© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 1, 60-62,
January 3, 2001
© 2001 Oxford University Press
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In Utero Exposures and Breast Cancer: a Study of Opposite-Sexed Twins
Affiliation of authors: Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
Correspondence to: Magnus Kaijser, M.D., Berzelius väg 15C, S-171 77 Stockholm, Sweden (e-mail: magnus.kaijser{at}mep.ki.se).
It has been suggested that hormonal exposures in utero influence the risk of breast cancer later in life (1). Estrogens are well-established risk factors for breast cancer (2), and there is a pronounced association between birthweight and antenatal estrogen exposure (3). Several epidemiologic studies (4–6) have found that preeclampsia, a perinatal event characterized by low maternal estrogen levels, is associated with a decreased risk of breast cancer, but the results in different studies (6–8) of the association between birthweight and breast cancer risk are not entirely consistent.
One possible reason for the divergent results could be the narrow range of antenatal estrogen exposure seen in singleton pregnancies. Twin pregnancies are characterized both by a broader range (9) and higher levels (9–11) of pregnancy estrogens. There is some evidence that these phenomena are even more pronounced in dizygotic twin pregnancies compared with monozygotic pregnancies (9,12), and most (5,13–16), but not all (8), studies of cancer risk among dizygotic twins show an increased risk of breast cancer. Dizygotic twins, therefore, constitute a suitable group for further studies of the association between antenatal hormonal exposures and breast cancer risk.
We chose to restrict our study to opposite-sexed pairs for two reasons: All opposite-sexed pairs are dizygotic, and, for twins not given names while still at the hospital, the uncertainty of who is who that can be present for same-sexed twins does not occur. This greatly facilitates data collection. We, therefore, conducted a study on the association between birthweight and breast cancer among female twins of opposite-sexed twin pairs. The study was approved by the Research Ethics Committee at the Karolinska Institutet, Stockholm, Sweden.
We used information retrieved through the Swedish Twin Registry on twins born between 1926 and 1967 (17). In the Twin Registry, 13 820 pairs were opposite sexed (18). Using the unique national registration number given to all Swedish citizens alive after 1947, we identified study subjects through record linkage between the Swedish Twin Registry and the Swedish Cancer Registry (19). Eligible case subjects were female twins with male co-twins who developed breast cancer between 1972 and 1995. Control subjects were drawn from the same population, age matched, and eligible if alive and without breast cancer at the time of diagnosis for the corresponding case subject.
We selected two control subjects for each case subject; however, when the first was located, we stopped searching for the other. Because of simultaneous data collection at different delivery units, we sometimes gathered information on both. We initially obtained birth records for 104 case and 127 control subjects. We restricted the study to twins with a reported gestational age of 33 weeks or more according to the last menstrual period, since being born before the 33rd gestational week has been reported to be an independent risk factor for breast cancer (5). This process left us with 90 pairs of case and control subjects.
Odds ratios (ORs) were modeled through conditional logistic regression, and adjustment variables were male sibling birthweight and gestational-duration categories (20). All P values are two-sided. Since our intention was to obtain a broad range of birthweight categories, we categorized birthweight in groups of 500 g. For trend tests, we used equidistant scores for the categories; for the analysis of interaction, we performed likelihood ratio tests.
The risk of breast cancer increased stepwise with increasing birthweight categories (Tables 1 and 2
). Compared with women with a birthweight of 2000 g or less, women with a birthweight of more than 3500 g had a 12-fold increase in breast cancer risk. Adjusting for male co-twin birth weight and duration of gestation only marginally affected the association. The P value for trend was .007 for the unadjusted model, whereas it was .03 for the adjusted model. Although statistically significant, these estimates were based on small numbers in the extreme categories. However, when the data were categorized in more equally sized groups, the associations were similar and retained statistical significance, albeit with lower point estimates.
