Affiliations of authors: M. Melbye, J. Wohlfahrt, U. Lei (Department of Epidemiology Research, Danish Epidemiology Science Center), B. Nørgaard-Pedersen (Department of Clinical Biochemistry), Staten Serum Institut, Copenhagen, Denmark; H. T. Mouridsen, Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen; M. Lambe, Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; K. B. Michels, Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, and Department of Epidemiology, Harvard School of Public Health, Boston, MA.
Correspondence to: Mads Melbye, M.D., Department of Epidemiology Research, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark (e-mail: mme{at}ssi.dk).
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ABSTRACT |
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INTRODUCTION |
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In this study, we have examined the relationship between -fetoprotein levels in maternal serum during pregnancy and the subsequent maternal risk of breast cancer in a cohort of 42057 Danish women who gave birth during the period from 1978 through 1996.
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MATERIALS AND METHODS |
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Population Registries
Since April 1, 1968, the CRS has assigned a unique identification number to all residents of Denmark. This number permits information from different registries to be linked. The CRS contains dates of any live births (which allows reconstruction of reproductive history for each woman) and dates of emigration and deaths (18). Information on stillbirths was available from the National Birth Registry.
-Fetoprotein Assessment
Measuring the level of -fetoprotein in maternal serum has been offered to all women receiving antenatal care in three Danish counties since 1978, and a screening program was introduced in 1980. Serum samples used for screening
-fetoprotein in maternal serum were taken during the second trimester of each pregnancy, before any amniocentesis was performed. Gestational age was recorded in completed weeks of pregnancy, estimated from ultrasound examination or from the date of the last menstrual period. For each pregnancy from an individual woman, the
-fetoprotein level in maternal serum was standardized by dividing the level by the median level in all measurements from singleton births taken at the same gestational age in the same calendar year (which gives multiples of the median [MoM]). For women who gave birth to more than one child during this period, several measurements of
-fetoprotein levels were available. Prepregnancy weight was available for only a subset of these women.
The median value of -fetoprotein in maternal serum for all pregnancies was 40000 IU/L of serum. The median value for the first pregnancy was also 40000 IU/L of serum, and it was 37000 IU/L of serum for two or more pregnancies. The median was 40000 IU/L of serum for first pregnancies occurring at age 24 years or younger to age 34 years; it decreased to 35000 IU/L of serum for first pregnancies at age 35 years or greater. Median levels of
-fetoprotein according to the age of the mother during a pregnancy in which
-fetoprotein was measured were as follows: 29 years or younger, 40000 IU/L; 3034 years, 39300 IU/L; 3537 years, 35000 IU/L; and 38 years or older, 36000 IU/L.
Patients With Breast Cancer
Women who developed breast cancer were identified by linkage with the DBCG because this register was complete until September 1, 1998. The DBCG collects detailed information on the breast cancer diagnosis, including tumor size, lymph node status, and receptor status (19,20). In a linkage between the DBCG Registry and the Danish Cancer Registry, the DBCG Registry was found to contain information on 94% of all patients with breast cancer reported to the Danish Cancer Registry (3). Reporting of cancer to the Danish Cancer Registry has been mandatory in Denmark since 1943 (21).
Design and Statistical Analysis
A cohort of 42057 Danish women was retrospectively established to include all women born in Denmark during the period from April 1, 1935, through March 31, 1978 (since information on reproductive history could be obtained for these women by linkage with the CRS), who gave birth to their first child during the period from 1978 through 1996 and for whom an -fetoprotein measurement was available for at least the first birth.
In this cohort, 117 women developed breast cancer by the end of follow-up on September 1, 1998. Women contributed person-time (years under observation) from the date of their first screening for -fetoprotein to a diagnosis of invasive breast cancer, death, emigration, or the end of follow-up on September 1, 1998 (at which date the DBCG was considered complete), whichever occurred first. Relative risk (RR) estimates were obtained by modeling incidence rates of breast cancer with the use of a log-linear Poisson regression model.
Because the relationship between -fetoprotein levels in maternal serum and the incidence of breast cancer appeared to be nonlinear,
-fetoprotein levels were categorized into four categories by quartiles of the MoM, using cut points based on the distribution of person-years. If a woman had more than one pregnancy during the study period and if
-fetoprotein was measured for more than one pregnancy, her
-fetoprotein information was updated when the new value was available. The study variable representing a woman's
-fetoprotein level is the value from her latest pregnancy, and the variable, therefore, is time dependent and can change after each pregnancy. Complete
-fetoprotein data for all pregnancies were available for 50% of the cohort. If
-fetoprotein levels were missing for a pregnancy after the first, the latest value was carried forward until the next pregnancy with an available value. Mothers of twins (or other multiple births) have at least twice the level of serum
-fetoprotein during pregnancy, compared with a mother carrying only one child, and probably also a different risk of breast cancer. In our analysis, this potential confounding effect of multiple births was avoided by excluding data from multiple-child pregnancies but including data from their other single-child pregnancies for these women.
