1 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO.
2 New York State Cancer Registry, New York State Department of Health, Albany, NY.
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ABSTRACT |
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age factors; breast neoplasms; birth weight; infant, premature; prenatal exposure delayed effects; risk factors; women's health
Abbreviations: CI, confidence interval; IGF-1, insulin-like growth factor-1; OR, odds ratio
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INTRODUCTION |
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However, findings regarding the association of specific pre- and perinatal factors with breast cancer risk have been inconsistent (9), perhaps in part because of differences between studies in the ascertainment and definition of exposure. Differences in age at breast cancer diagnosis may also help explain some of the variation in results. Some evidence suggests that the influence of early life factors may vary by age at breast cancer onset. In particular, the relation of breast cancer risk to parental age (1
, 14
, 15
), birth weight (3
, 4
), and other factors (3
) may be more apparent in younger women. Few studies have specifically investigated the influence of perinatal factors on the development of early-onset breast cancer (1
, 3
, 4
, 14
17
), and even fewer have had sufficient power to assess this association in very young women (3
, 16
), in whom the relative influence of perinatal factors on breast cancer risk may be especially pronounced (3
). In this population-based study of women born in New York State, we evaluated the relation between a woman's own birth characteristics and her risk for breast cancer before age 38 years.
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MATERIALS AND METHODS |
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Cases were defined as all women who were diagnosed with breast cancer in New York State between 1978 and 1995 and who were also born in New York State after 1957. These dates correspond to the years for which computerized cancer and birth registry data were available from the New York State Department of Health; birth records from New York City were added to the computerized New York State Department of Health birth registry beginning in 1970. Tumor record information for each woman was then linked to that regarding her own birth by using a custom algorithm and a standard graduated scoring system. Matching variables included the woman's social security number (64 points), full maiden name (32 points), date of birth (24 points), race (2 points), and county of residence (1 point). Successfully matched records were also checked manually to ensure accuracy. A total of 484 cases were matched to their birth records, representing an estimated matching success rate of 38 percent overall after adjustment for absence of New York City birth records prior to 1970 (correction factor calculated by using birth record (19551980) and population (19781995) data from New York State (18)). Among matched cases, age at diagnosis ranged from 14 to 37 years and averaged 30.3 years (standard deviation, 4.4). The distribution of successfully matched cases was similar to that of unmatched cases with regard to age at diagnosis, year of diagnosis, tumor stage at diagnosis, and marital status (table 1). A larger percentage of unmatched cases was categorized as non-White (table 1) because of the underrepresentation of New York Cityborn women among matched cases (18
). Over 95 percent of eligible cases were born prior to 1970, when computerized birth data for New York City were not yet available.
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By using information available in the upstate New York (1958 and later) and New York City birth (1970 and later) records, we investigated the relation of breast cancer risk to specific pre- and perinatal factors known or suspected to affect maternal-fetal hormone levels and/or germ cell mutations. These factors included birth weight (in increments of 1,000 g, as coded on the 19571968 birth records), gestational age (clinical estimate in weeks), multiple birth (yes vs. no), birth order, maternal marital status (married vs. unmarried), maternal age, paternal age, and maternal race. We also evaluated two complications of pregnancy for which data were sufficient for analysis: abruptio placentae (coded on the birth record as premature separation of the placenta) and preeclampsia/eclampsia (coded on the birth record as preeclampsia and/or eclampsia). During the time period in which the study subjects were born (19581976), these categories remained constant. From 1958 to 1967, an additional category for preeclampsia (unspecified toxemia) was also included, although none of the subjects in this study was coded positive for this diagnosis.
We used conditional logistic regression to evaluate the association between these factors and risk for breast cancer and to assess the influence of potential confounders (20). In addition, we conducted separate analyses stratified by factors shown in previous studies to modify the association between breast cancer risk and specific perinatal exposures (1
, 3
, 5
, 21
, 22
). These factors included birth order (first or second vs. later born), age at diagnosis (<30 vs.
