Estrogen Replacement Therapy and Breast Cancer

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OBGYN.net:  “We’re here at the EMAS Conference in Copenhagen, Denmark and one of the hot topics at this Conference is the use of estrogens and the risk of breast cancer.  Cecilia Magnusson, a doctor who is working as a researcher and epidemiologist in the Department of Epidemiology at the Karolinska Institute in Stockholm, told her story this morning about her research on this topic.  Cecilia, could you please tell us what’s the main message of your research?”

Dr. Cecilia Magnusson:  “Earlier studies on breast cancer risk after what we call HRT - that is all types of estrogen replacement with or without progestins - have focused on the use of estrogen only and breast cancer risk because the use of estrogen plus progestin have been introduced only recently in most countries.  What my research adds is a little bit of data on the use of estrogen plus progestin and breast cancer risk.  We did a nationwide population based case control study in Sweden during 1993-1995, and we included 3,000 patients and 3,000 controls.  We then looked at the use of different types of HRT combinations with regard to breast cancer risk.”

OBGYN.net:  “Excuse me, what type of patients do you mean?”

Dr. Cecilia Magnusson:  “Women with breast cancer; they had invasive breast cancer.  Incident breast cancer is not prevalent breast cancer.”

OBGYN.net:  “Was there a certain stage that they were in?”

Dr. Cecilia Magnusson:  “They were in all stages, we excluded all patients with cancer in situ so there were only invasive cancers but of all the stages.  Eligible for this study was all cases of breast cancer in Sweden during 1½ years, and we succeeded in including 85% of all of the breast cancer cases in Sweden during this time period.”

OBGYN.net:  “How did you select your controls?”

Dr. Cecilia Magnusson:  “The controls were randomly selected from the population registers in Sweden.  We did an age frequency match sampling so they were age frequency matched to the age distribution of the controls.”

OBGYN.net:  “Did you also look at the oral contraceptive history?”

Dr. Cecilia Magnusson:  “We measured a lot of exposures in these women, all of the known risk factors for breast cancer, and among those is history of oral contraceptive use.  We used the exposure of this information to adjust our analyses for HRT and breast cancer risk.”

OBGYN.net:  “So you had two groups?”

Dr. Cecilia Magnusson:  “Do you mean women with and without HRT?”

OBGYN.net:  “Yes, you had these two groups - the women with and without breast cancer.”

Dr. Cecilia Magnusson:  “Yes.”

OBGYN.net:  “And then you looked…”

Dr. Cecilia Magnusson:  “Then we looked at whether the breast cancer patient had used more or less hormones and for how long of a time they had used it as compared to controls.  In that way you can assess the influence of HRT on breast cancer risk, that’s what you do in a case control study.”

OBGYN.net:  “What did you find?”

Dr. Cecilia Magnusson:  “What did we find - that’s the interesting part maybe.  We found quite a strong duration dependent effect of HRT on breast cancer risk.  When I say HRT, I mean estrogen only used alone or estrogen in combination with progestins.  We didn’t find any effect of estrogen when used locally.  Vaginal estrogens had no effect whatsoever on breast cancer risk and not the orally administered Estriol which is a biological weak compound which is used in Sweden and I think in the Netherlands as well.”

OBGYN.net:  “So it’s mostly Estradiol and NETA too.”

Dr. Cecilia Magnusson:  “Yes, and in Sweden our data applies mostly to Estradiol with or without the addition of testosterone tried progestins.”

OBGYN.net:  “So it’s NETA.”

Dr. Cecilia Magnusson:  “Yes, NETA, and this was the overall result - there was no effect for the weak or vaginal estrogens but a rather strong effect of estrogen alone or estrogen taken with progestins.  After ten years of use, we had a 2 ½ relative risk, that’s 2 ½ times the risk of the women without the HRT of breast cancer in women who had ten years of estrogen alone or estrogen plus progestin.”

OBGYN.net:  “Perhaps, we can show this in the slide that we’re projecting at this moment.”

