer risk with use of estrogen-only hormone therapy after hysterectomy persists long term, researchers affirmed in an analysis of the Women's Health Initiative (WHI) trial.
Women who used estrogen for a median of six years had a 23% lower invasive breast cancer over a median of almost 12 years of follow-up (0.27% versus 0.35% per year with placebo, P=0.02), reported Garnet L. Anderson, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues in Lancet Oncology online.
That benefit was concentrated largely among low-risk groups, such as those without benign breast disease or a family history of breast cancer.
"Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms," the group wrote. "However, our data do not support use of estrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer."
Unlike some other trials of unopposed postmenopausal estrogen therapy, the estrogen-only portion of WHI had suggested a preventive effect, which persisted into the first analysis of the long-term phase of follow-up at a median of 10.7 years.
That raises important questions about the disparity between studies, Anthony Howell, MD, of the University Hospital of South Manchester, England, and Jack Cuzick, PhD, of Queen Mary University of London, noted in an accompanying commentary.
Estrogen & Breast Cancer Risk: Factors of ExposureEstrogen is a hormone that is necessary for the normal development and growth of the breasts and organs important for childbearing. It helps control a woman's menstrual cycles and is essential for reproduction. Estrogen also helps maintain the heart and healthy bones. However, a woman's risk for breast cancer is associated with lifetime exposure to estrogen. Understanding how estrogen works in the body, knowing about how chemicals in the environment can affect body estrogen levels, and how diet and lifestyle factors affect estrogen exposure over a lifetime, may help women make more informed decisions about their bodies and their environment.What is estrogen? The hormone estrogen works as a chemical messenger in the body. It is essential for normal sexual development and functioning of female organs important for childbearing like the ovaries and uterus. Estrogen also helps regulate a woman's menstrual cycles. It is necessary for the normal development of the breast. It also helps maintain the heart and healthy bones.
Is estrogen exposure related to a woman's risk for breast cancer?
Estrogen may be implicated in breast cancer risk because of: 1) its role in stimulating breast cell division; 2) its work during the critical periods of breast growth and development; 3) its effect on other hormones that stimulate breast cell division, and 4) its support of the growth of estrogen-responsive tumors. The BCERF Fact Sheet #09, Estrogen and Breast Cancer Risk: What is the Relationship?, explores how estrogen works and how it might affect the development of breast cancer in greater detail.
Written and revised by
Gerald Hurowitz, M.D.
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Because women with a high lifetime exposure to estrogen may be at higher risk for breast cancer, it is important to understand how lifestyle and environmental factors may affect the levels of estrogen in her body.
"Most observational studies on the use of estrogen-only hormone replacement suggest an increased risk of breast cancer, whereas some show risk neutrality, and a few agree with the reduced risk reported by the WHI," they wrote.
Causes of breast cancer - the estrogen controversy No one knows what causes breast cancer, and no one can clearly say why we are seeing an increase in breast cancer cases. More women develop breast cancer than men — about 100 cases in females for every one in a man. Women’s bodies make more estrogen than men’s. Therefore, the conventional wisdom has been that estrogen causes breast cancer.
Some would label this guilt by association; many direct links are missing. One of the biggest missing links is that women’s estrogen levels actually fall as they age, decreasing dramatically after menopause, but the incidence of breast cancer increases with age. The risk ratio that we all hear about - that one in eight women get breast cancer - is for women over 90 years of age. The rate for women in their 50’s is more like one in 50.
So obviously there is much more than estrogen going on in the development of breast cancer, and it is being over-simplistic to think of estrogen as a bad poison when it comes to breast health. Estrogen is a very beneficial hormone in general - it stimulates tissues to grow when we need it to, and it is also a helpful player in response to stress. Let’s explore what we know about the causes of breast cancer, what we don’t know, and what this may mean for you.
While randomized, controlled trials are typically given precedence, "the overall weight of evidence in terms of number of independent studies is also important, and the WHI trial is the only randomized, controlled trial examining estrogen therapy that supports this view," they added.
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One difference is that the median time to nonadherence to estrogen therapy in the trial was only 3.5 years, which was much shorter than the time noted in studies reporting increased risks, Anderson's group said.
A benefit is plausible, both groups agreed, if breast cancer cells that developed under low estrogen conditions are inhibited by the change to a higher estrogen environment and vice versa.
In the current analysis, women given estrogen who developed breast cancer were significantly less likely to die from the disease (hazard ratio 0.37, P=0.03) or any cause (HR 0.62, P=0.04). Howell and Cuzick suggested that a withdrawal response may be at work.
"For patients with advanced breast cancer who respond and then progress on high-dose estrogen, stopping of treatment could result in a response (withdrawal response), suggesting that the tumor had adapted to grow at the higher dose," they said.
Breast cancer is the second most common cancer in women world-wide with 1.05 million new cases being estimated in the year 2001. In developed countries, it is the most common cancer in women. Populations from countries of North America are at high risk of breast cancer, with incidence rates in US white women going up to 103.7 per 100,000. High rates are also reported from Europe and Australia. In the United Kingdom, nearly 30,000 new cases of breast cancer are diagnosed every year with nearly 15,000 deaths reported from this disease.