30 years), and maternal age at delivery (<30 vs.
30 years). Since breast cancer incidence and mortality patterns differ by race (23
), and the association of adult risk factors with breast cancer has been reported to vary by stage at diagnosis (in situ or localized vs. regional or with distant metastases) (24
), we also examined the potential modifying effects of race and disease stage.
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RESULTS |
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Stratified analyses suggested that young African-American women were more likely than young White women to be diagnosed with advanced-stage disease (OR = 2.1, 95 percent CI: 1.3, 3.3) but not with in situ or localized tumors (OR = 1.0, 95 percent CI: 0.6, 1.7). The association of Black race with breast cancer risk also appeared stronger among first- or second-born women (OR = 3.6, 95 percent CI: 2.0, 6.5) than among those born later (OR = 1.1, 95 percent CI: 0.6, 1.9) and among those born to younger mothers (OR = 1.9, 95 percent CI: 1.3, 2.7 vs. OR = 1.0, 95 percent CI: 0.5, 2.1, respectively, for maternal ages <30 and 30 years). In contrast, we found little evidence for a modifying influence of tumor stage, birth order, race, or maternal age on the association between breast cancer risk and other birth characteristics (i.e., maternal parity, multifetal gestation, and parental age) for which case numbers were sufficient for meaningful analysis. Likewise, our data did not support an interaction between age at diagnosis and any perinatal or demographic factors.
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DISCUSSION |
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In this population-based study of very young New York Stateborn women, risk for early-onset breast cancer was influenced by several perinatal factors, some of which may reflect hormonal or other exposures in utero. Our results suggest a J-shaped relation between a woman's own birth weight and her subsequent risk of developing breast cancer and that high birth weight carries an especially pronounced increase in risk. Birth weight is associated positively with circulating estrogen levels (25, 26
) and, possibly, insulin-like growth factor-1 (IGF-1) activity (27
); conversely, fetal weight is correlated negatively with both fetal and maternal levels of IGF-1 binding protein. Both estrogens and IGF-1 are thought to be important in fetal growth (27
) and mammary gland development (28
) and to play a central, synergistic role in the initiation and promotion of breast cancer (29
32
). Recent work with rodent models has also shown that exposure to estrogens during fetal and early postnatal development can increase mammary tumorigenesis by altering both proliferation and differentiation of the mammary gland (28
).
Two US studies have demonstrated strong positive links between higher birth weight and breast cancer risk (3, 4
), while two Swedish studies reported weak or no associations (2
, 7
). However, stratified analyses from the US investigations suggest that birth weight is more strongly related to early than to later-onset breast cancer, perhaps helping to explain some of the inconsistencies among studies. In agreement with our findings, Sanderson et al. also reported a J-shaped association between birth weight and breast cancer risk among women aged 2145 years; that association was especially pronounced among women aged 30 years or less at diagnosis (OR = 3.3, 95 percent CI: 1.0, 11.0 for a birth weight of
4,000 g) (3
). In contrast, these investigators observed no association among women aged 50 years or more. Similarly, Michels et al. found a stronger relation between high birth weight and breast cancer risk among women less than age 50 years than in those aged 50 years or more (4
).
In our study, maternal placental abruption and severe prematurity appeared to reduce subsequent risk for very early onset breast cancer. To our knowledge, this is the first study to investigate the association between abruptio placentae and breast cancer risk. Of the two studies that have examined the influence of severe prematurity, one reported an increased risk for breast cancer among women born at less than 33 weeks (2), while another found no association (4
). One population-based study of Swedish men, however, observed that birth at 35 weeks or less strongly reduced risk for another hormone-related neoplasm, prostate cancer (OR = 0.31, 95 percent CI: 0.09, 1.00) (33
), although this finding was based on small numbers of cases. Both abruptio placentae and prematurity are associated with elevated levels of human chorionic gonadotropin (34
37
) and alpha-fetoprotein (37
41
). Thought to be important in differentiation of the human breast, human chorionic gonadotropin has been shown to inhibit growth of human breast cancer cell lines (42
), to be a potent differentiating and apoptotic agent in rodent models of breast cancer (42
44
), and to be associated with reduced breast cancer risk in premenopausal women (45
). Likewise, alpha-fetoprotein has been shown to reduce growth of estrogen-responsive tissues and to cause regression of estrogen-dependent breast cancer in rodents (46
, 47
).
