' ' ' ' ' Hormone Replacement Therapy G U E 5 T E D I TOR I AL. The Society of Obstetricians and G yn a eco I og i sts of Canada

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1 ' ' ' ' ' G U E 5 T E D I TOR I AL ' ' ' ' ' The Society of Obstetricians and G yn a eco I og i sts of Canada COUNCIL MEMBERS 199S-1996 PRESIDENT Dr. Garry Krepart - Winnipeg PAST PRESIDENT Dr Rodolphe Maheux- Quebec PRESIDENT ELECT: Dr. Nan Schuurmans- Edmonton EXECUTIVE VICE-PRESIDENT: Dr Andre B Lalonde - Ottawa ASSOCIATE EXECUTIVE VICE-PRESIDENT: Dr Robert Kinch -Ottawa TREASURER: Dr. Antonin Rochette- Lorettevolle VICE PRESIDENTS: Dr Robert Reid - Kingston Dr Thomas Baskett - Halofax REGIONAL CHAIRS & DEPUTY CHAIRS WESTERN REGION Dr Don Davis - Medicone Hat Dr Jan Christllaw -White Rock CENTRAL REGION Dr Chuo Kin Yuen- Winnipeg Dr. Thirza Smith -Saskatoon ONTARIO REGION Dr Donna Fedorkow- Hamilton Dr Catherine Claire Kane - Ottawa QUEBEC REGION Dr Cajetan Gauthoer- Levis Dr Vyta Senikas - Montreal ATLANTIC REGION Dr. David A. Knickle - Charlottetown Dr Garth Christoe - Fredericton PUBLIC REPRESENTATIVE Ms Janet MacMillan- Halofax JUNIOR FELLOW REPRESENTATIVE Dr. Georges Sylvestre - Montreal ASSOCIATE MD REPRESENTATIVE Dr T Riley - Oakville ASSOCIATE NURSING REPRESENTATIVE Ms. Marie-Josee Trepanier- Ottawa NATIONAL OFFICE EXECUTIVE VICE-PRESIDENT Dr Andre B. Lalonde DIRECTOR OF COMMUNICATIONS Martine Joly 774 Echo Drive Ottawa, Ontario K1S SNS tel: (613) or fax: (613) Hormone Replacement Therapy It is an adage of the newspaper business that when dog bites man there is no story, but when man bites dog, the presses must roll. This certainly seems to be the case when medications are concerned, and recently, further controversy has arisen about a possible link between hormone replacement therapy (HR T) and breast cancer. Any link between HR T and breast cancer would indeed be a cause for concern. Breast cancer is the most common female malignancy, and HRT one of the most common prescriptions. In an era of evidence-based medicine it is clear that the information provided to the patients so that they can make informed decisions, must be of the highest calibre, and it is here that problems arise. The evidence with respect to a relationship between breast cancer and HRT is variable. It is a valid assumption that when there is a great variability in the reported risks, the true risk may be small. Nevertheless, even a small increased risk of breast cancer is of major significance and so it is essential to weigh the merits of every publication in this field. It must be accepted that if the truth is that there is no relationship between HRT and breast cancer, then simple variability amongst subjects John A. Collins, MD, FRCSC, McMaster University Patrick J. Taylor, MD, FRCSC, University of British Columbia and study methods would lead to different results which could be soothing or alarming. The most extreme results in one direction would be comforting and very upsetting in the other direction. In the tradition of man bites dog, it is the disturbing studies which gamer most public attention. Recent headlines described the Nurses Health Study which showed that the risk of breast cancer was 3 2 percent higher for users of estrogen and 41 percent higher for those women who used estrogen and progesterone.' Simultaneously, a prospective study showed that the risks for estrogen were 0 percent and for estrogen plus progesterone, 20 percent. 2 A recent retrospective study found no increase in the breast cancer risk for women using HR T. 3 These latter studies did not receive the same degree of public attention. JOURNAL SOGC 107 FEBRUARY 1996

