Study shows no evidence of increased breast cancer risk from In Vitro Fertilization (IVF) treatments

In a study from the Netherlands, women who used ovarian stimulation treatments for in vitro fertilization (IVF) were NOT found to be at increased risk of developing breast cancer in the long term.

The authors followed up over 19,000 Dutch women who underwent IVF treatments between 1983 in 1995 (over 12 years) and compared their risk of developing breast cancer to a control group of around 6000 women.

In a cohort of more than 25,000 women who were followed for more than 20 years after fertility treatments, breast cancer risk in IVF-treated women was not markedly different from that in the general population or in women who underwent other fertility treatments, according to the July 19 JAMA report.

“These results are reassuring for doctors and women treated with IVF in the past indeed, because of the strengths of the study, especially adjustment for confounding and long complete follow-up, and because of the consistency of the results,” first author Dr. Alexandra W. van den Belt-Dusebout, Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, told Reuters Health by email.

“The risk did not increase with larger numbers of IVF cycles or with longer follow-up,” she added. “We did not identify possible subgroups at increased risk. The risk did not differ by type of fertility drugs or subfertility diagnosis.”

IVF procedures might influence breast cancer risk by causing temporary changes in estradiol and progesterone levels. Yet prior studies of breast cancer risk after IVF treatment have been inconclusive.

“This analysis adds to the literature especially because earlier studies, even reviews and a meta-analysis, had methodological limitations, especially relatively short follow-up and relatively small numbers of breast cancers, missing detailed information on IVF treatments or comparison with the general population only,” Dr. van den Belt-Dusebout explained.

“Furthermore, earlier results were conflicting, some studies reported no increase of breast cancer, whereas others reported increased risks in subgroups of IVF treated women. Therefore, a large study with long follow-up was needed. The results of this long-term cohort study lacked these earlier methodological limitations,” she said.
Among 25,108 women in the cohort, 19,158 started IVF treatment between 1983 and 1995 (IVF group, average number of IVF cycles 3.6) and 5,950 started other fertility treatments between 1980 and 1995 (non-IVF group).

The mean age at entry was 33; the median age at end of follow-up was 54 in the IVF group and 55 in the non-IVF group.

No evidence of increased breast cancer risk with IVF treatments for infertility.
No evidence of increased breast cancer risk with IVF treatments for infertility.

After a median follow up of 21 years, 839 cases of invasive breast cancer and 109 cases of in situ breast cancer were documented in the Netherlands Cancer Registry. The risk of breast cancer in the IVF group was similar to that of the general population (standardized incidence ratio 1.01) and the non-IVF group (hazard ratio 1.01).

 The cumulative incidences of breast cancer at age 55 were 3.0% in the IVF group and 2.9% for the non-IVF group (p=0.85) and the risk did not increase with longer time since treatment or number of IVF cycles.

“These findings are consistent with the absence of a significant increase in the long-term risk of breast cancer among women treated with these IVF regimens,” the authors write in JAMA.

“This nationwide study is unique because it includes a large number of IVF-treated women and women having undergone other fertility treatments, who have been followed for more than 20 years, with detailed treatment information,” Dr. van den Belt-Dusebout told Reuters Health.

 “Furthermore, near complete information was obtained on cancer incidence and regarding the most important confounding factors, parity and age at first birth,” she continued. “Moreover, the risk of breast cancer among IVF-treated women is compared with the risk among women from the general population and among women having undergone other fertility treatments.”

“Although the results are based on women treated in the Netherlands starting their IVF treatments between 1983 and 1995, we believe the results are also applicable for women in other Western countries, because IVF regimens were similar in different countries in similar periods,” she noted.

“Because many women in our cohort did not yet reach menopause, it remains important to follow-up the women in the OMEGA cohort to evaluate the risk of postmenopausal breast cancer after IVF. Furthermore, for more recently treated women we cannot be sure yet, because different IVF protocols have been used. However, it is not very likely that more recently treated women would have an increased risk of breast cancer, because these protocols do more resemble women’s natural menstrual cycle,” Dr. van den Belt-Dusebout said.

 “In more recent protocols,” she explained, “the down regulation phase is shorter and the stimulation is milder with lower doses of hormones than in the earlier periods. But, to be sure, we need to evaluate their breast cancer risk in a comparable study. We have already collected data from women treated between 1995 and 2001. We will analyze those data in the near future, also with regard to other hormone-related cancers such as ovarian tumors and endometrial cancer.”
The study was published in JAMA (link to journal).

SCIENTIFIC ABSTRACT:

Importance  Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up.

Objective  To assess long-term risk of breast cancer after ovarian stimulation for IVF.

Design, Setting, and Participants  Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19 158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group.

Exposures  Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires.

Main Outcomes and Measures  Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]).

Results  Among 25 108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes).

Conclusions and Relevance  Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

van den Belt-Dusebout AW, Spaan M, Lambalk CB, et al. Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer. JAMA. 2016;316(3):300-312. doi:10.1001/jama.2016.9389.