Dutch study finds protective effect in some instances.

Women undergoing in vitro fertilization treatment did not seem to have an increased risk of breast cancer years later, according to a large Dutch study.

After a median follow-up of more than 2 decades, breast cancer incidence among IVF patients was relatively comparable (standardized incident ratio 1.01, 95% CI, 0.93-1.09) with a subfertile non-IVF comparison group (SIR 1.00, 95% CI 0.88-1.15), reported Alexandria W. van den Belt-Dusebout, PhD, of the Netherlands Cancer Institute in Amsterdam, and colleagues.

Cumulative incidence of breast cancer at age 55 was also nonsignificant when comparing the two groups (3.0% for IVF group and 2.9% for non-IVF group, P=0.85), the authors wrote in the Journal of the American Medical Association. The group also noted that, in some IVF patients, the risk seemed to be lower.

In an email to MedPage Today, van den Belt-Dusebout said that because the use of IVF is relatively recent, long-term breast cancer risk was not yet known.

“Earlier studies [on IVF] that reported no increase of breast cancer based their conclusions on shorter follow-up and smaller numbers of breast cancers, whereas some studies reported increased risks in subgroups of IVF treated women,” she said. “Because of the conflicting results in the literature and methodological limitations of earlier studies, even in reviews and a meta-analysis, a large study with long follow-up was needed.”

This study included patients from a historical cohort examining subfertility (the OMEGA study) over a mean period of 21.1 years following treatment Overall, the authors looked at data from 25,108 women who underwent IVF treatment from 1983 to 1995. Women had a mean age of 32.8 at baseline and a mean number of 3.6 IVF cycles.

They found 839 cases of invasive breast cancer and 109 cases of in situ breast cancer during the follow-up period.

The authors reported that IVF treatment appeared to reduce a woman’s risk of breast cancer in some instances, specifically an increased number of IVF cycles (seven or more) was associated with a significantly decreased risk (HR 0.55, 95% CI o.39-0.77) compared with one to two cycles (P=0.001 for trend).

“The finding that more IVF cycles was associated with further decreases in risk is intriguing,” said Nanette Santoro, MD, of University of Colorado School of Medicine in Aurora, in an email to MedPage Today. “Although the trend was not large, it implies that IVF cycles, which may expose women to high levels of both estrogen and progesterone, may actually be protective in a manner similar to how pregnancy is protective against breast cancer.”

Santoro, who was not involved with the research, added that that the findings of the overall study support the widely held belief that IVF is a short exposure that should not have a major impact on a woman’s breast cancer risk.

Van den Belt-Dusebout said she was surprised by both the reduced risk associated with an increasing amount of IVF cycles and among women who responded poorly to their first IVF cycle (<4 collected oocytes versus >4 collected oocytes, HR 0.77, 95% CI 0.61-0.96).

However, not all IVF patients experienced a decline in breast cancer risk. Parous women (who had previously given birth) were linked with a significant increased risk in breast cancer versus nulliparous women (HR 1.35, 95% CI 1.16-1.73). Women who were age 40 and older at first birth did have a more than two-fold increased risk of breast cancer compared with women younger than age 25 (HR 2.52, 95% CI 1.71-3.73).

Study limitations included more missing data in the non-IVF group (33% versus 16% in the IVF group). In addition, age at menopause and menopausal status were unknown for most women, because most women were not postmenopausal at the questionnaire completion and the study was based on IVF treatment protocols used until 1995.

Van den Belt-Dusebout told MedPage Today that group team plans to address these issues, including further study of the OMEGA cohort to identify postmenopausal breast cancer risk, as well as a separate study examining women undergoing IVF treatment from 1995 to 2001.

“It is not very likely that more recently treated women would have an increased risk of breast cancer, because these protocols are more like the natural menstrual cycle … the downregulation phase is shorter and the stimulation is milder than in the earlier periods,” she said.