Andrey Nailor, M.D.·Published 6 June 2008·14 min read
Key points
This section addresses reproductive factors during the course of a woman's life in relation to risk of breast cancer.
Age at Menarche Menarche represents the development of the mature hormonal environment of a young woman, and the onset of monthly cycling of hormones that induce ovulation, menstruation, and cell proliferation within the breast and endometrium.
Although menarche is most clearly related to the onset of ovulation, some, but not all, studies suggest that hormone levels may be higher through the reproductive years among women who have early menarche.
Menstrual Cycle Characteristics Shorter cycle length has been quite consistently related to greater risk of breast cancer, although not all studies support this relation.
This section addresses reproductive factors during the course of a woman's life in relation to risk of breast cancer. An underlying concept is that ovarian hormones initiate breast development and that subsequent monthly menstrualcycles induce regular breast cell proliferation. This pattern of cell division terminates with a natural menopause, as indicated by cessation of ovulation and menstrual periods.
Age at Menarche Menarche represents the development of the mature hormonal environment of a young woman, and the onset of monthly cycling of hormones that induce ovulation, menstruation, and cell proliferation within the breast and endometrium. Earlier age at menarche has been consistently associated with increased risk of breast cancer. Most studies suggest that age at menarche is related to both premenopausal and postmenopausal breast cancer risk.
Although menarche is most clearly related to the onset of ovulation, some, but not all, studies suggest that hormone levels may be higher through the reproductive years among women who have early menarche. In addition, early menarche may be associated with more rapid onset of regular, ovulatory menstrual cycles and hence greater lifetime exposure to endogenous hormones. Whether the levels of ovarian hormones or their cyclic characteristics are the underlying influence on breast cancer risk is undetermined; both likely play a role.
Menstrual Cycle Characteristics Shorter cycle length has been quite consistently related to greater risk of breast cancer, although not all studies support this relation. Shorter cycle length during ages 20 to 39 years may be associated with higher risk of breast cancer, perhaps because the shorter cycle length is associated with a greater number of cycles and more time spent in the luteal phase, when both estrogen and progesterone levels are high. Long and irregular cycles may also be related to reduced risk of breast cancer.
Ovulatory infertility, an indicator of infertility due to hormonal causes, has not been consistently related to risk of breast cancer, although one cohort study suggested a substantially lower risk among women with this condition (relative risk of 0.4 compared with women with no infertility history). The significant inverse association seen in this study may be due to the young age of the cohort and thoroughness of investigation of the cause of infertility in this group of health professionals.
Pregnancy and Age at First Full-Term Pregnancy Nulliparous women are at increased risk of breast cancer compared with parous women. This risk is evident after age 40 to 45 years, but not for breast cancer diagnosed at younger ages. In the majority of epidemiologic studies, a younger age at first full-term pregnancy predicts a lower lifetime risk of breast cancer. The reduction in risk after pregnancy compared with nulliparity is not immediate but takes 10 to 15 years to manifest. In fact, risk of breast cancer is increased for the first decade after the first pregnancy. The proliferation of breast cells during the first pregnancy results in differentiation into mature breast cells prepared for lactation; this may also lead to growth of mutated cells and excess risk over the next decade. Epidemiologic evidence for the transient excess risk after the first pregnancy is consistent. Less clear is the presence of a transient increase in risk after subsequent pregnancies; some studies suggest an adverse effect, but others do not.
Written and revised by
Andrey Nailor, M.D.
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The first pregnancy is associated with permanent changes in the glandular epithelium and with changes in the biological properties of the mammary cells. After the differentiation of pregnancy, epithelial cells have a longer cell cycle and spend more time in G1, the phase that allows for DNA repair. The longer the interval from menarche to first pregnancy, the greater the adverse effect of the first pregnancy. The later the age at first full-term pregnancy, the more likely that DNA mistakes have occurred that will be propagated with the proliferation of mammary cells during pregnancy. The susceptibility of mammary tissue to carcinogens decreases after the first pregnancy, reflecting the differentiation of the mammary gland. This is seen in the age-dependent susceptibility of the breast to radiation, reviewed in the section Ionizing Radiation.