Analyses were adjusted for attained age in 5-year intervals (34 years, 3539 years, 4044 years, and
45 years), calendar period (before 1993 versus 1993 and after), age at birth of first child (
24 years, 2529 years, 3034 years, and
35 years), and parity (one child versus two children or more). The attained age is the age at any time during follow-up; for patients with breast cancer, this is their age at diagnosis. All variables were treated as time-dependent variables in the analyses. To evaluate the potential effect modification of the association of
-fetoprotein with breast cancer, we also conducted analyses stratified by attained age, maternal age at first child's birth, age at latest pregnancy with an
-fetoprotein measurement, time since latest pregnancy with an
-fetoprotein measurement, and number of pregnancies. For the stratified analyses,
-fetoprotein levels in maternal serum that were the median value or higher were compared with levels that were less than the median.
Tests for the trend of the RR of breast cancer in women with -fetoprotein levels of one MoM or more compared with those of less than one MoM across the levels of the stratification variables were performed by including an interaction term between
-fetoprotein and the stratification variable. The various categories of the stratification variables in these trend analyses were represented by the median value of the categories.
The association between the level of -fetoprotein in maternal serum from the latest pregnancy and survival after a diagnosis of breast cancer was analyzed by Cox's proportional hazards method, with adjustment for tumor size, number of positive lymph nodes, age at diagnosis, and protocol allocation. The vital status of study participants was followed from the date of breast cancer diagnosis to October 1, 1998.
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RESULTS |
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Table 1 shows the distribution of factors characterizing the population at risk including the number of cases of breast cancer and person-years of follow-up. Table 2
shows the association between
-fetoprotein levels in maternal serum and the risk of breast cancer. Women in the highest two quartiles (quartiles 3 and 4) of serum
-fetoprotein levels had a statistically significantly lower incidence of breast cancer than women in the lowest two quartiles (quartiles 1 and 2). Women in the two highest quartiles of serum
-fetoprotein levels had about half the risk of breast cancer as women with serum
-fetoprotein levels that were just below the median, after adjustment for age, calendar period, parity, and maternal age at first child's birth. Adjusting only for age and calendar period produced virtually identical results. Adjusting for prepregnancy weight did not alter the results; therefore, the results are presented unadjusted for this variable. When we restricted the cohort to women for whom we had complete information on serum
-fetoprotein levels for each birth during follow-up, the RR estimates relative to quartile 2 (referent quartile) were 0.91 (95% CI = 0.511.64) for quartile 1, 0.56 (95% CI = 0.291.08) for quartile 3, and 0.46 (95% CI = 0.250.86) for quartile 4.
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DISCUSSION |
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The current study is, to our knowledge, the only one in which repeated measures of -fetoprotein in maternal serum are available for consecutive pregnancies. To our knowledge, the only previous epidemiologic study in which the association between
-fetoprotein levels in maternal serum and breast cancer has been considered was a casecontrol study nested in the Californian Child Health and Development Studies (CHDS) (22). In this study of 573 women, third-trimester blood samples were taken during the period from 1959 through 1966 and subsequently frozen; later, levels of
-fetoprotein were determined in these samples. These blood samples were taken during only one pregnancy; thus,
-fetoprotein levels in maternal serum were available for only that pregnancy (at arbitrary birth order). No overall association was found in that study (22) between
-fetoprotein levels in maternal serum for that one pregnancy and the risk of breast cancer. The authors did, however, report a reduced risk of breast cancer for women with high
-fetoprotein levels in maternal serum during the one index pregnancy, provided the women's first pregnancy occurred when they were young. We also found that the lowest RR of breast cancer was among women whose first pregnancy occurred when they were younger than 24 years old. In contrast to the findings in the previous study, however, we did not find an increased risk of breast cancer associated with high
-fetoprotein levels in maternal serum among women who were older than 26 years during their first pregnancy.