The incidence rate of breast cancer has been rising both in the developed and developing countries and it is becoming frequent in some developing countries like Egypt and Tunisia. Carcinoma breast is the second most common cancer among Indian women, and an increasing trend in its incidence has been observed in most of the metropolis with Mumbai toping the list.
Sex-hormones have been implicated in various human cancers such as endometrial cancer, breast and prostatic cancer (among sex-organ related neoplasm) or colon cancer, gall-bladder cancer, kidney cancer, etc.( non sex-organ related neoplasm). However, the association between estrogen and breast cancer assumes special significance since breast cancer represents an enormous public health problem. Breast cancer risk is enhanced by increasing the duration of exposure to endogenous ovarian hormones, so early menarche or late menopause increases the risk. Further, the risk of breast cancer is directly related to the age at which women bear first child. An early first, full-term pregnancy seems to have a protective effect. Women whose first pregnancy is delayed to their late 30s are at a higher risk than multiparous women. Unmarried women tend to be at a higher risk than married women.
Further, nulliparity increases and high parity decreases the risk of breast cancer, at least after the age of 50. Nevertheless, the endocrine mechanisms concerning pregnancy and risk of breast cancer are poorly understood. Exogenous hormonal factors such as estrogen replacement therapy and combined oral contraceptive use may cause a small increase in the risk for breast cancer.
Withdrawal responses might explain the improved prognosis of women who developed breast cancer while receiving estrogen therapy, and previous reports have linked withdrawal responses to therapy cessation and extended remission, they added.
Overall, the WHI estrogen trial included more than 10,000 women, ages 50 to 79, without a uterus. They were randomized to 0.625 mg per day of oral conjugated equine estrogen or placebo.
While the trial was stopped early over elevated stroke risk, follow-up continued until the scheduled end date, and an extended surveillance period that included 7,645 women.
Whereas the stroke and other risks faded after the intervention, the reduced incidence of breast cancer with estrogen therapy persisted without a difference between the intervention phase and the postintervention phase (HR 0.79 and 0.75, respectively, P=0.76).
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Adjusting for nonadherence actually boosted the apparent protective effect to an HR of 0.68, and to HR 0.58 when looking only at the intervention period.
In subgroup analyses, the lower breast cancer incidence with estrogen appeared only in women without history of benign breast disease and those without a mother or sister with breast cancer (P=0.01 and P=0.02 for interaction).
But age, body mass index, years since menopause, and gap between menopause and hormone therapy initiation didn't significantly impact the effect. Detection bias from mammography differences was unlikely, the researchers noted.
They cautioned though about the small numbers of breast cancer deaths, some attrition for extended follow-up, and the median of only 4.7 years of post-intervention follow-up.
Being overweight or obese
Being overweight or obese has been found to increase breast cancer risk, especially for women after menopause. Before menopause your ovaries produce most of your estrogen, and fat tissue produces a small amount of estrogen. After menopause (when the ovaries stop making estrogen), most of a woman's estrogen comes from fat tissue. Having more fat tissue after menopause can increase your chance of getting breast cancer by raising estrogen levels. Also, women who are overweight tend to have higher blood insulin levels. Higher insulin levels have also been linked to some cancers, including breast cancer.
But the connection between weight and breast cancer risk is complex. For example, the risk appears to be increased for women who gained weight as an adult but may not be increased among those who have been overweight since childhood. Also, excess fat in the waist area may affect risk more than the same amount of fat in the hips and thighs. Researchers believe that fat cells in various parts of the body have subtle differences that may explain this.
Whether the results could be generalized to lower estrogen doses, other preparations, or longer durations of estrogen use is not known, they added.
But the results do not apply to combination therapy with estrogen and progestin for postmenopausal women who haven't gone through a hysterectomy. In the other arm of the WHI trial, combination therapy was associated with increased cancer incidence, delayed diagnosis, and higher mortality of breast cancer, the group warned.
What are the risk factors for breast cancer
Simply being a woman is the main risk factor for developing breast cancer. Although women have many more breast cells than men, the main reason they develop more breast cancer is because their breast cells are constantly exposed to the growth-promoting effects of the female hormones estrogen and progesterone. Men can develop breast cancer, but this disease is about 100 times more common among women than men.
"The comparability of breast cancer incidence rates for the placebo groups in the two trials suggests that differences in hormone therapy, rather than hysterectomy, is the primary determinant," they concluded.
The study was funded by the National Heart, Lung and Blood Institute and Wyeth. The WHI program is funded by the National Heart, Lung and Blood Institute, NIH, and the U.S. Department of Health and Human Services.
Anderson reported having no conflicts of interest. A co-author reported having been a consultant for AstraZeneca, Novartis, Amgen, and Pfizer; receiving funding support from Amgen; and serving on speakers' bureaus for AstraZeneca and Novartis.
Howell and Cuzick reported having no conflicts of interest.
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Primary source: Lancet Oncology Source reference: Anderson GL, et al "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" Lancet Oncol 2012; DOI:10.1016/S1470-2045(12)70075-X.
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