1 Istituto di Ricerche Farmacologiche `Mario Negri', via Eritrea 62, 20 157 Milan, 2 Prima Clinica Ostetrico Ginecologica, Università degli Studi di Milano and 3 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy
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Abstract |
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Key words: breast cancer/fertility drugs
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Introduction |
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Fertility treatments stimulate ovulation, and consequently may influence breast cancer risk. Several studies have investigated the possibility of an association between infertility (Cowan et al., 1981; Vessey et al., 1985
; Ron et al., 1987
; Morabia and Szklo, 1989
; Bernstein et al., 1995
; Garland et al., 1998
), treatments for infertility (Vessey et al., 1985
; Venn et al., 1995
; Rossing et al., 1996
) and breast cancer risk. Some studies detected a small increase in risk of breast cancer associated with hormone-related infertility (Ron et al., 1987
; Garland et al., 1998
), others (Morabia and Szklo, 1989
; Bernstein et al., 1995
) a small decrease, and others again a general lack of association (Cowan et al., 1981
; Vessey et al., 1985
).
Available information about the relationship between pharmacological treatment for infertility and breast cancer risk is also inconsistent. In one study, chorionic gonadotrophin for infertility treatment was associated with a non-significant decreased risk of breast cancer (Vessey et al., 1985). In a cohort of infertile women, the risk among women who had taken an ovulation-inducing drug (clomiphene) was lower than that of infertile women who had not used it (Rossing et al., 1996
), but the reduced risk was not related to duration of use. Conversely, an Australian cohort study (Venn et al., 1995
) showed an increased breast cancer risk in women treated with ovulation-stimulating drugs compared to infertile women who did not receive treatment, or to women with unexplained infertility, although the difference was not significant. A cohort study conducted in Israel (Modan et al., 1998
) showed a non-significant difference in incidence of breast cancer between patients treated with fertility drugs and untreated ones. An Italian case control study (Braga et al., 1996
) showed no association between any fertility treatment and breast cancer risk. Nevertheless, the possibility that the use of specific drugs may be related to this neoplasia could not be excluded: for women who specifically reported a pharmacological treatment for infertility, the odds ratio (OR) was above unity, although not significantly (Braga et al., 1996
).
To provide further data on this still open question, we analysed the relationship between fertility drugs and breast cancer, using data from a case control study conducted in Northern Italy.
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Materials and methods |
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The cases included women aged <75 years with histologically confirmed breast cancer diagnosed within the year preceding the interview, who had been admitted to the National Cancer Institute of Milan, several teaching and general hospitals and the Ospedale Maggiore (which includes the four largest teaching and general hospitals in Milan). A total of 3415 women (median age 52 years; range 2374) was interviewed.
The controls included women residing in the same area, who had been admitted in the same period for acute conditions in the same network of hospitals where cases were identified, for diseases other than malignant, hormonal or gynaecological conditions. The interviewers visited selected clinics on selected days and identified and approached all patients eligible as controls on the basis of age and diagnosis of admittance. The number of controls was not determined a priori. A total of 2916 controls (median age 54 years; range 2174) was included. Of these, 29% were admitted for traumatic conditions, 26% had non-traumatic orthopaedic disorders, 16% were admitted for acute surgical conditions, and 30% had other miscellaneous illnesses, e.g. nose, ear, throat or dental disorders.
A structured questionnaire was used to obtain data on personal characteristics and habits, a short food frequency questionnaire, a problem-oriented medical history, menstrual and reproductive factors, infertility history and related use of fertility drugs. Less than 3% of the eligible subjects refused the interview.
Data analysis
OR, and the corresponding 95% confidence intervals (CI), were computed using multiple logistic regression (Breslow and Day, 1980). All the regression equations included terms for age in quinquennia and area of residence. Further models included years of education (<7, 711,
12), parity (nulliparae/parae) and history of infertility (no/yes).
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Results |
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Discussion |
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The low prevalence of infertility and of use of fertility drugs is probably due to the relatively high proportion of women aged 60 years and over, who underwent fertility assessment and treatment less frequently than younger women.
In general, however, studies of cancer in infertile women are affected by low statistical power and inability to distinguish between the potential role of fertility drug exposure and that of the underlying disorder(s). Moreover, it is often difficult to obtain information about whether infertility depends on ovulation disorders or has other causes, and women rarely report specific fertility treatments accurately.
These limitations notwithstanding, this study adds evidence supporting the absence of an association between fertility drug treatments and breast cancer, which is consistent with most, though not all, previous reports. It is conceivable that exposure to fertility treatment may affect only subgroups at risk of breast cancer (for example women with a family history of breast cancer), or with a mutation in the breast cancer gene 1 (BRCA1). Along these lines it has been suggested that an effort be made to identify early in life women at risk of late onset disease (Wagner and Ahner, 1998). In our study, however, we had no information on the presence of BRCA1 and, due to the limited absolute numbers, we were unable to analyse the risk of breast cancer after exposure to fertility treatment in subgroups of women at risk (for example those with a family history of the diseases).
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Acknowledgments |
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Notes |
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References |
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Submitted on October 7, 1998; accepted on February 5, 1999.