1. This prospective cohort study found that breast cancer risk among women treated with in vitro fertilization (IVF) was not significantly different compared to women receiving fertility drugs (but not IVF), nor the general population.
2. Risk for breast cancer was significantly decreased for women who received 7 or more IVF cycles, compared to women who received only 1-2 cycles, and compared to women who responded poorly to IVF after the first cycle.
Evidence Rating Level: 1 (Excellent)
Study Rundown: In vitro fertilization (IVF) procedures temporarily decrease estradiol and progesterone levels by down-regulation of the menstrual cycle. Given its inverse relationship with estradiol, it has been speculated that IVF may influence breast cancer risk. Evidence relating the long-term ovarian stimulation during IVF to breast cancer risk has, however, been scarce. This prospective cohort study identified and followed subfertile women who began IVF stimulation between 1983 and 1995, and compared them to women who were treated with non-IVF fertility treatments. The results showed that long term IVF treatments were not associated with differences in breast cancer risk. Despite this, those treated with 7 or more IVF treatment sessions experienced a significant reduction in their risk of breast cancer compared to those who had 1 or 2 sessions.
This study directly addressed the knowledge gap about the effects of longitudinal IVF treatments on breast cancer risk. It provided a sufficient cohort size and long-term follow-up to analyze the subgroups with power. However, the study is limited a number of ways. First, information about the causes of subfertility was sporadic and unmeasured confounders may be biasing the results. Second, the age of menopause was not collected, and if IVF treatment and menopause are associated, this study may have misinterpreted the effects of therapy. Finally, IVF protocols were based on now outdated guidelines, and newer methods may have different effects on the risk of breast cancer. Overall, the study suggests that IVF treatments in subfertile women are not associated with a significant change in breast cancer risk.
In-Depth [prospective cohort]: This study aimed to quantify the association between IVF treatments in subfertile women and the risk of developing breast cancer. In 1995-1996, a group of women from 12 IVF clinics participating in the Netherlands OMEGA study were identified as having started either IVF or non-IVF treatments (e.g. tubal surgery, intrauterine insemination, or hormonal treatments). A total of 25 108 women (19 158 on IVF, 5950 on other therapy) were consented and completed a risk factor questionnaire. Information on all patients, including the number of IVF cycles and the diagnosis of breast cancer, was collected in 2012 (IVF cohort median follow-up 20.7 year, non-IVF 23.5 years). Outcome measures included (1) comparing in situ and invasive breast cancer incidence in the IVF and non-IVF groups to women in the general population, (2) cumulative incidences of breast cancer at age 55 years, using Cox proportional hazard ratios, (3) dose response associations with breast cancer and total number of IVF cycles, number of follicle-stimulating hormone and human menopausal gonadotropin ampules, and number of oocytes collected.
Breast cancer risks were not increased in the IVF group (standard incidence ratios or SIR 1.01, 95%CI 0.93-1.09) nor the non-IVF group (SIR 1.00, 95%CI 0.88-1.15) compared to the Dutch general population. Cumulative incidences of breast cancer at age 55 were not significantly different in the IVF group compared to the non-IVF group (3.0% v.s. 2.9%, p = 0.85), after adjusting for age of first birth and for parity. Within the IVF group, breast cancer risk decreased with more IVF cycles (p for trend = 0.001), with significantly decreased risk with 7 cycles or more (HR 0.55, 95%CI 0.39-0.77) compared to 1-2 IVF cycles.
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