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Department of Cancer Epidemiology, University of Uppsala, Sweden

by Sean Henahan, Access Excellence, America Online

Even the most complicated scientific studies depend on the fundamentals of good design and methodology. When the studies are epidemiological in nature, the picture becomes even more complex. Recent epidemiologic studies have produced contrasting results regarding the potential risk of hormone replacement therapy and risk of breast cancer in menopausal women. How does one go about sifting the scientific wheat from the statistical chaff? I asked noted breast cancer researcher and epidemiologist Ingemaar Persson, M.D., of the department of cancer epidemiology, University of Uppsala, Sweden, to clarify some of these issues.

Q: Could you give us a little information on the reasons estrogen is suspected of being involved in the development of breast cancer in the first place?

A:There are numerous pieces of circumstantial evidence suggesting a possible link between estrogen and breast cancer. One thing is that the etiology of breast cancer is associated with reproductive risk factors, such as early menarche (onset of menses) and late menopause, whereas protective factors include early age at first birth, oopherectomy and early menopause. These pieces fit together with an expectation that ovarian sex steroids would affect breast cancer risk. Exactly how and when we don't know. We know too little about the mechanisms of these factors on breast cancer development.

In addition, steroid hormones are known to regulate the growth of normal breast epithelium. In some animal studies, estrogens have been implicated in the development of tumors, but this has not been seen in all studies.

Q: HRT is a different use of these hormones than is the case with oral contraceptives. Since HRT has only been used for some 30 years, is this a long enough period to even be able to tell if there are any adverse effects?

A:I think so. If you look at the findings in a large number of studies, you find that there are inconsistent results, but there are many studies now showing that with many years of estrogen intake there may be a moderate increase in risk. This may have to do with the number of years and the amount of exposure to estrogen.

Q:People reading the newspapers may be confused to read conflicting reports suggesting an increased or decreased risk of breast cancer in association with HRT. For example we recently saw a report from Harvard suggesting a possible increased risk, and a contrasting report from Seattle not suggesting increased risk. Can you describe how you reconcile these kinds of studies?

A:This is a very complicated question. In the first place, it is wrong to try and make conclusions from only two studies. In this case, both studies were non-randomized observational studies. In such studies there are a lot reasons one might come up with different estimates of risk depending on the methods used in the studies or shortcomings in those methods. That is a very real reason we see discrepant results. It is very, very important when we look at individual studies to make a judgment on the quality of that study.

Q: Could meta-analysis help clarify the picture?

A:This is very controversial. With meta-analysis you lump together risk estimates from a large number of studies. This means you end up combining bad studies with good studies, qualitatively speaking. That doesn't really guarantee that you end up with true answers. However, these studies do offer the advantage of increasing the numbers in the analysis.

Q:What about potential confounding factors. such as differences among estrogens, and the use of combination therapy involving progestin?

A:In Europe we tend to use estradiol (steroid containing estrogenic properties) compounds, while in the US you tend to use the conjugated estrogens (estrogenic compounds derived from the urine of pregnant mares). These could produce different effects, but I don't think so. These two common regimens give about the same effect on endometrial cancer risk, the same effects on osteoporosis, same effects on coronary heart disease, and the same effects on relief of menopausal symptoms. So I don't think there is much difference there.

There could be a difference in another area, the duration and amount of estrogen intake. This is fundamental. If you are looking at a relationship between exposure to something and development of disease, it might be that a specific amount of exposure is needed for a specific time, to have an effect. That means if you compare short term users to long-term users, the results are not comparable.

Q: How can genetic factors be fitted into the risk equation? How can you control for the portions of the population who may already be at increased risk? A:The proportion of women who are assumed to have the BRCA gene mutations is very small, around five percent. I don't believe it would affect the results of studies of this nature. However, another question is whether genetic factors may play a role in women taking HRT, that is- the phenomenon of interaction. That is currently hypothesized, , but there are not very good data, yet. You could examine the presence of genes in a case-control study.

What we do now is ask women, do you have a mother and/or sister who developed breast cancer at a young age. If the answer is yes, there is a higher likelihood that the person may have genetic predisposition to breast cancer. If you combine first degree heredity risk for breast cancer with HRT , there are some hints, although not well established, of an interaction. This is an interesting area of research.

Q:A number of health benefits have been attributed to estrogen replacement. These include reduced risk of heart disease and heart attack and protection against osteoporosis. How do you calculate the ratio of risks and benefits in a situation like this?

A:There is some indication of these benefits. But even here, there is a question of how much these protective effects could be due to selection. This is a very tricky problem. It's been shown, in Sweden at least, that women who are selected by doctors to receive HRT are or who select themselves to go to the doctor, and who decide to take HRT for a long time are not 'ordinary average' people. They have higher incomes, they have higher level of exercise, and smoke less. These differences could suggest that these women already have a lower risk for heart disease. Nonetheless, this doesn't mean that these factors would explain all of the pronounced protective effects seen with estrogen replacement. in epidemiologic studies. Taken together, the studies suggest that women taking HRT have up to a 50% reduction in incidence of heart attack, compared to those not taking HRT. The same may be true for osteoporosis.

Q:In recent years progestins (drugs which mimic progesterone, a hormone produced by the corpus luteum) have often been added to estrogen regimens. How does the addition of progestin change the picture?

A:This is another tricky question. If you are discussing estrogen and heart disease, this is currently an area of debate. There may be some adverse effects of progestin on lipoproteins (cholesterol and related compounds), whereas estrogens appear to benefit lipids. Some researchers have wondered if this positive pattern may be reversed with the addition of progestin. Nobody knows.

The effect of progestin on the risk for breast cancer is another issue. The Harvard study concluded that there is no difference in risk relationships between estrogen alone and estrogen plus progestin. We have seen this in terms of breast cancer in our own studies.

Q:What is the message for women who are contemplating HRT, what should their doctors be telling them based on the current data? A:The doctor can tell the patient- there may be some increased risk of breast cancer in some people, but there is more reason to think there are potential benefits from HRT. It is very important to state that short-term use of HRT has no adverse effects. The risk we are considering would not be seen until ten to 15 years of estrogen intake. So women who are having hot flashes or other symptoms of menopause, are in need of treatment, and estrogen will improve their quality of life for a period of years.

It is different to consider HRT for prevention of coronary heart disease or osteoporosis. Both heart attacks and hip fractures tend to occur in late age. This means you are talking about long-term treatment, even lifetime treatment. This is where increased breast cancer risk may manifest. This is where you have to weigh the potential benefits against potential risks in each individual.


  1. J.L. Stanford et al."...ERT in Relation to Risk of Breast Cancer in Middle-aged Women", JAMA, 7/13/95.

  2. I. Persson et al. "HRT and Breast Cancer: A remaining controversy", JAMA, 7/13/95.

  3. Brinton et al., "ERT and Breast Cancer Risk", Epidemiologic Reviews,Vol. 15, No.1.

Related information at other Web sites

Oncolink's Frequently Asked Questions about Cancer, University of Pennsylvania

Science Update-Breast Cancer and Hormone Replacement

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