Reproductive Factors

Age at Menopause
Early studies of age at menopause and risk of breast cancer focused on women who had undergone bilateral oophorectomy at a young age; these women have a greatly reduced risk of breast cancer. Women who underwent bilateral oophorectomy before age 45 years have approximately one-half the risk of breast cancer of those who had a natural menopause at age 55 years or older. On average, the risk of breast cancer increases by some 3% per year of delay in age at menopause. Although some studies suggest that the effect of age at menopause decreases with advancing age at breast cancer diagnosis, this may reflect greater error in recall of age at menopause as women are further removed from the event. Adjustment for error in recall removes this apparent decrease in the effect of menopause with advancing age.

The reduction in risk of breast cancer with early menopause is probably due to the cessation of breast cell division with the termination of menstrual cycles and the decline in endogenous hormone levels, which become substantially lower than during the premenopausal years.

Models of Reproductive Factors and Breast Cancer Incidence
Biomathematical models relating epidemiologic risk factors of breast cancer can provide a structure to view the process of carcinogenesis. In addition, such models summarize the impact of multiple variables and provide a means of identifying areas that require more research. The classic models of carcinogenesis proposed by Armitage and Doll and by Moolgavkar and Knudson are the best known. Pike et al. reviewed the epidemiologic evidence in the early 1980s and proposed a model of tissue aging that accounted for the relationship between reproductive risk factors and breast cancer incidence. Ultimately, models ideally will be developed that take into account all known risk factors.

The mathematical model proposed by Pike was based on the observed age-incidence curve and on the known relation of the age at menarche, first birth, and menopause to the risk of breast cancer. The Pike model built on earlier work by Moolgavkar et al., who fitted mathematical parameters to breast cancer incidence data from several countries. The Pike model related breast cancer rates to the growth of the breast. The model allowed a short-term increase in risk with first pregnancy followed by a subsequent decrease in risk.

Finally, at menopause, the breast begins an involutional process that is thought to reflect a decrease in cell turnover and eventual disappearance of epithelium. The original Pike model, however, did not include terms for the second or subsequent births or for the spacing of pregnancies, nor did it easily accommodate pregnancies after age 40 years. Although controversy has existed about whether the bearing of additional children beyond the first reduces the risk of breast cancer, substantial evidence (reviewed in the section Number and Spacing of Births) indicates that both the number of births and their spacing are associated with risk: The greater the number of births and the more closely they are spaced, the lower a woman’s risk of breast cancer.

An extension of the Pike model of breast cancer incidence used prospective data from the Nurses’ Health Study and added a term to summarize the spacing of births. Nonlinear models produced parameters that were difficult to interpret, but a subsequent modification allowed ready estimation of relative risks, thus making the results more accessible to epidemiologists and clinicians familiar with the relative risk as a measure of the relation between an exposure and disease. Before menopause, the incidence of breast cancer increased 1.7% for each 1-year increase in age at first birth. Closer spacing of births was related to significantly reduced risk of breast cancer. For each additional year of delay between the first and second births, for example, the risk of breast cancer increased by 0.4%. The increase in risk with first pregnancy originally observed with this modified Pike model has since been documented in a prospective study from Sweden and in an analysis from an international case control study. The effects of age at first and subsequent births on breast cancer incidence were still greater after menopause.

According to the extended Pike model, a parous woman with a single birth at age 35 years has a 34% increase in breast cancer incidence at the time of the birth relative to a nulliparous woman. The excess risk goes down very slowly over time. Even at age 70 years, such a woman has a 19% excess risk relative to a nulliparous woman. Conversely, a parous woman who had first birth at an early age and multiple births conceived at a young age has a slight excess risk immediately after the first birth relative to the nulliparous woman (relative risk, 1.10); this risk slowly diminishes over time, reaching equality with the nulliparous woman at age 32 years and continuing to decline until menopause (age 50), at which time the relative risk is 0.82. Because the relationship between breast cancer incidence and reproductivehistory changes with age, cumulative incidence rather than age-specific incidence is a useful summary. A woman with one birth at age 35 years has a 21% excess risk over the age period of 30 to 70 years compared with a nulliparous woman, whereas a woman with births at ages 20, 23, and 26 years has a 25% decrease in risk over the same age period compared with a nulliparous woman.

In the original Pike model, factors associated with reduced risk of breast cancer were each considered to slow the rate of “breast tissue aging,” which correlates with the accumulation of molecular damage in the pathway to breast cancer. In the Rosner and Colditz extension of the Pike model, the rate of tissue aging was highest between menarche and first birth, consistent with the hypothesis that this is the period when the breast is most vulnerable to mutagenesis. The transient increase in the risk of breast cancer associated with the first pregnancy is followed by a 20% decrease in the rate of breast tissue aging. This observation helps explain the crossover effect in certain subgroups of women: Around menopause, rates of one subgroup that were initially higher drop below rates of a second subgroup. For instance, using data from New York State, Janerich and Hoff showed a crossover in breast cancer incidence between single and married women at age 42 years, such that married women had a higher incidence before this age and lower mortality thereafter. A similar crossover of incidence has been reported for African-American and white women in the United States, consistent with the distribution of age at first birth by race. Over many decades, pregnancy rates have been higher and age at first birth has been younger for African-American women than for white women.

The age-incidence curve from biomathematical models of reproductive events and breast cancer incidence also mirrors the observed patterns of breast cancer incidence in many countries. In China and many developing countries, the estimated number of births in the early 1960s was 6.5 births per woman and is not associated with a late age at first birth. Also, the average age at menarche in China was approximately 17 years, even through the 1960s. When the Rosner model is fitted with menarche at age 16 years, first birth at age 19 years, 6 births spaced a year apart, and menopause at age 50 years, the annual rate of breast cancer incidence for 65-year-old women in China is estimated to be 93.6 per 100,000. For the cohort of U.S. women born from 1921 to 1925, the average age at menarche was approximately 13.5 years, the median age at first birth was 23 years, the mean number of children was 3, and the mean interval between births was 3 years. Considering these characteristics, and holding age at menopause constant at 50 years, the annual rate of breast cancer incidence predicted for 65-year-old U.S. women is 279 per 100,000—close to the observed SEER rate of 300 per 100,000 for women of this age, and approximately three times the rate for Chinese women. Applying this model to typical reproductive patterns for women from low-incidence countries suggests that that reproductive factors alone account for more than one-half of the international variation in the risk of breast cancer. Further development of these models to include other risk factors will provide an increasingly comprehensive prediction of breast cancer risk.

Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz

W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
B. Rockhill: Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts
D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts
G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts



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