Affiliations of authors: J. R. Cerhan, J. E. Olson, T. A. Sellers, Department of Health Sciences Research, Mayo Clinic, Rochester, MN; L. H. Kushi, A. R. Folsom, Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis; S. S. Rich, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; W. Zheng, University of South Carolina School of Public Health, South Carolina Cancer Center, Columbia.
Correspondence to: James R. Cerhan, M.D., Ph.D., Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: cerhan.james{at}mayo.edu).
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ABSTRACT |
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INTRODUCTION |
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Data on the relationship between zygosity status and the levels of estrogen and other pregnancy hormones are available from only a single small study (4), which found that dizygotic (compared with monozygotic) twin pregnancies have elevated levels of human placental lactogen but not of urinary estrogen. Levels of serum estrogen (11) and gonadotropin (11,12) are higher in mothers who have had dizygotic twins than in mothers who have had monozygotic twins or singletons, which is consistent with the relationship between hormone levels and dizygotic twinning (13). Finally, estrogen levels are higher in singleton pregnancies with a female fetus (14,15), but no data exist on whether maternal or fetal estrogen levels vary by zygosity and sexes of the twins in a pregnancy, although levels of human chorionic gonadotropin in both maternal and cord blood are higher in female-female and female-male twins than in male-male twins at delivery (16). Given this background, we evaluated whether membership in a twin pair, zygosity, and sex of the co-twin were associated with postmenopausal breast cancer risk in a cohort of older women from the state of Iowa.
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SUBJECTS AND METHODS |
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Total mortality and cancer incidence from 1986 through 1996 were determined by linkages to the Iowa death certificate database and the Iowa Cancer Registry, the latter of which is part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program1 (20). Linkage was based on a combination of Social Security number; first name, last name, and maiden name; birthdate; and ZIP code. The linkage data were supplemented by information from the four follow-up surveys and, for survey nonrespondents, by linkage to the National Death Index.
For these analyses, we excluded women who were premenopausal, had had a mastectomy or partial breast removal, or had reported any cancer other than skin cancer at baseline in 1986, which left 37 105 women in the at-risk cohort. We further excluded women who were deceased at the time of the 1992 questionnaire or who did not respond to it (n = 7618), as well as women who responded to it but who had missing data on twin status (n = 290), which left 29 197 women in the at-risk cohort; the latter two exclusions eliminated 290 cases of breast cancer that occurred among the nonrespondents through 1996.
Length of follow-up time for each woman was calculated from the date of return of the baseline questionnaire to 1) the date of a breast cancer diagnosis in Iowa, 2) the date of her emigration from Iowa, or 3) the date of her death. If none of these events occurred, the date of last follow-up was considered to be December 31, 1996. Cox proportional hazards regression (21) was used to estimate the age- and multivariate-adjusted risk ratios (RRs) and their 95% confidence intervals (CIs) for the association between aspects of twin membershipi.e., whether the woman belonged to a pair of twins and the nature of that pairand breast cancer incidence. The assumption of proportional hazards for the main exposure of interest (twin membership) was tested and found not to be violated.
Multivariate RRs were adjusted for factors associated with breast cancer risk in this dataset,
including educational level (less than high school, some high school or graduated from high
school, or
more than high school), family history of breast cancer (no or yes), age at menarche (<12
years, 12
years, 13 years, 14 years, or >14 years), age at first live birth (<20 years, 20-24 years, 25-29
years, 30 years, or nulliparous), height in meters (as a continuous variable), body mass
index (i.e.,
weight in kg/height in m2) at baseline (as a continuous variable), body mass index
at age
18 years (as a continuous variable), waist-to-hip ratio (as a continuous variable), use of hormone
replacement therapy (never, former, or current), and alcohol use (none, <4 g/day, or
4
g/day).
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RESULTS |
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There were 538 twins (1.8%) in the at-risk cohort of 29 197. Of these twins, 24% (n = 130) reported being monozygotic, 63% (n = 337) reported being dizygotic, and 13% (n = 71) were not sure of their zygosity status or their zygosity status information was missing; of the women who reported that they were not sure of their zygosity status, all reported a female co-twin. Of the 463 women with complete data on both zygosity and sex of the co-twin (four women had missing data on the sex of their twins), 40% had a male co-twin, 32% had a dizygotic female co-twin, and 28% had a monozygotic female co-twin. There were 25 pairs of twins who both participated in the Iowa Women's Health Study: 12 pairs who were concordant for dizygotic status, seven pairs who were concordant for monozygotic status, and three pairs who were concordant for reporting "not sure of zygosity status." Only three pairs of twins were discordant in their report of zygosity: In two pairs, one twin reported being dizygotic, while the other twin reported being unsure of her zygosity status; and in one pair, one twin reported being monozygotic, while the other twin reported not being sure of her zygosity status.
There were no striking differences in the major known breast cancer risk factors in this
dataset
between singletons and twins (Table 1). From 1986 through 1996
(301 777
person-years of follow-up), 1230 breast cancers were identified in the at-risk cohort. Compared
with
singletons, women who were members of a twin pair showed a statistically significant increase in
their
risk of breast cancer after adjustment for other breast cancer risk factors (RR = 1.72;
95% CI = 1.22-2.42) (Table 2
). Elevated risk was confined
to
dizygotic twins (RR = 1.77; 95% CI = 1.16-2.70), as there was no elevation
in
risk for women who were a monozygotic twin (RR = 1.04; 95% CI =
0.43-2.50). In addition, risk was higher if the sex of the other twin was female (RR =
1.82;
95% CI = 1.20-2.75) rather than male (RR = 1.49; 95% CI =
0.80-2.78), and the highest risk was seen for female dizygotic twins (RR = 2.14;
95% CI
= 1.21-3.79).