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4 ' ' ' It is recognized that HR T has some beneficial effects, including a reduction in the incidence of coronary artery disease and protection against osteoporosis. 4 These benefits are believed to exist based on current evidence but cannot be fully confirmed without prospective randomized studies. It is important that the current arguments about a possible relationship between breast cancer and HRT be explored thoroughly. Women should not be placed in the position of having to refuse HR T because of an unrealistic appreciation of the potential risk of breast cancer. Small risks are notably difficult to detect with the use of epidemiologic methods. A further problem is that neither case control nor cohort comparison studies can determine whether or not HR T causes breast cancer. Both types of studies are observational and not experimental. In cohort studies, the groups are defined according to HRT exposure; in case control studies, subjects are identified as those with a diagnosis of breast cancer. Observational studies are limited to exploring associations between such exposures as HR T and events such as breast cancer, but they cannot determine whether exposures like HR T cause breast cancer. In both types of approaches, the apparent association may simply arise by chance, or may occur due to bias in group selection. In the cohort studies, the baseline characteristics of HRT users often differ from non-users in such important variables as age, which of itself has an important effect on the incidence of the disease. In case control studies, breast cancer cases are selected and a history of HR T is documented for cancer cases and control subjects. In these studies, the selection of the control group is of critical importance so that it is as similar as possible to the subset of the population from which the cases arose. It is the responsibility of epidemiologists conducting such studies to anticipate sources of bias and to collect detailed information about confounders. If the current published data are examined, it is recognized that the association between breast cancer and HR T has been evaluated in more that 40 epidemiological studies. The lowest estimate of overall risk was 0.15 (95% CI 0, 3.52) in a small randomized trial/ and the highest was 1.84 (95% CI 1.05, 3.23) in a case control study. The great majority of published estimates lie between 0.8 and 1.2 which suggests that there is little or no alteration in the risk of breast cancer associated with HRTuse. In seven meta-analyses which have been published,4.6-tt an increased risk of breast cancer for HRT users (1.06, 95% CI, 1.00, 1.12) was identified in one meta-analysis only. 10 In addition to addressing the question purely of increased incidence, individual metaanalyses evaluated the cancer risk related to longer duration of use, u higher dosages, 9 combined estrogen and progesterone, 4 6 and current versus past use ofhrt. 8 It appeared from these meta-analysis studies that duration, dose, progesterone, and current use effects were not consistently observed in the meta-analysis. Thus, several important questions with respect to HRT and breast cancer still cannot be resolved with present epidemiological and meta-analytic methods. How then can we provide accurate information to our patients? The honest answer is that we cannot. We can, however, give the best interpretation of our current state of knowledge, leaving the fmal decision to the individual woman, and for her the most important question is, what is her personal risk? Of all the numerous factors determining risk for an individual, the most relevant is age. Table 1 gives estimates of breast cancer incidence for ten years after ages 50 and lt is during these years that most women decide for or against HR T. Included also in this table is a breakdown of what the increased risks of breast cancer may be if the relative risk is 1.1 or 1.3, and it must be remembered that a risk of 1.3 is translated in the lay literature as a 30 percent greater risk of the disease. If we take the example of 100 women aged 50 who are not using HRT, by the time they have reached the age of 70, will have developed breast cancer. This is also the number who will develop breast cancer if there are no risks associated with HR T, and all these women are taking replacement therapy. If the TABLE 1 RISK OF BREAST CANCER WITH AGE f-- - For a woman free from breast cancer at age 50 or 60 years, probability of developing breast cancer by age 60 or 70 years. - _!!esent Ag_e 50 years 60 years,...-hrt Risk Cancer Risk (%) Age 60 _ A_l;!e JOURNAL SOGC 110 FEBRUARY 1996

5 ' ' ' relative risk is 1.3 with HRT, the 30 percent rise in the disease translates to an increase from to Individual women must weigh this small increased risk of developing breast cancer by the age of 70, against the potential benefits of HR T. It must be stated further that on the currently available evidence it is likely that the worst case (relative risk of 1.3) is in fact an overestimate. It seems from the current published evidence, that if there is an effect of HR T on breast cancer the effect is small. There is undoubtedly a pressing need for further research and perhaps it is worth reiterating the statement by the authors of a large Swedish study.ll "The net effect of hormonal replacement with regard to length and quality of life is beneficial." 14 Having made these statements in this editorial it is hoped that a balanced picture has been presented to our readership. It is unlikely that these apparently comforting figures will be reported in the lay media. It must never be forgotten that dog bites man is never news. 10. Sillero-Arenas M, Delgado-Rodriguez M, Rodigues-Canteraas R, Bueno-Cavanillas A, Galvez-Vargas R. Menopausal hormone replacement therapy and breast cancer: a meta-analysis. Obstet Gynecol1992;79: Steinberg KK, Thacker SB, Smith SJ et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991 ;265: Feuer EJ, Wun L-M, Boring CC, Flander WD, Timmel MJ, Tong T. The lifetime risk of developing breast cancer. J Natl Cancer lnst 1993;85: Bergkvist L, Adami H-0, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogenprogestin replacement. N Eng I J Med 1989;321 : Adami H-0, Persson I. Hormone replacement and breast cancer: a remaining controversy? JAMA 1995;274: REFERENCES J SOGC 1996;18: Colditz GA, Hankinson SE, Hunter DJ et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332: Schairer C, Byrne C, Keyl PM, Brinton LA, Sturgeon SR, Hoover RN. Menopausal estrogen and estrogen-progestin replacement therapy and risk of breast cancer (United States). Cancer Causes and Control 1994;5: Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995;2747: Grady D, Rubin SM, Petitti DB et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992; 117,12: Nachtigal! LE, Nachtigal! RH, Nachtigal! RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979;54: Armstrong BK. Oestrogen therapy after the menopause-boon or bane? Med J Aust 1988;148: Bates SK. Postmenopausal estrogen replacement therapy and breast cancer. J SOGC 1990;12: Colditz GA, Egan KM, Stampfer MJ. Hormone replacement therapy and risk of breast cancer: results from epidemiologic studies. Am J Obstet Gynecol 1993;168: Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch Intern Med 1991; 151 : JOURNAL SOGC 111 FEBRUARY 1996