Our finding of a rising breast cancer risk with increasing maternal age is consistent with some (2, 5
, 6
, 15
, 17
, 48
50
) but not all (3
, 51
) studies. A large cohort study reported an increased risk of breast cancer death for women born to very old mothers (age
45 years) only, although the data were not stratified by patient age (52
). Data from several investigations suggest that the relation between maternal age and breast cancer risk may be stronger in younger women (1
, 14
, 15
, 22
). For example, an earlier investigation reported an increasing case-control difference in mean maternal age with decreasing age at cancer onset (14
). In a recent study of women aged 2054 years, Weiss et al. reported no association between maternal age and breast cancer risk in the group overall but found evidence for a positive relation among women less than age 45 years (1
). Data from Le Marchand et al. suggest a still stronger association between maternal age and breast cancer risk among women less than age 33 years (15
).
In our study, older paternal age was also linked to increased breast cancer risk, although adjusting for maternal age substantially reduced this association. Some studies have suggested a positive link between paternal age and breast cancer risk (5, 14
, 15
, 53
), while others have indicated no relation after controlling for maternal age and other risk factors (22
, 48
, 51
, 52
). Again, some of this variability in findings could in part reflect differences in age at diagnosis. Of the three studies that presented adequate age-stratified data (14
, 51
, 53
), two suggested a stronger association between paternal age and breast cancer in very young women (14
, 53
).
Older parental age may be associated with elevated rates of germ cell mutations, rendering the offspring more susceptible to early-onset breast cancer, just as inherited germ-line mutations (e.g., BRCA1 and BRCA2) increase risk for breast cancer at young ages. Increasing paternal age, especially more than 40 years (54, 55
), has been associated with an increased frequency of mutations in the offspring (11
). The idea that older maternal age might also increase the rate of somatic mutations in ovarian germ cells is not new. The risk of fetal chromosomal abnormalities clearly increases with increasing maternal age (54
, 55
). Chromosomal disorders and genetic diseases of defective chromosome repair have been associated with a dramatically increased risk for several early-onset cancers (56
). This elevated risk may reflect an impaired ability to repair DNA damage and correct mutagenic changes, as suggested by the marked radiosensitivity that characterizes several of these disorders (56
). If maternal age influences not only the risk for congenital genetic disorders but also the ability to repair DNA damage, even the apparently genetically normal offspring of older mothers may be more vulnerable to mutagenic changes that lead ultimately to the initiation and promotion of breast cancer.
Factors other than genetic mutations may also explain the observed elevation in breast cancer risk among young women born to older mothers. The hormonal and nutritional environment characterizing the pregnant uterus changes as a woman ages. Older mothers are at increased risk for a host of adverse pregnancy outcomes unrelated to genetic defects (57). Evidence also exists that older mothers have altered hormonal profiles during pregnancy (58
), including increased production of catecholestrogens (59
), which have been implicated in the initiation and promotion of breast cancer (60
, 61
).
In our study, high birth rank was also associated with an increased risk for early-onset breast cancer, but this effect was substantially attenuated after adjustment for maternal age. Previous findings regarding birth rank and later breast cancer have been inconsistent. While some have suggested an increased risk among first-born women (21) that may be modified by maternal age (22
), most studies have reported little or no association between birth rank and breast cancer risk (3
, 5
, 15
, 17
, 49
).