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When birthweight was analyzed as a continuous variable, the unadjusted OR for breast cancer increased 2.4 for each kilogram increase in birthweight and 2.3 after adjustment. We found no association between breast cancer risk and preeclampsia or other maternal disease during pregnancy. The association between birthweight and breast cancer risk was even more pronounced for those diagnosed before 50 years of age. For these 55 case subjects, the unadjusted OR for breast cancer was 5.0 (95% confidence interval [CI] = 1.63 to 15.1) for each kilogram increase in birthweight, and the adjusted OR was 4.3 (95% CI = 1.24 to 14.7).
When stratifying the analysis on male co-twin birthweight and duration of gestation, no statistically significant effect modification could be found (P = .53 and P = .62, respectively). Because of a few observations in some strata, however, the power of this analysis was limited.
The study design was a population-based, case–control study, and data were obtained from birth records completed prospectively. All records were not found, but it is almost inconceivable that there would be any association between birthweight among infants born after the 32nd gestational week and the possibility to retrieve the birth record 35–73 years later. We could not adjust for known risk factors for breast cancer; however, since these risk factors are not likely to be associated with female birth weight, we consider it unlikely that they confound our observed results.
Our findings are in accordance with the findings of Michels et al. (7), although more pronounced. The strong association between birthweight and breast cancer risk in our study could suggest that antenatal exposure to other factors present in an opposite-sexed twin pregnancy is important for breast carcinogenesis.
Howdeshell et al. (21) have found that a chemical estrogen, bisphenol A, can reduce the time to puberty in mice when the mice are exposed to high endogenous estrogen levels, whereas it has no effect on those exposed to low levels. It is possible that our results mirror a similar mechanism. Androgens interact with estrogens through competitive binding to sex hormone-binding globulin, and female twins with male co-twins and high birthweight are exposed in utero both to androgens from their brothers (22,23) and to high endogenous estrogen levels (10,11,24–26). A similar interaction between endogenous hormone levels and exposures of different exogenous hormonal factors could also be the reason for the discrepant results of the studies of birthweight and breast cancer risk among singletons (5,7,8).
In conclusion, we have found that, among female twins with male co-twins, high birthweight constitutes a strong independent risk factor for breast cancer. These results give further credence to the hypothesis that breast cancer risk is influenced by hormonal exposures in utero.
NOTES
Supported by contract FAIR 98–4756 from the European Commission, Directorate-General XII, Science, Research and Development, Brussels, Belgium.
REFERENCES
1 Trichopoulos D. Hypothesis: does breast cancer originate in utero? Lancet 1990;335:939–40.[CrossRef][Web of Science][Medline]cancerlit;90220118
2 Lipworth L. Epidemiology of breast cancer. Eur J Cancer Prev 1995;4:7–30.[Web of Science][Medline]cancerlit;95245278
3 Kaijser M, Granath F, Jacobsen G, Cnattingius S, Ekbom A. Maternal pregnancy estriol levels in relation to anamnestic and fetal anthropometric data. Epidemiology 2000;11:315–9.[CrossRef][Web of Science][Medline]
4 Sanderson M, Williams MA, Daling JR, Holt VL, Malone KE, Self SG, et al. Maternal factors and breast cancer risk among young women. Paediatr Perinat Epidemiol 1998;12:397–407.[CrossRef][Web of Science][Medline]cancerlit;99022555
5
Ekbom A, Hsieh CC, Lipworth L, Adami HO, Trichopoulos D. Intrauterine environment and breast cancer risk in women: a population-based study. J Natl Cancer Inst 1997;89:71–6.
