Hormone Replacement Therapy and Breast Cancer

Courtesy of FIGO

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Dr. Robert Reid:  “Thank you very much.  It’s always a very great honor for me to share the podium with such leaders in the field as Dr. Pinotti, and his data is certainly very compelling and represents many years of diligent research.  What I’m going to do in the next twenty minutes is not to provide a detailed review and critique of all the recent publications, because certainly there would not be time to do that, but what I hope I can accomplish is to leave you with some useful clinical counseling tools that will assist you in counseling patients that you may encounter in your practice.  I’ve entitled this talk – ‘Hormone Replacement Therapy and Breast Cancer Risk Communication Gone Awry.’  

This is the front cover of the New York Times magazine about a decade ago when a famous model who had undergone mastectomy agreed to pose for this picture.  I think this one picture, perhaps more than most of the other material that had been in the lay literature, shocked the North American public and really raised this concern about the defeminizing nature of radical breast cancer surgery and alarmed women and made them very concerned about anything that might potentially increase their risk of breast cancer.  Our newspapers are replete with scary stories, and I picked just one headline out of many that appeared in the newspaper in the past year and this says – ‘Rise in invasive lobular carcinoma rates matches rise in HRT use.’  When I read this, I thought they could have written that it matches the rise in seat belt use as well, and what is alarming is the way the media is taking information on hormone replacement therapy and breast cancer and generating sensational stories.  This then generates thousands of phone calls to physicians by women who are on hormone replacement therapy because they don’t know quite how to interpret this kind of headline.  What happens when good news comes along?  I apologize if you can’t see this, I had to put glasses on to find the article and I don’t use glasses but this is Time Magazine, and this is the women’s health page with the big headline – ‘Are Cigars Safe?’ – filling the whole page and a little thumbs up over here saying – ‘Reassuring news for women, estrogen does not seem to be linked to breast cancer.’  That’s not really news so it’s put in a postage stamp size article up in a corner where you can hardly find it.  Scientific American did a detailed review on various cancers that affect women, and I thought this one statement really summarized the issue that we are facing in counseling women in North America and I’m sure in other parts of the world.  It states – ‘It’s largely fear of breast cancer that fuels the debate about hormone replacement therapy.’ 

  I’ve been involved in a national public awareness program on menopause and osteoporosis in Canada, and when we’d go out into small communities across the country doing public forums, this is the first question, it’s the last question, and it’s most of the questions in between.  Women want to know if we are doing something as professionals, and if we’re prescribing medication that’s going to increase their risk of breast cancer.  I found it very helpful to review several facts about breast cancer for women who are sitting in my office, and the first is that over 90% of breast cancers occur in non-users of hormone replacement therapy.  It’s amazing how few women understand that, and then the fact that data on the rising incidence of breast cancer with advancing age came long before hormone replacement therapy was ever used.  The absolute numbers of breast cancers are increasing due to population demographics, and so women who are in the menopausal age will see a friend or neighbor get breast cancer, they’re in that age group where it will happen.  You can be sure that if that friend or neighbor is using hormone replacement therapy, the first comment will be - I wish I’d never taken that prescription.  But I explain to my patients that you have to be very careful about associations and really ask the question are they causally related - did A cause B or not?  Many women do not realize that in the twenty years after they start making decisions about menopause management, between the ages of 50-70, they have a 4.5% risk of breast cancer if they take no hormones.  So that’s a very important piece of information to give to them, and the last piece of information is that much of our available evidence suggests that breast cancers may take up to ten years to become clinically detectable at the rate of cellular division and growth.  Yet, there was a large article in the Toronto Star, our local Toronto paper, with a woman being interviewed and a sensational story and picture that she started her estrogen three months ago and now she has breast cancer.  My reading of that is she was very lucky that the doctor started her on estrogen and sent her for a mammogram so her breast cancer was found but the public’s reading of that is three months of estrogen treatment caused this big cancer in this woman.  

Now the most useful data that I’ve seen in the past few years was the Collaborative Group on hormonal factors in breast cancer, and what they did was they looked at 90% of the published world data on the relationship between hormone replacement therapy and breast cancer and they came up with some numbers that I think are useful in clinical practice.  What they indicated was that with no HRT use, the woman had a 45 per 1,000 baseline risk of breast cancer in the twenty years between 50-70.  If she used estrogen for five years, they concluded that risk went to 47 or an additional 2 cancers.  If she used estrogen for ten years, during that interval it went to 51 or an additional 6 cancers, and for fifteen years it might go as high as 57 or an additional 12 cancers per 1,000 women or a 1% increase.  

Now the problem is that there have been some difficulties in interpreting this, and I would ask the question, does estrogen cause breast cancer?  One of the things they found that was quite interesting was any increased risk of breast cancer attributable to HRT completely disappeared within five years of stopping HRT use.  Well, how would you explain that if estrogen was inducing new cancers that took ten years to develop?  That doesn’t make sense.  So could there be some other explanation for this?   In a very interesting editorial that accompanied that article in the LANCET, they made this comment, and I’ve highlighted certain words - ‘The finding that long term users had a higher risk of localized but not metastatic tumors is consistent with differential screening and earlier ascertainment of breast cancer among hormone users.’  Is this possible?  I was quite struck by this piece of data that I’m sure many of you have seen, this is a piece of data that came from the Raloxifene Breast Cancer Prevention trials, and this is the control data arm.  I looked at this, and I could not figure out why every year there was a jump in the detection of breast cancer.  You know it should be a nice smooth line so why are these big jumps every year?  The answer is the protocol called for mammography each year so you can see the impact of doing mammography on breast cancer detection.  Now you go back to the collaborative reanalysis and say did estrogen users have more mammography?  In three of the largest studies that contributed to the data in that analysis there was excess rates of mammography in the estrogen users, hence, increased detection of breast cancers at an early stage.  Maybe that’s good news for women that they’re getting better surveillance when they’re started on hormone replacement therapy, and Lacroix in this editorial concluded with a very important statement that was totally lost on the lay press – ‘This apparent increased risk of breast cancer should be viewed only as a possibility, not a certainty.’  So these very small numbers that were observed in the reanalysis we’re not even sure they’re true but maybe we were just picking the cancers up that were pre-existing.  