We (Wohlfahrt J: unpublished data) and others (23) have previously shown that the effect of pregnancy on the risk of breast cancer approximates a short-term increase in risk followed by longer term protection. In the present study, the association between -fetoprotein levels in maternal serum and a reduced incidence of breast cancer was particularly strong among women with a pregnancy at a young age. In these women, a recent pregnancy is associated with an increased risk of breast cancer that is greater than the risk for nulliparous women. Consequently, high levels of
-fetoprotein might be associated not with a reduction in the risk of breast cancer but, rather, with a smaller increase in the risk of breast cancer. For obvious reasons, our study did not include nulliparous women. However, we found no difference in the association between breast cancer risk and high levels of
-fetoprotein according to years since the last childbirth (see Table 3
). The short-term effect is, therefore, probably not related to the
-fetoprotein level in maternal serum during pregnancy.
There are a number of possible explanations for the difference in the overall association between breast cancer risk and -fetoprotein levels reported by the CHDS group (22) and by us. First, in the CHDS cohort, the
-fetoprotein level was available from only one pregnancy and, thus, that index pregnancy could represent any pregnancy. In contrast, we had several measurements of
-fetoprotein levels in maternal serum; we measured
-fetoprotein levels in maternal serum for all first pregnancies and for the majority of the other pregnancies. If there were important differences among
-fetoprotein levels in maternal serum from different pregnancies, we would capture their influence more effectively with our updated analyses. Furthermore,
-fetoprotein in maternal serum was measured during the third trimester in the CHDS cohort and during the second trimester in our study. As is acknowledged in the study by the CHDS group (22) as a potential limitation of their cross-sectional approach, the consistency of third-trimester
-fetoprotein levels in maternal serum between subsequent pregnancies has not been studied (24). In addition, the majority of patients with breast cancer in the CHDS were postmenopausal at diagnosis, whereas most of our patients with breast cancer were diagnosed premenopausally. Our conclusions of a positive association between a high
-fetoprotein level in maternal serum during pregnancy and a lower incidence of breast cancer cannot be extrapolated to postmenopausal women on the basis of our data. Finally, although both studies had a large number of patients with breast cancer overall, the number of patients in the stratified analyses was relatively small, leaving room for some variability between results.
Our cancer registry included detailed information on characteristics of the breast cancer at the time of diagnosis, which allowed a more detailed analysis of the association of risk of breast cancer with -fetoprotein level in maternal serum. There was a clear tendency among women with high levels of serum
-fetoprotein to have a particularly low incidence of breast tumors that had aggressive characteristics at the time of diagnosis, such as large tumor size and positive lymph node status. The most striking finding was that women with high levels of
-fetoprotein, compared with women with low levels of serum
-fetoprotein, showed a particularly reduced incidence of large tumors, i.e., tumors larger than 2 cm (RR = 0.24; 95% CI = 0.110.50). In line with these results, women with high levels of serum
-fetoprotein also appeared to have a better overall survival than women with low levels, even after adjustment for important characteristics influencing survival. This finding, however, was based on a limited number of deaths and should be viewed with due caution.
The prospective nature of our cohort design limited the potential for biases related to differential misclassification and selection. Thus, all covariate information was obtained independently of the exposure and was not dependent on recall. In our analysis, we were not able to adjust for a number of known risk factors for breast cancer, such as family history of breast cancer, height, body mass index, age at menarche, and age at menopause. Because the majority of our patients with breast cancer were diagnosed before age 50 years, confounding by menopausal status is unlikely. As reported by the CHDS group, we found no confounding effect of prepregnancy weight. Thus, it is unlikely that adjustment for height or body mass index would alter the results. The Danish population is very homogeneous, and the vast majority are Caucasian. The present investigation only included women born in Denmark; therefore, the study population almost exclusively represents Caucasians. Thus, confounding by race is not an issue.
In conclusion, we found that a high -fetoprotein level in maternal serum during the second trimester of pregnancy was associated with a subsequent reduction in the overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer among primarily premenopausal women. This association appeared strongest if the woman's pregnancy occurred at a young age. The present findings are potentially important. First, they may offer a complementary explanation as to why the risk of breast cancer is lower in parous women than in nulliparous women. Moreover, our results indicate that even time-limited exposure to high levels of
-fetoprotein can lower the risk of breast cancer overall and of advanced breast cancer in particular. If confirmed in future studies, and given the availability of recombinant
-fetoprotein, these findings may open up new venues for the prevention of breast cancer. However, any practical implications await a better understanding of whether the observed association of a reduced risk of breast cancer with high levels of
-fetoprotein reflects a direct effect of
-fetoprotein on tumor carcinogenesis or the effect of another substance closely interacting with
-fetoprotein.
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NOTES |
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We appreciate the comments from the anonymous reviewers.
