The unsuccessful use of fertility drugs was associated with a reduced risk of young-onset breast cancer, although women who did go on to conceive saw an increased risk for the disease, according to researchers.

In a retrospective sister-matched case-control study, women who had used fertility drugs but had not conceived a 10-plus-week pregnancy under treatment showed a statistically significantly decreased risk of breast cancer compared with nonusers (OR 0.62, 95% CI 0.43 to 0.89), reported Clarice Weinberg, PhD, from the National Institute of Environmental Health Sciences in Research Park Triangle, N.C., and colleagues.

Also, women who had used any fertility drugs showed a nonstatistically significant decreased risk of breast cancer, compared with nonusers (OR 0.82, 95% CI 0.63 to 1.08), they wrote in the July 6 Journal of the National Cancer Institute.

However, women who had used fertility drugs and conceived a 10-plus-week pregnancy did have a statistically significantly increased risk of breast cancer compared with women who had been unsuccessfully treated.

“Our data suggest that exposure to a stimulated pregnancy is enough to undo the reduction in risk associated with a history of exposure to ovulation-stimulating drugs,” the group wrote.

The widespread use of ovulation-stimulating fertility drugs has raised concerns about their link to breast cancer, but results from previous research have been too varied to make a definitive connection.

A recent meta-analysis of published studies was inconclusive because of methodological limitations, such as incomplete control for confounding and small numbers of case subjects (Breast Cancer Res Treat 2010; 124: 13–26.)

The current Two Sister Study included women diagnosed with breast cancer (1,422) under the age of 50 years, and their breast cancer-free control sisters (1,669). They were studied between September 2008 and December 2010. The mean age of control sisters was 47.7 years at enrollment, and the mean age of case sisters was 44.7 years at diagnosis.

Participants were asked about fertility medication usage, the type of fertility medication, when they began the medication, the number of menstrual cycles of use, and whether any treatment had resulted in a pregnancy lasting 10 or more weeks. Fertility-drug use was categorized as: nonuser; clomiphene citrate (CC) only; follicle-stimulating hormone (FSH) only; or both CC and FSH.

The researchers found that women who reported use of CC alone, or both CC and FSH, without any success showed a nonstatistically significantly reduced odds of young-onset breast cancer compared with nonusers of these drugs:

  CC only: OR 0.61, 95% CI 0.41 to 0.90
  CC and FSH: OR 0.53, 95% CI 0.29 to 0.96

Women who had used fertility drugs and conceived a 10-plus week pregnancy under treatment showed a statistically significant increased risk of breast cancer compared with unsuccessfully treated women (OR 1.82, 95% CI 1.10 to 3.00).

But their risk was not increased compared with women who had not used fertility drugs (OR 1.13, 95% CI 0.78 to 1.64).

The study had some limitations. Fertility-drug use was self-reported by the participants so recall bias may have been present. Also, the authors said they did not have data on specific diagnosis for infertility, and the sisters with breast cancer were on average younger than their control sisters. Lastly, they delayed contact for at least a year after diagnosis to allow for treatment and recovery, and some of the sisters with more aggressive cancers may have died before they could be contacted.

In an accompanying editorial, Louise Brinton, PhD, from the National Cancer Institute in Rockville, Md., said that the study’s findings were hard to interpret in the context of previous studies, which have “ranged from reduced risks to increased risks to the absence of any relationship.”

She noted that the reduced overall risk associated with drug usage reported by the researchers may be related to the fact that CC is a selective estrogen receptor modulator similar to tamoxifen, an established chemopreventive.

Brinton observed that the increased risk seen in successfully treated women may be related to the increased exposure to ovarian hormones, as well as “the dual effect of pregnancy on breast cancer risk, namely a short-term transient increase that dissipates with time and eventually leads to a long-term risk reduction.”

She also found the study’s focus on women who developed breast cancer before age 50, which is more often associated with genetic factors than breast cancers diagnosed at a later age, was another complicating factor in interpreting its results.

“Because of such complexities, results from individual investigations must be cautiously interpreted and weighed against the considerable benefits associated with fertility drug usage, including a high probability of carrying pregnancies to term, which can lead to substantial long-term reductions in breast cancer risks,” Brinton stated.

Primary source: Journal of the National Cancer Institute
Source reference: Fei C, et al “Fertility drugs and young-onset breast cancer: Results from the Two Sister Study” J Natl Cancer Inst 2012; DOI: 10.1093/jnci/djs255.

Additional source: Journal of the National Cancer Institute
Source reference: Brinton LA “Breast cancer risk after use of fertility drugs: Stimulating new controversy” J Natl Cancer Inst 2012; DOI: 10.1093/jnci/djs275.