6 Ekbom A, Trichopoulos D, Adami HO, Hsieh CC, Lan SJ. Evidence of prenatal influences on breast cancer risk. Lancet 1992;340:1015–8.[CrossRef][Web of Science][Medline]cancerlit;93023331
7 Michels KB, Trichopoulos D, Robins JM, Rosner BA, Manson JE, Hunter DJ, et al. Birthweight as a risk factor for breast cancer. Lancet 1996;348:1542–6.[CrossRef][Web of Science][Medline]cancerlit;97108554
8 Sanderson M, Williams MA, Malone KE, Stanford JL, Emanuel I, White E, et al. Perinatal factors and risk of breast cancer. Epidemiology 1996;7:34–7.[Web of Science][Medline]cancerlit;96245840
9 Kappel B, Hansen K, Moller J, Faaborg-Andersen J. Human placental lactogen and dU-estrogen levels in normal twin pregnancies. Acta Genet Med Gemellol (Roma) 1985;34:59–65.[Medline]
10 Duff DB, Brown JB. Urinary oestriol excretion in twin pregnancies. J Obstet Gynaecol Br Commonw 1974;81:695–700.[Web of Science][Medline]
11 TambyRaja RL, Ratnam SS. Plasma steroid changes in twin pregnancies. Prog Clin Biol Res 1981;69A:189–95.
12 Does breast cancer originate in utero? [letter]. Lancet 1990;335:1604.[Medline]cancerlit;90286809
13 Braun MM, Ahlbom A, Floderus B, Brinton LA, Hoover RN. Effect of twinship on incidence of cancer of the testis, breast, and other sites (Sweden). Cancer Causes Control 1995;6:519–24.[CrossRef][Web of Science][Medline]cancerlit;96161586
14
Cerhan JR, Kushi LH, Olson JE, Rich SS, Zheng W, Folsom AR, et al. Twinship and risk of postmenopausal breast cancer. J Natl Cancer Inst 2000;92:261–5.
15
Hsieh CC, Lan SJ, Ekbom A, Petridou E, Adami HO, Trichopoulos D. Twin membership and breast cancer risk. Am J Epidemiol 1992;136:1321–6.
16 Weiss HA, Potischman NA, Brinton LA, Brogan D, Coates RJ, Gammon MD, et al. Prenatal and perinatal risk factors for breast cancer in young women. Epidemiology 1997;8:181–7.[Web of Science][Medline]cancerlit;97373158
17 Pedersen NL, Lichtenstein P, Faire UD, Ahlbom A, Floderus B, Svartengren M. An (inter)national resource. The Swedish Twin Registry on twins informs on the role of environment and heredity in diseases. Lakartidningen 1996;93:1127–30.[Medline]
18 Medlund P, Cederlof R, Floderus-Myrhed B, Friberg L, Sorensen S. A New Swedish Twin Registry. Acta Medica Scandinavica, Suppl. 1976. 111 p.
19 Mattsson B, Wallgren A. Completeness of the Swedish Cancer Register. Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol 1984;23:305–13.[Web of Science][Medline]cancerlit;85068818
20 SAS Institute. SAS/STAT software: changes and enhancements through release 6.12. Cary (NC): SAS Institute Inc., 1997.
21 Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. Exposure to bisphenol A advances puberty. Nature 1999;401:763–4.[CrossRef][Medline]
22 Dempsey PJ, Townsend GC, Richards LC. Increased tooth crown size in females with twin brothers: evidence for hormonal diffusion between twins. Am J Hum Biol 1999;11:577–86.[CrossRef][Web of Science][Medline]
23
Glinianaia SV, Magnus P, Harris JR, Tambs K. Is there a consequence for fetal growth of having an unlike-sexed cohabitant in utero? Int J Epidemiol 1998;27:657–9.
24 Gerhard I, Vollmar B, Runnebaum B, Klinga K, Haller U, Kubli F. Weight percentile at birth. II. Prediction by endocrinological and sonographic measurements. Eur J Obstet Gynecol Reprod Biol 1987;26:313–28.[Web of Science][Medline]
25 Hardy MJ, Humeida AK, Bahijri SM, Basalamah AH. Late third trimester unconjugated serum oestriol levels in normal and hypertensive pregnancy: relation to birth weight. Br J Obstet Gynaecol 1981;88:976–82.[Web of Science][Medline]
26 Petridou E, Trichopoulos D, Revinthi K, Tong D, Papathoma E. Modulation of birthweight through gestational age and fetal growth. Child Care Health Dev 1996;22:37–53.[CrossRef][Web of Science][Medline]
Manuscript received May 24, 2000; revised October 30, 2000; accepted November 1, 2000.
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