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REFERENCES |
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1 Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev 1993;15:3647.[Medline]
2 Rosner B, Colditz GA, Willett WC. Reproductive risk factors in a prospective study of breast cancer: the Nurses' Health Study. Am J Epidemiol 1994;139:81935.[Abstract]
3 Wohlfahrt J, Andersen PK, Mouridsen HT, Adami HO, Melbye M. Reproductive history and stage of breast cancer. Am J Epidemiol 1999;150:132530.[Abstract]
4 Russo J, Russo IH. Influence of differentiation and cell kinetics on the susceptibility of rat mammary gland to carcinogenesis. Cancer Res 1980;40:267787.[Abstract]
5 Guyton AC. Textbook of medical physiology. 8th ed. Philadelphia (PA): Saunders; 1991.
6 Norgaard-Pedersen B. Human alpha-fetoprotein. Scand J Immunol 1976;suppl 4:745.
7 Gitlin D, Boesman M. Sites of serum alpha-fetoprotein synthesis in the human and in the rat. J Clin Invest 1967;46:10106.[Medline]
8 Seppala M, Ruoslahti E. Radioimmunoassay of maternal serum alpha fetoprotein during pregnancy and delivery. Am J Obstet Gynecol 1972;112:20812.[Medline]
9 Seppala M, Ruoslahti E. Alpha fetoprotein in amniotic fluid: an index of gestational age. Am J Obstet Gynecol 1972;114:5958.[Medline]
10
Hau J, Chemnitz J, Teisner B, Tornehave D, Svendsen P. Induction of murine -fetoprotein synthesis by oestradiol. Acta Endocrinol (Copenh) 1984;106:1414.[Medline]
11
Jacobson HI, Bennett JA, Mizejewski GJ. Inhibition of estrogen-dependent breast cancer growth by a reaction product of -fetoprotein and estradiol. Cancer Res 1990;50:41520.[Abstract]
12
Attardi B, Ruoslahti E. Foetoneonatal oestradiol-binding protein in mouse brain cytosol is foetoprotein. Nature 1976;263:6857.[Medline]
13 Bennett JA, Semeniuk DJ, Jacobson HI, Murgita RA. Similarity between natural and recombinant human alpha-fetoprotein as inhibitors of estrogen-dependent breast cancer growth. Breast Cancer Treat 1997;45:16979.[Medline]
14 Mizejewski GJ, Dias JA, Hauer CR, Henrikson KP, Gierthy J. Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment. Mol Cell Endocrinol 1996;118:1523.[Medline]
15 Jacobson HI, Bennett JA, Mizejewski GJ. Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol. Cancer Res 1990;50:41520.[Abstract]
16 Mizejewski GJ, Vonnegut M, Jacobson HI. Estradiol-activated alpha-fetoprotein suppresses the uterotropic response to estrogens. Proc Natl Acad Sci U S A 1983;80:27337.[Abstract]
17 Jacobson HI, Janerich DT. Pregnancy-altered breast cancer risk: mediated by maternal serum AFP? In: Mizejewski GJ, Jacobson HI, editors. Biological activities of alpha-fetoprotein. Vol 2. Boca Raton (FL): CRC Press; 1989. p. 93100.
18
Melbye M, Wohlfahrt J, Olsen JH, Frisch M, Westergaard T, Helweg-Larsen K, et al. Induced abortion and the risk of breast cancer. N Engl J Med 1997;336:815.
19 Andersen KW, Mouridsen HT. Danish Breast Cancer Cooperative Group (DBCG). A description of the register of the nation-wide programme for primary breast cancer. Acta Oncol 1988;27:62747.[Medline]
20
Kroman N, Jensen MB, Wohlfahrt J, Mouridsen HT, Andersen PK, Melbye M. Factors influencing the effect of age on prognosis in breast cancer: population based study. BMJ 2000;320:478.
21 Storm HH. The Danish Cancer Registry, a self-reporting national cancer registration system with elements of active data collection. IARC Sci Publ 1991;95:22036.[Medline]
22 Richardson BE, Hulka BS, Peck JL, Hughes CL, van den Berg BJ, Christianson RE, et al. Levels of maternal serum alpha-fetoprotein (AFP) in pregnant women and subsequent breast cancer risk. Am J Epidemiol 1998;148:71927.[Abstract]
23
Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med 1994;331:59.
24 Richardson BE, Hulka BS, Peck JL, Calvin JA. Senior author's reply to invited commentary: beyond the twinning effect [letter]. Am J Epidemiol 1998;148:7301.
Manuscript received October 4, 1999; revised March 29, 2000; accepted April 4, 2000.
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