Now there’s another interesting observation and that ties in with this and that is that HRT users have better outcomes once the breast cancer diagnosis is made, and there are two theories.  One is that HRT users receive better surveillance, hence, their cancers are found at an earlier stage but the second one is that HRT results in a better-differentiated type of cancer, which exhibits less aggressive behavior.  I draw your attention to two studies that have addressed survival, the National Cancer Institute study by Willis in 1996 showed that HRT users had a 16% decreased mortality, and Schairer the author who generated the rather alarming report in the past year about estrogen and breast cancer, actually reported in 1999 that current users of estrogen at the time of diagnosis had a 50% decreased mortality twelve years later.  Now when we talk to patients and we present these numbers, the first thing women say when they see this number two is – well, that means I should stop using estrogen at five years then.  I tell them - just a second, let’s put this into perspective of other risks that you knowingly accept or maybe unknowingly accept.  You can look in the literature and find very interesting well controlled studies looking at things such as alcohol intake - two glasses of wine a day increases the attributable risk from 45 baseline to 72 or an additional 27 breast cancers in that same twenty year period.  Lack of exercise – Thune, in the New England Journal of Medicine, reported if you don’t exercise four times a week for ½ hour your risk goes up by twice the amount that would be induced by fifteen years of estrogen replacement therapy.  Weight gain - more than 20 kilograms or late menopause doubles your risk.  Women don’t know these numbers and when they see these numbers and look at these uncertain numbers that we’re not even sure are true, and compare it to these other risks, suddenly it puts it in perspective.  So all of these risks - late menopause, increase in body mass index, alcohol excess, and lack of exercise are far higher than the risks attributed to the longest use of HRT in the collaborative reanalysis.  

Now what about the recent data that’s rather alarming about combined estrogen-progestin therapy?  There have been a number of studies published now, each of which suggests a relative risk of 1.4.  I hesitate to say a 40% increase because the next thing I’ll hear in the paper tomorrow is that women have a 40% chance of getting breast cancer if they take progestin.  It’s amazing how often I see other physicians that don’t know how to interpret what a relative risk means.  This .4 means your risk is increased over your baseline risk by 40%.  What about the strength of the data on the combined estrogen-progestin therapy?  There’s still very limited data published; the Schairer report looked at only 101 cases of ever use of progestin, and the Ross report had only 100 cases.  There are concerns about surveillance and reporting bias in these studies.  We don’t have survival data so do we know whether these people survived better than before and the problem or the dilemma we will face is there’s rapidly changing formulations of estrogen and progestin so data on information that we had from ten years ago may not be very helpful in counseling patients of the future.  Late breaking news about estrogen and breast cancer, which was not picked up by the media to any extent.  Each of those reports that talked about an increased risk of breast cancer with estrogen and progestin in the 100 patients that were reported or that had breast cancer, they commented that there was no increased risk associated with estrogen by itself.  That was not picked up by the media so now we have more evidence that there’s little if any impact of estrogen by itself on breast cancer risk.  The final minute of my presentation I want to take you to the other common misconception and that is - my mother got breast cancer; I cannot take hormone replacement therapy.  

These are some statistics that I put together to help myself remember; I’ve got a very bad memory.  I wanted to be able to remember when I was counseling patients about the impact of the number of first- degree relatives and the age at which the first-degree relative developed breast cancer.  If somebody had a single relative over age fifty, her risk is very marginally different from the baseline population risk of 10%.  So the woman who says her mother got breast cancer at seventy-eight and she can’t take hormone replacement therapy, well, the first thing is that her risk because of her mother’s history is not very much increased.  I’m going to show you in the next slide that estrogen does not seem to increase her risk from that number, and the reason this table is useful is you just double it when you go in either direction.  So if you have two relatives, you double that number.  If your relative was over age fifty, you double the number.  If you have two relatives over age fifty, you double the number again.  It’s a rough ballpark number, and a rough way to help remember those statistics.  Two studies have looked at family history in breast cancer recently, which were reported in the Annals of Internal Medicine, and what they concluded, was, yes, family history increases your risk as I just showed you.  But the addition of HRT did not increase that risk any further, and so HRT users, in fact, in these studies overall had a reduced mortality rate.  So every woman has to individualize and look what her particular benefits and risks are and family history should not necessarily preclude her considering HRT as an option in the menopausal years.  So if a woman has a family history of breast cancer, she can consider it if appropriate but she needs to do something because of her increased risk, she needs to start breast cancer screening at least five to ten years before the age at which her youngest first-degree relative was first diagnosed.  

So my take-home message about HRT and breast cancer is there is very positive news about estrogen alone, it has little impact on breast cancer risk.  I’m not sure when I hear the debates and the other forums about endometrial ablation versus hysterectomy, and I think about this because with hysterectomy you require estrogen alone replacement, with endometrial ablation you require continuous combined therapy.  How many people in the discussion about endometrial ablation discussed that with their patients at this point in time?  Breast cancers in HRT users have a better prognosis, and I think at the moment, we must conclude that there is uncertainty about the risk associated with combined estrogen-progestin therapy because of the limited data set and more studies are needed.  

Thank you very much.”