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Hormone Therapy and Breast Cancer: An Expert Interview With JoAnn E. Manson, MD, DrPH

Authors: JoAnn E. Manson, MD, DrPHFaculty and Disclosures


Editor's Note

JoAnn Manson, MD, DrPH, Professor of Medicine and Elizabeth Fay Brigham Professor of Women's Health at Harvard Medical School, and Chief of the Division of Preventive Medicine and Co-Director of the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital in Boston, recently spoke with Medscape Scientific Director, Dr. Brown, regarding menopause management in the primary care setting. During this Interview, Dr. Manson provided her perspective on the relationship between hormone therapy and breast cancer.

Dr. Brown: Thank you, Dr. Manson, for joining Medscape to share your views on menopause management in primary care, specifically focusing on the relationship between hormone therapy (HT) and breast cancer. What is the current evidence on the risk of breast cancer associated with HT during menopause?

Dr. Manson: The risk of breast cancer is greater with estrogen plus progestin (EPT) than with estrogen-alone therapy (ET). This has been consistently found in randomized clinical trials (RCTs) and in observational studies. In fact, in the Women's Health Initiative (WHI) among women with a hysterectomy, even 7 years of ET was not associated with an increased risk of breast cancer. In contrast, in the EPT trial among women with an intact uterus, the risk of breast cancer began to increase with 4 to 5 years of use. With EPT, a 24% increase in risk of breast cancer was observed over the full 5.6-year treatment period. However, the risk was even greater when we limited the analyses to women who were compliant with their study pills. There is clearly an increase in the risk of breast cancer with EPT. Although with ET no increase was seen with up to 7 years of treatment in the WHI, observational studies suggest that even with ET, breast cancer risk may begin to increase after 10 to 15 years of use.

Additional Information Regarding the WHI Trials
The trials within the WHI are, for some outcomes, the only large, relatively long-term RCTs to date of postmenopausal women using HT. The WHI trials have several characteristics that may limit the ability to generalize the findings. These include the use of only one formulation of estrogen (conjugated estrogens), alone or with one progestin (medroxyprogesterone acetate), and only one route of administration (oral). Moreover, women studied in the WHI were older (mean age, 63 y) -- mostly more than 10 years beyond menopause, with more risk factors than younger women who typically use HT for menopause symptoms. They were also largely without severe menopause-related symptoms.

Dr. Manson: It's also important to note that EPT has been found to increase breast density and, thus, may interfere with mammogram readings and actually obscure the diagnosis of breast cancer in earlier stages. Increased breast density has been linked to increased breast cancer risk in some studies.

Dr. Brown: Is the level of breast cancer risk observed for women using HT considered to be clinically significant over the background rates of breast cancer?

Dr. Manson: Yes, it is a clinically significant risk. It amounts to about 1 extra case of breast cancer per 1,000 women using EPT per year, which is an increase from a background rate of about 3 per 1,000 to 4 per 1,000 per year of EPT use. Any increase in the risk of breast cancer is clinically important. Women are very concerned about breast cancer; it is an important health concern. However, in absolute terms, this risk is quite low and, if a woman is severely symptomatic with hot flashes and night sweats that interfere with sleep and impair quality of life, the benefits from HT are likely to outweigh the risks, especially if a woman limits herself to short-term treatment.

Short-term HT used for only 2 to 3 years, which is as long as many women would require hormones, should not appreciably increase the risk of breast cancer. It is really a duration issue. Once you use EPT for 4 to 5 years or longer, breast cancer risk does become an important consideration.

Dr. Brown: How do different formulations affect safety for women who are interested in HT?

Dr. Manson: Research on the type of hormone formulation and risk of breast cancer is limited. There is no conclusive evidence that different formulations of estrogen -- estradiol versus conjugated estrogens, transdermal versus oral, micronized progesterone versus synthetic progestin -- have differential effects on breast cancer. There are no large-scale RCTs addressing those questions and no rigorous head-to-head comparisons.

The strongest evidence is that adding a progestin will increase risk of breast cancer compared to estrogen alone. Also, there is limited evidence that taking estrogen with the progestin in a continuous-combined fashion (ie, both hormones used daily) may be more deleterious than taking it cyclically (ie, daily estrogen with cyclic or infrequent progestin).

In terms of dose, there is really no conclusive evidence from large-scale RCTs that low-dose HT is less likely to increase risk of breast cancer than higher doses. However, this is a reasonable assumption based upon what we know from mammographic breast density studies, research in animals, and all available clinical evidence.

