Cecilia Magnusson, MD

:        “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?”

:  “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.”

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

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

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

:  “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.”

:        “How did you select your controls?”

:  “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.”

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

:  “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.”

:  “Do       you mean women with and without HRT?”

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

:  “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.”

:  “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.”

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

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

:  “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.”

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

:  “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.”

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

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.”              

:        “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.”

:  “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.”

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

:  “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.”

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

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

Articles

OBGYN.net Conference CoverageFrom the European Menopause and Andropause Society (EMAS) 5th Congress, Copenhagen, Denmark-July, 2000

Cecilia Magnusson, MD

Articles

Estrogen Replacement Therapy and Breast Cancer