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DISCUSSION |
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We relied on self-report of twin membership, co-twin sex, and zygosity. The first two variables would be expected to be reported accurately, as long as the co-twin was born. The self-report of zygosity would be accurate for co-twins of the opposite sex, but zygosity may not be known or may be incorrectly reported for a certain percentage of same-sex twins. However, this misclassification would be expected to be random with respect to breast cancer status (for both prevalent and incident cases) and would likely at tenuate any association with breast cancer risk.
A potential survival bias could occur in these data because twin membership was not determined until 6 years after baseline (at the third follow-up in 1992), and thus approximately half of the breast cancer cases were prevalent and represent breast cancer survivors. However, there was little evidence for such a bias because there were no striking differences in breast cancer risk factors in 1986 between women who participated in 1992 and those who did not, and the breast cancer rates for 1986-1992 were similar for participants and nonparticipants. Most importantly, exclusion of prevalent cases (i.e., cases diagnosed between baseline and 1992) did not alter our results.
There are relatively few studies of twinship and breast cancer risk. In a medical records-based case-control study nested in a cohort of births at five Swedish hospitals from 1874 through 1961, Ekbom et al. (8) found that dizygotic twins (crude odds ratio [OR] = 1.52) but not monozygotic twins (OR = 0.59) were at increased breast cancer risk (mainly after menopause) compared with singletons (no CIs reported). Adjustment for maternal age, socioeconomic status, parity, pregnancy toxemia, neonatal birthweight, prematurity, and jaundice did not attenuate the results obtained by Ekbom et al. for dizygotic twins (OR = 1.72; 95% CI = 0.92-3.20). Hsieh et al. (6), using data from an international case-control study, found an elevated OR for breast cancer for women who were twins (crude OR = 1.58; no CI reported) compared with singletons, and this association was only slightly attenuated (OR = 1.40; 95% CI = 0.77-2.55) after adjustment for age, parity, age at first birth, age at menarche, height, body mass index, maternal age at birth, birth order, and menopausal status. However, in contrast to our study, risk was slightly higher if the co-twin was male (OR = 1.54; 95% CI = 0.64-3.71) rather than female (OR = 1.30; 95% CI = 0.58-2.92), and the association was weaker among postmenopausal women (OR = 1.14; 95% CI = 0.53-3.45) than among premenopausal women (OR = 2.03; 95% CI = 0.74-5.55); however, none of these estimates were statistically significant. In contrast to our findings, Sanderson et al. (9), using two population-based, case-control studies conducted in the Seattle, WA, area, found no association with being a twin (yes/no) for women aged 50-64 years (OR = 0.9; 95% CI = 0.4-2.2) and a suggestive inverse association for women aged 21-45 years (OR = 0.6; 95% CI = 0.3-1.3). This study did not include data on zygosity.
Studies of the breast cancer experience occurring in registries of twins compared with the general population have found both increased risk (7) and null results (24,25), although the design of the twin registry of one of the null studies (25) has been criticized on methodologic grounds (24), and reanalysis of the other null study (24) suggests that dizygotic twinsbut not monozygotic twinsare at elevated breast cancer risk compared with singletons (6). The positive twin study (7) found that the increased risk of breast cancer was confined to dizygotic twins aged 20-29 years (standardized incidence ratio = 6.7; 95% CI = 2.9-13.1).
At an ecologic level, there is a strong correlation (r = .74; P<.005) between the twinning rate, which is due almost exclusively to the dizygotic twinning rate (23), and breast cancer mortality (26).
Thus, in aggregate, our study is consistent with several other studies, using different study designs, which suggest that being a twin and being a dizygotic twin, in particular, are associated with an elevated breast cancer risk. Our finding that the relative risk was greatest for female dizygotic twins has, to our knowledge, not been reported previously. As noted above, there is little evidence that the association between twin membership and breast cancer risk is confounded by other perinatal or traditional reproductive and adult breast cancer risk factors. Other childhood and adolescent breast cancer risk factors (e.g., diet and anthropometric measurements) could be potential confounders, but few such factors are currently known and we had no data to address this issue.
The use of surrogate exposures such as twin membership to evaluate the hypothesis that intrauterine estrogen levels are associated with breast cancer risk has several important limitations. First, twin membership is an inexact surrogate for elevated estrogen levels, although any misclassification would be expected to make it more difficult to detect an association. Second, the levels of many other hormones, including human chorionic gonadotropin, human placental lactogen, follicle-stimulating hormone, luteinizing hormone, and progesterone, are elevated during pregnancy, and these hormones, or other hormonal changes during pregnancy, may be of greater relevance. Third, most hormone levels have been measured in the maternal circulation, while it is the fetal circulation that is of most interest, and the interactions between maternal, placental, and fetal steroid production and exchange are complex and incompletely understood. Finally, dizygotic twinning not only is a surrogate for elevated in utero estrogen or other hormonal levels but also has many other correlatesincluding race, older maternal age, higher maternal parity, greater maternal height, and a maternal family history of dizygotic twinning (27); thus, alternate explanations of the twinning association must be considered.
In summary, we found a statistically significant, positive association between twin membership and breast cancer risk that was strongest for dizygotic female twins. These data provide support for the role of intrauterine influences on breast cancer risk.
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NOTES |
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Manuscript received May 13, 1999; revised November 17, 1999; accepted November 29, 1999.
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