The use of hormone replacement therapy following menopause appears to increase women's risk of developing breast cancer--in particular, a form of cancer known as a lobular tumor. Overall, results of a case-control study conducted among about 1,400 members of a managed care plan in Washington State suggest that recent, long-term use of hormone replacement therapy raised women's odds of developing breast cancer significantly over those of women who had never used postmenopausal hormones (odds ratios, 1.6-1.8). Moreover, the odds of lobular carcinoma were significantly elevated among women currently receiving oral estrogen (2.0) or a combination of estrogen and pro-gestin (3.9), while neither treatment approach significantly raised the odds of other forms of breast cancer. Similarly, women who had used oral hormone replacement therapy for most or all of the preceding five years had substantially increased odds of lobular breast cancer (odds ratio, 3.1), but their odds of developing other forms of breast cancer were only moderately elevated (1.5).1
To investigate the extent to which the use of replacement hormones contributes to the development of breast cancer, researchers identified women aged 50-74 who were enrolled in the Group Health Cooperative of Puget Sound and had had a first occurrence of primary breast cancer diagnosed between July 1, 1990, and December 31, 1995. Each breast cancer patient was linked with a woman randomly selected from the cooperative membership who was similar in duration of membership and age, and who served as a control. After excluding women with other cancers, those whose menopausal status was unknown and premenopausal women, the investigators were left with 705 women with breast cancer and 692 controls for analysis.
To study the women's use of hormones, the researchers relied on computerized pharmacy records that had been kept since 1977. All pills containing estrogen and progestin, as well as topical vaginal cream containing estrogen, were classified as hormone replacement therapies. In addition, the researchers studied responses from a breast cancer screening questionnaire that had been mailed to health plan enrollees aged 40 and older; they used this information to help estimate women's lifetime exposure to hormone replacement therapy.
Women were considered current users of hormone replacement therapy if they had received two or more prescriptions for it in the six months preceding the reference date (one year before diagnosis for women with cancer and a comparable date for controls). Enrollees were judged to have been past users if their pharmacy records showed two or more prescriptions for hormone replacement therapy but none in the preceding six months, or if they had indicated in the breast cancer screening questionnaire that they had used postmenopausal hormones. Women's use of continuous combined hormonal therapy or of sequential treatment was ascertained from pharmacy records of the number and type of pills prescribed.
Few background characteristics appeared to be related to the occurrence of breast cancer: The odds that cancer had developed were not significantly affected by women's age at menopause or at menarche, their parity or age at first birth, or their use of oral contraceptives. However, women with a family history of breast cancer and those who had had one or more mammograms prior to diagnosis had significantly elevated odds of breast cancer (age-adjusted odds ratios, 1.5-2.0). When the women's age, the year of diagnosis and the number of mammograms before diagnosis were taken into account, current use of combined hormone replacement therapy was associated with significantly elevated odds of breast cancer (odds ratio, 1.5); current use of oral estrogen only and past use of hormone therapy were not.
By contrast, a number of measures of recent use of supplementary hormones--i.e., use within the five years preceding the reference date--revealed significant associations with breast cancer risk. Women who had used any oral hormone replacement therapy for more than 56 months had significantly higher odds of breast cancer than nonusers (odds ratio, 1.7), and those who had used oral estrogen alone for the entire five-year period had similarly increased odds (1.8). Breast cancer odds were significantly elevated among women with about 36 months or more of combination or sequential hormonal treatment (1.6 each).
Finally, the researchers used histological and other information to classify the types of breast cancers identified--lobular tumors (which involve milk-producing cells in the breast) and other breast tumors (which primarily involve the ducts through which breast milk is usually delivered). They found that the odds of lobular carcinoma were significantly elevated among women currently receiving oral estrogen (odds ratio, 2.0) or combination treatment (3.9). In contrast, the odds of other forms of breast cancer were not significantly raised by either treatment approach. Likewise, women who had used oral hormone replacement therapy for 57 or more months in the past five years had substantially increased odds of lobular breast cancer (odds ratio, 3.1), but only moderately elevated odds of other forms of breast cancer (odds ratio, 1.5).
Using standard rates of breast cancers of various types, the investigators calculated that among nonusers of hormone replacement therapy, approximately 230 cases of ductal breast cancer and 23 instances of lobular breast cancer would occur per 100,000 women per year. In contrast, they estimated that among women who had used hormone replacement therapy for five years, 349 occurrences of ductal breast cancer and 70 of lobular breast cancer could be expected per 100,000 women per year.
The investigators comment that the pharmacy data on which the study was based offer information only on medications distributed, not on what was consumed. Moreover, no information was available on several potentially confounding variables, among them previous breast biopsies, history of breastfeeding and educational level. The researchers point out, however, that some previous studies have suggested similar associations between hormone replacement therapy and breast cancer, and they conclude that "the magnitude of risk, the fact that an association is biologically plausible, and a similar finding in other studies all argue in support of the causal nature of [the] association."--M. Klitsch
1. Chen C-L et al., Hormone replacement therapy in relation to breast cancer, JAMA, 2002, 287(6):734-741.