Dr. Cecilia Magnusson:  “Yes, then we were very interested in how different types of HRT regiments were related to breast cancer risk because, as you said before, earlier studies focused on estrogen only use so we were very interested in estrogen plus progesterone, progestin use.  When we compared estrogen only and estrogen plus progestin overall as one group, there were no differences, it was a quite strong effect with both treatments.  But then we looked in more detail, and as you can see here in this slide, we looked at estrogen plus cyclic addition with NETA, as you call it, and estrogen plus continuous addition of NETA and we compared these two groups.  We then saw that the addition of continuous use of progestins appeared to have a stronger influence on breast cancer risk than the cyclic addition of progestins.  So this is the first study to look at this ever so the results have to be cautiously interpreted but this is what we found and this is what we have to look into further in the future to see whether this is true or not.  It is supported by literature from mammography studies where the use of continuously combined estrogen plus progestin therapies induce a greater amount of mammography density increase in the breasts than do the cyclic addition of progestins or the estrogen alone treatment.  It a bit debated but it seems now that mammography density is a marker of breast cancer risk but it’s all debated and I would say we desperately need more data.”

OBGYN.net:  “In which direction will your research go in the coming years?”

Dr. Cecilia Magnusson:  “We have very bombastic plans for the future because we feel that this area of research is so important that what we really want to do and what we’re talking to the Swedish government and the NIH about is to do a cohort study in Sweden, actually including all Swedish women between 50-79 years of age, that’s one million women and ask them to fill out a questionnaire for us and follow all these women up.  Then you can follow them up for quite a short period of time because there’s so many, so in two or three years you have 5,000 breast cancer cases and 6,000 cardio.  But in a cohort study, you can look at all events; we can look at breast cancer but we can also look at cardiovascular disease, osteoporosis, deep vein thrombosis, and the other outcomes that are very interesting with HRT use.  That’s our bombastic plans, this is not something that’s yet financed or this is what we’re working on to do now.”

OBGYN.net:  “So for this Conference you showed us that there is a difference in using estrogens alone versus estrogens plus NETA and that there’s also a difference when you take it continuously instead of sequentially.”

Dr. Cecilia Magnusson:  “In our data, the differences between cyclic and continuous addition of progestin, there is not so much of a difference between estrogen alone and estrogen plus cyclic addition of progestin in our data but there are other data.  Catherine Schairer from the NCI reported in JAMA this year from her cohort study where they compared estrogen plus progestin and estrogen alone and their estrogen plus progestin is conjugated estrogens with MPA added cyclicly, and they have a high risk for this estrogen plus cyclic MPA than they have for estrogen alone.”

OBGYN.net:  “Do you have any suggestions in which direction the research for new drugs could be?”

Dr. Cecilia Magnusson:  “I think we need a lot more studies, like biological studies - what happens in the breast glands.  That’s one type of study that we need, and not only the cell studies - what happens in the cell culture because then the breast is obviously devoid of its very complex hormonal media that is in the breast gland, we want in vivo studies of what’s actually going on in the gland.  We want from reduction plastic surgery or some sort of in vivo model to work on - how these different compounds work, how do the testosterone drive progestins act in the breast, how do the progesterone drive progestins act in the breast, what does tibolone do to the breast, and what do androgens do to the breast?  The other type of studies we need, except for the clinical trials at the Women’s Health Initiative that we’re all waiting for, we need bigger epidemiological studies where we can look in detail at the different compounds and the regiments and their effect on the breast cancer risk.  The Women’s Health Initiative is obviously a very wonderful study, it probably will not be able to answer all our questions because there’s obviously only treatment with conjugated estrogens plus MPA or conjugated estrogens alone and we need to follow it for many, many years and we’ll still have lack of power to see some of the effects that we are interested in studying.  I think we need the clinical trials but we also need to address this with epidemiological studies but bigger ones than before.”

OBGYN.net:  “Perhaps at the next EMAS Conference in about three years in Jerusalem we’ll know more - we hope from you.”

Dr. Cecilia Magnusson:  “We hope so, that’s really up to the Swedish government.”

OBGYN.net:  “Thank you very much.”