The Role of Hormone Replacement Therapy in the Risk for Breast Cancer and Total Mortality in Women with a Family History of Breast Cancer

It is well known that a family history of breast cancer is an important risk factor for the disease. A critical issue is how to advise patients with a family history of breast cancer about perimenopausal and postmenopausal use of hormone replacement therapy (HRT). Hoskins and colleagues [1] have provided guidelines on assessment and counseling of women with such a history, including a recommendation that they avoid exogenous estrogens. A considerable body of literature has discussed the association of HRT and risk for breast cancer. Interpretation of available data is not consistent: Two meta-analyses [2, 3] found a positive association, and two others [4, 5] found no association. More recent studies have not clarified the issue [6-8]. Findings on increased risk in women with a family history of breast cancer have been more consistent. A meta-analysis [3] of five studies that had examined the issue suggested that the risk for breast cancer associated with HRT was elevated among women without a family history of breast cancer (relative risk [RR], 1.5 [95% CI, 1.2 to 1.7]) but was even greater among women with a family history (RR, 3.4 [CI, 2.0 to 6.0]). Of the studies not included in the meta-analysis, some [9-12] but not all [6, 7, 13] reported similar observations. Beyond the issue of the effects of HRT on the incidence of breast cancer, further consideration of the concomitant effect of HRT on risk for death is warranted. A recent report from the Nurses' Health Study [8] suggests that hormonal therapy lasting at least 5 years is associated with a 45% increase in the rate of death from breast cancer. Analytic epidemiologic studies suggest that women who receive HRT have a significantly lower risk for death, primarily because of protection against cardiovascular disease [14-17]. Thus, it is important to examine all-cause mortality when considering the risks and benefits of HRT use [18], especially among women with a family history of breast cancer. As part of the Iowa Women's Health Study, a prospective cohort study of 41 837 women who were 55 to 69 years of age at baseline in 1986, data were collected on self-reported family history of breast cancer in first-degree relatives and on history of HRT use. These data were used to examine the risks for postmenopausal breast cancer, case fatality, and total mortality. Methods The Iowa Women's Health Study Cohort Participants in the Iowa Women's Health Study were selected from a random sample of all women between 55 and 69 years of age who had a valid Iowa driver's license in 1985 [19]. This sampling frame comprised approximately 94% of female Iowa residents in that age range. The primary purpose of the study was to examine the association of obesity and body fat distribution with the incidence of cancer and mortality rate. A total of 41 837 women returned a mailed questionnaire (response rate, 42.7%). Three follow-up questionnaires mailed in October 1987, August 1989, and June 1992 were used to collect information on incident self-reported disease and each participant's current residence. Only minor demographic differences were seen at baseline between respondents and nonrespondents [20]. Nonrespondents have subsequently been found to have a higher 5-year incidence of cancer and rate of death (primarily death from diseases related to smoking) [21]. The incidence of breast cancer, however, was similar among respondents and nonrespondents (RR, 1.01 [CI, 0.9 to 1.1]). Self-reported items on the baseline questionnaire included education level; marital status; smoking history; usual alcohol intake during the past year; physical activity; reproductive history; and history of various medical conditions, including diabetes and heart disease. We asked women whether they had menstruated in the past year and asked them to state the age at which and the reason why their periods had stopped (natural menopause, surgery, medication, or other). We asked them whether they had ever used pills, other than birth control pills, which contain estrogen or other female hormones and how long they had used them. Response categories for duration of use were one month or less, 2-6 months, 7-12 months, 13 months-2 years, 3-5 years, or more than 5 years. Participants were asked whether their mothers, sisters, or daughters had ever had breast cancer. No information was collected on the number of relatives in a given category or on the age of relatives. For exclusion purposes, we ascertained the presence of prevalent cancer by asking participants whether they had ever been told by a physician that they had any form of cancer, excluding skin cancer. Participants reported their current height and weight and their weight at 18 years of age. A paper measuring tape was sent so that a friend, spouse, or relative could measure the circumferences of the waist (1 inch above the umbilicus) and the hips (maximum). The