Researchers at the National Cancer Institute performed an extended follow-up on a cohort of 12,193 women who had been evaluated for infertility at 5 US sites between 1965 and 1988. Passive and active questionnaire techniques were used to achieve follow-up through 2010 with 81.1% of the eligible population (n = 9892). Hazard risks (HRs) and 95% confidence intervals (CIs) were determined through Cox regression.
Breast cancer was observed in 749 women over the course of the 30.0 median years of follow-up (285,334 person-years). Risk was not associated with ever use of clomiphene citrate among the 38.1% of patients who used the drug (HR = 1.05, 95% CI, 0.90-1.22 vs never use). Patients who underwent multiple cycles saw somewhat higher risks, with the risk of invasive forms of cancer being significantly elevated, according to medical records (HR = 1.69; 95% CI, 1.17-2.46). Even after adjusting for causes of infertility and multiple breast cancer predictors, the risk remained mostly unchanged. Gonadotropins were inconsistently associated with risk and used by 9.6% of women mainly in combination with clomiphene. The association reached significance, however, in women with invasive cancers who had taken the drugs and remained nulligravid (HR = 1.98; 95% CI, 1.04 – 3.60).
The study authors concluded that the connection between breast cancer risk and nulligravid women likely reflects on the underlying cause of infertility, whereas the risk associated with multiple clomiphene cycles remains unclear. They urged additional research on the long-term effects of fertility drugs on breast cancer, especially because the population studied was relatively young.