Our finding of an increased risk for breast cancer, and particularly for advanced-stage breast cancer, among young African-American women is consistent with those of previous studies (19, 23
). The Black-White differences in breast cancer incidence and mortality remain largely unexplained (62
), although socioeconomic, adult lifestyle, and genetic factors may all play a role (23
). Intrauterine exposures, including maternal diet and circulating hormone levels during pregnancy, may also be important. Experimental work with rodent models has shown a high maternal fat intake during pregnancy to increase mammary tumorigenesis in female offspring, in part by increasing circulating estrogen levels (28
). Black women are more likely than White women to report a diet high in fat (63
), and Black women less than age 45 years appear particularly at risk for a higher dietary fat intake (64
). In a matched cross-sectional study of 40 primiparous women, Henderson et al. found that first-trimester estrogen and testosterone levels were 3037 and 48 percent higher, respectively, in Black than in White women (65
), which may in part reflect this higher fat consumption.
The present study of very early onset breast cancer has several strengths, including its large size and its population-based design. Data on birth characteristics were derived from vital records and were thus gathered far in advance of breast cancer diagnosis. Hence, any bias in exposure ascertainment is unlikely to be related to subsequent diagnosis of breast cancer in this study. In particular, the influence of interviewer, recall, or diagnostic bias is likely to be nil.
Use of state vital record and tumor registry data as our information source had some inherent limitations. We were unable to adjust for adult risk factors, including the subject's own reproductive history, family history of breast cancer, or body mass index. However, it seems improbable that confounding by unmeasured variables could explain our findings. First, in several previous investigations, adjustment for reproductive and other potentially confounding factors did not appreciably alter the risk estimates associated with maternal age (48, 49
), preterm birth (2
, 4
), high birth weight (3
, 4
), or other perinatal factors (1
, 2
). In addition, some established risk factors appear more weakly related to very early onset breast cancer. For example, the association between nulliparity and breast cancer risk is less apparent among women less than age 40 years (66
, 67
).
A potential source of bias is underreporting of certain pregnancy outcomes in the New York State vital records. In particular, the recorded incidence of preeclampsia (1.5 percent) was lower than would be expected given current incidence estimates of 46 percent of pregnancies in the general US population (68, 69
). However, such reporting omissions are likely to be nondifferential with respect to later breast cancer diagnosis and thus would tend to reduce rather than inflate risk estimates. Since gestational age estimates were based on the last menstrual period, a method that tends to overestimate true gestational age (70
, 71
), preterm birth is also likely to have been underreported. In addition, the incidence of abruptio placentae in controls (1.4 percent) was consistent with incidence rates reported in several large, earlier studies (72
) but was slightly higher than current estimates of 0.81.0 percent (73
). However, any such misclassification is again unlikely to be differential with regard to subsequent breast cancer diagnosis. More importantly, vital record data on birth weight and maternal age, the two factors that showed the strongest associations with breast cancer risk in this study, are likely to be both complete and accurate.
The relatively low matching success rate among cases is also a potential source of bias. However, matching failure is unlikely to be related to the exposures of interest and thus to affect the observed associations. Demographically, matched cases were also similar to unmatched cases, which argues further against a differential bias in case selection. Some controls may have been diagnosed with breast cancer in another state, and some may also have died prior to the age at which the corresponding cases were diagnosed. However, both mortality and breast cancer are rare at the age of less than 38 years. Any mortality related to perinatal factors would be expected to occur primarily during the first year of life, and all controls who died during this period were removed from the study.
In brief, the results of this study offer further evidence that early life factors may be important determinants of early-onset breast cancer. In particular, our findings of increased breast cancer risk with high birth weight and older maternal age are consistent with a mediating influence of either intrauterine hormonal factors or germ cell mutations.
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ACKNOWLEDGMENTS |
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The authors acknowledge Gene Therriault, Director, and Peter Herzfeld, Research Scientist, of the Bureau of Biometrics, New York State Department of Health for their patience and persistence in creating the linked data set and for offering numerous helpful suggestions and comments during various stages of this project.
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NOTES |
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REFERENCES |
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