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      Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects

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          Abstract

          In a Norwegian, prospective study we investigated breast cancer risk in relation to age at, and time since, childbirth, and whether the timing of births modified the risk pattern after delivery. A total of 23 890 women of parity 5 or less were diagnosed with breast cancer during follow-up of 1.7 million women at ages 20–74 years. Results, based on Poisson regression analyses of person-years at risk, showed long-term protective effects of the first, as well as subsequent, pregnancies and that these were preceded by a short-term increase in risk. The magnitude and timing of this adverse effect differed somewhat by birth order, maternal age at delivery and birth spacing. No transient increase in risk was seen shortly after a first birth below age 25 years, but an early first birth did not prevent a transient increase in risk after subsequent births. In general, the magnitude of the adverse effect was strongest after pregnancies at age 30 years or older. A wide birth interval was also related to a more pronounced adverse effect. Increasing maternal age at the first and second childbirth was associated with an increase in risk in the long run, whereas no such long-term effect was seen with age at higher order births.

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          Transient increase in the risk of breast cancer after giving birth.

          The effect of pregnancy on the risk of breast cancer is not clear. We tested the hypothesis that the risk of breast cancer increases transiently after pregnancy but then falls to a level below that of age-matched nulliparous women. We conducted a case-control study of a nationwide cohort in Sweden, using a computerized record linkage between the Cancer Registry and the Fertility Registry. The study subjects were women born from 1925 through 1960 who were resident citizens of Sweden at the time of the 1960 census. A total of 12,666 patients with breast cancer were compared with 62,121 age-matched control subjects. We used conditional logistic regression to estimate odds ratios for the development of breast cancer at different ages, according to maternal age at first delivery (in uniparous as compared with nulliparous women) and age at second delivery (in biparous as compared with uniparous women). Uniparous women were at higher risk of breast cancer than nulliparous women for up to 15 years after childbirth and at lower risk thereafter. The excess risk was most pronounced among women who were older at the time of their first delivery (odds ratio 5 years after delivery among women 35 years old at first delivery, 1.26; 95 percent confidence interval, 1.10 to 1.44). Women who had two pregnancies had a less striking increase in risk. Pregnancy has a dual effect on the risk of breast cancer: it transiently increases the risk after childbirth but reduces the risk in later years. In women with two pregnancies, the short-term adverse effect is masked by the long-term protection imparted by the first pregnancy. A plausible biologic interpretation is that pregnancy increases the short-term risk of breast cancer by stimulating the growth of cells that have undergone the early stages of malignant transformation but that it confers long-term protection by inducing the differentiation of normal mammary stem cells that have the potential for neoplastic change.
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            'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer.

            For most cancer sites there is a linear log-log relationship between incidence and age. This relationship does not hold for breast cancer, and certain 'key' breast cancer risk factors suggest that breast tissue does not 'age' in step with calendar time. A quantitative description of 'breast tissue age' is suggested which brings the age-incidence curve of breast cancer into line with the common log-log cancers and explains quantitatively the known key risk factors. The model also explains the 'anomalous' finding that although early first birth is protective, late first birth carries a higher risk than nulliparity. US breast cancer rates are some four to six times the rates in Japan--the model suggests that the key risk factors, when considered jointly with weight, can explain about 85% of the difference.
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              Nurses' health study: log-incidence mathematical model of breast cancer incidence.

              In 1983, Pike et al. developed a mathematical model to quantify the effects of reproductive risk factors on the incidence of breast cancer. In 1994, we modified that model to correct some deficiencies in the original model, including a lack of terms for spacing of births and an inability to easily accommodate births after age 40 years. Our extended Pike model, while improving on the original, still has serious disadvantages, such as difficulty in translating model parameters into relative risks (RRs) and an incomplete fit to data that slightly overestimated incidence for premenopausal women with an early age at first birth and that underestimated incidence for post-menopausal women with a late age at first birth. We undertook both the development of a new mathematical model to quantify the effects of reproductive risk factors on breast cancer incidence and validation of the model. A new log-incidence model of breast cancer incidence was developed using nonlinear regression methods, and a study population consisting of 89,132 women in the Nurses' Health Study from which a total of 2249 incident cases of breast cancer were identified. Subjects were followed from the return of the 1976 Nurses' Health Study questionnaire until June 1, 1990, or until the last questionnaire was returned, until the development of any cancer, or until death, yielding 1,148,593 person-years of follow-up. The log-incidence models were fitted using iteratively reweighted least squares analysis. The log-incidence model provided a better fit to that data than the extended Pike model, with parameter estimates interpretable in terms of RRs. This new model can be fitted using standard commercially available statistical software. In the model, younger parous women are generally at slightly higher risk than nulliparous women, which is true for both the observed and expected RRs, and older parous women, aged 55-64 years with an early age at first birth, are at lower risk than nulliparous women,while older women with a late age at first birth are at substantially higher risk than nulliparous women. Log-incidence models, such as this one, provide an efficient framework for modeling the effect of lifestyle risk factors on breast cancer incidence that may be specifically targeted to certain time periods of a woman's reproductive life.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                14 December 2004
                14 January 2005
                17 January 2005
                : 92
                : 1
                : 167-175
                Affiliations
                [1 ]Department of Mathematics, University of Bergen, Johannes Brunsgt. 12, 5008 Bergen, Norway
                [2 ]Cancer Registry of Norway, Montebello, 0310 Oslo, Norway
                [3 ]Center for International Health, University of Bergen, Armauer Hansens hus, 5020 Bergen, Norway
                Author notes
                [* ]Author for correspondence: grethea@ 123456mi.uib.no
                Article
                6602302
                10.1038/sj.bjc.6602302
                2361726
                15597097
                bb1fe2cb-6305-459c-bf0f-c491c282450d
                Copyright 2005, Cancer Research UK
                History
                : 21 June 2004
                : 20 September 2004
                : 25 October 2004
                Categories
                Epidemiology

                Oncology & Radiotherapy
                age at births,birth interval,time since births,breast cancer,pregnancies
                Oncology & Radiotherapy
                age at births, birth interval, time since births, breast cancer, pregnancies

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