Dr. Brown: Are risks and benefits of so-called "bioidentical" hormones similar to those of other HT products?

Dr. Manson: Bioidentical hormones are those chemically the same as those made by the human body. For women, these include estradiol and progesterone, hormones available in FDA-approved brands that can be purchased from retail pharmacies. There is no conclusive evidence that bioidentical HT is any safer than traditional HT in terms of breast cancer risk. There are no large RCTs of clinical breast cancer events comparing bioidentical HT with traditional formulations. Bioidentical HT, especially transdermal estradiol, may have the advantage of being less likely to cause blood clots, and being less likely to adversely affect the liver's production of inflammatory markers and clotting factors. But, in terms of breast cancer risk, there is no conclusive evidence. Women have been led to believe that bioidenticals are safer and more effective than traditional HT, but the evidence for that claim is lacking.

Often, however, the term "bioidentical HT" is used to describe custom-compounded hormones. Again, there is no evidence that these products are better or safer than government-approved brands, and there is less oversight of purity and dose consistency.

Dr. Brown: How do you recommend that a physician, nurse practitioner, or nurse address patient fears of breast cancer considering the extensive media coverage of HT and its risks?

Dr. Manson: First, it is important to emphasize the differences between ET and EPT to a woman who has had a hysterectomy and is taking ET. A woman without a uterus has no need for a progestin. The next issue is duration of use. A woman who is going to use HT short term, even EPT for only 2 to 3 years, should not be anxious about the risk of breast cancer. Women still need to be vigilant about regular mammograms, clinician breast exams, and self-exams. However, with short-term HT, the risk of breast cancer is not a major factor in the equation. The risk of breast cancer is a much more important factor with long-term use and decisions need to be made carefully about continuing treatment for more than 5 years. I emphasize the importance of treatment duration. Discuss the duration issue with a woman, aim for short-term treatment, and try to discontinue HT if at all possible within 3 to 4 years. The lowest effective dose is the mantra now, and there is some evidence that the lower doses of estrogen are less likely to increase mammographic breast density, which may mean that they are less likely to increase the risk of breast cancer. So, I think that we can start low and strive for the lowest dose effective for treating her symptoms of hot flashes and night sweats.

In terms of reassuring women about HT use, it is going to come down to the overall benefits and risks for the individual woman and whether her symptoms of hot flashes and night sweats are severe enough to override these other concerns. She is likely to get improvement in symptoms with HT. Currently, the only clear indication for systemic HT is moderate to severe hot flashes and night sweats; HT should not be used for prevention of cardiovascular disease or other chronic diseases, due to known risks. This an important point to emphasize.

If a woman has only vaginal dryness and urogenital symptoms, low-dose vaginal estrogen can be used, which will avoid the risks of systemic estrogen.

Dr. Brown: If breast cancer rates are declining, what might this be attributable to?

Dr. Manson: Although there is still controversy about the reasons for the declining rates of breast cancer in recent years, the lower rates may be due to a combination of decreased use of HT and a change in mammogram screening patterns. However, there is evidence that long-term HT use, especially of EPT, will increase the risk of breast cancer. Hopefully, women are less likely to use HT for long duration, given all the information about benefits and risks. Many women who were not appropriate candidates for HT have stopped treatment, and this has probably also contributed to the decline in breast cancer. Of some concern is that there may be less vigilance about mammography. Often, when women stop using HT, they become more complacent about regular mammograms. The WHI findings we reported recently suggest that an increased risk of breast cancer persisted for the 2 to 3 years after stopping HT (Heiss et al. JAMA 2008;299:1036-1045). This further supports the need for women to remain vigilant about screening tests for breast cancer even after discontinuing HT.

Dr. Brown: Is there anything else you would like to add before we wrap up?

Dr. Manson: The bottom line is that there are ways to minimize the risk of breast cancer with the use of systemic HT, which include avoiding long duration of treatment, using the lowest effective dose, and being diligent about breast screenings and examinations.

I understand that concern about breast cancer is uppermost in women's minds. But I hope that there will also be discussion of the overall pattern of benefits and risks of HT and how this varies according to each woman's risk factor status. It is going to come down to the individual benefit/risk profile for each patient.

Dr. Brown: We would like to thank Dr. Manson very much for joining us and putting HT and breast cancer risk into perspective.

This activity is supported by an independent educational grant from Wyeth.

This activity was developed in cooperation with The North American Menopause Society (NAMS).

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