Number and Spacing of Births A higher number of births is consistently related to lower risk of breast cancer; each additional birth beyond the first reduces long-term risk of breast cancer. Although in some analyses this has not been independent of earlier age at first birth, the overall evidence indicates an independent effect of greater parity. In addition to a protective effect of higher parity, several studies indicate that more closely spaced births are associated with lower lifetime risk of breast cancer. This may be due to the breast's having less time to accumulate DNA damage before it attains maximal differentiation by repeated pregnancies.{pagebreak}
Lactation As early as 1926, the proposal was made that a breast never used for lactation is more likely to become cancerous. This hypothesis is consistent with knowledge of breast physiology and breast carcinogenesis, as well as with patterns of international variation in breast cancer incidence: Rates are lower in populations in which breast-feeding is both common and of long duration. The overall evidence from case control and cohort studies supports a reduction in risk with longer duration of breast-feeding, but the findings have varied substantially in the level of risk reduction. A review of 32 studies published through 1998 (R. Blum and G. Colditz, personal communication, 1998) showed that only 2 were prospective,and only 16 of 32 demonstrated a statistically significant lower risk with longer duration of breast-feeding.51 The strongest results supported at least a 50% reduction in risk for women who breast-fed for 2 or more years, but this was in the setting of extremely high parity. Some of the differences may relate to the pattern of breast-feeding, for example, whether feeding was exclusively from the breast or supplemented with other food; this needs to be evaluated further.
Social norms regarding parity and breast-feeding in American culture have limited the ability even to study this potential preventive behavior; the population that breast-feeds at all is small, and the group that breast-feeds over an extended period is even smaller. For example, despite the strong recommendation of the American Academy of Pediatrics that infants be breast-fed through the first 6 months of life because of unequivocal benefit to the infant, in 1988 breast-feeding was practiced by only 32% of new mothers. Although low, this still represents a doubling since 1970.
Spontaneous and Induced Abortion Close to one-quarter of all clinically identified pregnancies in the United States end as induced abortions, and for women whose pregnancies continue for 8 to 28 weeks, the probability of spontaneous abortion ranges from 8% to 12%. It has been suggested that breast cells are the most vulnerable to mutation when breast tissue consists of rapidly growing and undifferentiated cells, such as during adolescence and pregnancy. In early pregnancy, the number of undifferentiated cells increases as rapid growth of the breast epithelium takes place. If the pregnancy continues to term, these cells differentiate by the third trimester; thus, the number of cells susceptible to malignancy decreases.
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The interruption of the differentiation of breast cells that takes place as a result of spontaneous and induced abortions has been hypothesized to increase a woman's risk of developing breast cancer. This hypothesis appears to be supported by a meta-analysis that included data from 28 published reports on induced abortion and breast cancer incidence. This analysis, however, based largely on case control studies, contains the underlying serious potential for bias in retrospective studies of the relationship between abortion and breast cancer. Induced abortion can be an extremely sensitive topic, and reporting on abortion history by women with a life-threatening condition such as breast cancer may be more complete than reporting by women without breast cancer.
Other studies provide a different picture of the association between breast cancer and abortion. In a hospital-based case control study including 1,803 women with breast cancer, the relative risk among parous women was 1.1 (95% confidence interval of 0.9 to 1.5) for women with a history of any induced abortion compared with women who had never had induced or spontaneous abortion. The relative risk associated with induced abortions in nulliparous women was 1.3 (95% confidence interval, 0.9 to 1.9). Spontaneous abortions similarly were not associated with increased breast cancer risk. Although selection bias could not be ruled out, this large study provided little support for an increase in breast cancer risk in association with spontaneous or induced abortion. In another large case control study, only abortions performed before they were legal in the United States were associated with risk of breast cancer, thus supporting the likelihood of bias in case control studies. Given these concerns regarding recall bias in case control studies of induced abortion and risk of breast cancer, greater weight must be placed on the results from prospective studies that are by design free from such recall bias.
By far the strongest study on the association between breast cancer and abortion was a population-based cohort study made up of 1.5 million Danish women born April 1, 1935 through March 31, 1978. Of these women, 280,965 (18.4%) had had one or more induced abortions. After adjusting for potential confounders of age, parity, age at delivery of first child, and calendar period, the risk of breast cancer for women with a history of induced abortion was no different from that for women who had not had an induced abortion (relative risk, 1.0; 95% confidence interval, 0.94 to 1.06). The number of induced abortions in a woman's history also had no significant relation to risk of breast cancer. A statistically significant increase in risk was found among the very small number of women with a history of second-trimester abortion. Results from this population-based prospective cohort thus provide strong evidence against an increase in risk of breast cancer among women with a history of induced abortion during the first trimester. Taken as a whole, and accounting for the limitations of the case control study design, the available evidence does not support any important relation between induced abortion and risk of breast cancer.{pagebreak}
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.
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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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