height, weight, and circumference measurements obtained by this protocol are valid and reliable [22]. Anthropometric values were used to derive current body mass index (weight in kg/height in m2), body mass index at 18 years of age (based on their current height), and the ratio of waist circumference to hip circumference. The second follow-up survey included questions on use of mammography, including whether the participants had ever undergone mammography and the length of time since the last mammography had been done. Cohort Follow-up Cases of breast cancer (codes 500 to 509 of the International Classification of Diseases for Oncology, Second Edition) among Iowa residents were ascertained through the State Health Registry of Iowa, which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (SEER) [23]. Each year, registry cases and cohort members were matched by a computer according to social security number, name, maiden name, and date of birth. Primary tumor site, date of diagnosis, nonspecific extent of disease, and tumor size were obtained for each incident cancer case from 1986 through 1993. Information on deaths was obtained from the State Health Registry of Iowa for Iowa residents and from the National Death Index for women who did not respond to the three follow-up surveys. Causes of death were coded according to the International Classification of Diseases, Ninth Revision [24]. Data Analysis Participants with the following baseline characteristics were excluded from the analysis: premenopausal status (n = 569), total or partial mastectomy (n = 1870), history of any cancer other than skin cancer (n = 2293), and unknown family history of breast cancer (n = 1186). After women with these characteristics were excluded, 35 919 women remained in the at-risk cohort for analysis. Women were considered to be at risk for breast cancer from January 1986 through 31 December 1993 or until one of the following censoring events occurred: diagnosis of breast cancer, death, relocation to an area other than Iowa, or other loss to follow-up. Person-years of follow-up for the mortality analyses were calculated from completion of the 1986 baseline questionnaire until death or the end of 1993. Characteristics of the women were collapsed into natural categories or quartiles. Use of HRT was categorized by status (current, former, and never) at baseline and by duration ( 5 years or >5 years). To describe the association of family history, HRT, and other variables with the incidence of breast cancer and total mortality rate, we computed age-adjusted rates and 95% CIs [25]; multivariate-adjusted relative risks and 95% CIs were derived through proportional hazards regression models by using the SAS program PHREG (SAS Institute, Cary, North Carolina) [26]. Multiplicative interactions were evaluated by comparing the 2 log likelihoods of models with and without the cross-product (interaction) terms within the context of proportional hazards regression. Results Risk Factors and Incidence of Breast Cancer After 8 years and more than 275 000 person-years of observation, 1085 cases of postmenopausal breast cancer were documented. The association of accepted risk factors [27] with incidence of breast cancer was evident in this cohort. Early age at menarche, late age at first birth, high waist-to-hip ratio, high body mass index, education, and alcohol intake were associated with increased risk; high body mass index at 18 years of age was associated with decreased risk (Table 1). All subsequent analyses of the incidence of breast cancer include adjustment for these risk factors in addition to current age, type of menopause, and age at menopause. Table 1. Multivariate-Adjusted Relative Risks for Potential Risk Factors for Breast Cancer among 35 919 Postmenopausal Women* Hormone Replacement Therapy and Incidence of Breast Cancer by Family History A family history of breast cancer in mothers or sisters was reported by 12.2% of the cohort at risk. Approximately 38% of the cohort at risk reported having ever received HRT. The frequency of reported use did not differ by family history: 38.3% of women without a family history and 37.7% of women with a family history (P > 0.2). Duration of use was similar (P > 0.2). After adjustment for the risk factors listed in Table 1, the relative risks for breast cancer among women who had formerly received HRT for 5 years or less or for more than 5 years were 1.04 and 0.89, respectively. The multivariate adjusted relative risks for current short-term ( 5 years) and long-term (>5 years) users of HRT were 1.34 (CI, 0.98 to 1.82) and 1.17 (CI, 0.90 to 1.51), respectively. The age-adjusted incidence rates of breast cancer associated with HRT use by family history of breast cancer are shown in Table 2. Among women without a family history of breast cancer, the rate of breast cancer in those who were currently receiving HRT and had been receiving it for at least 5 years was 41 cases per 10 000 person-years, a rate not significantly greater than the 36 per