Breast and Gynecological Cancer Risk Is Minimal With IVF

Nancy A. Melville

July 12, 2018

Women who receive assisted reproductive technology, such as in vitro fertilization (IVF), have no increased risk of invasive breast or uterine cancer, according to a new population-based study of more than 250,000 British women.

The study, published online July 11 in BMJ by Carrie L. Williams of UCL Great Ormond Street Institute of Child Health, in London, UK, and colleagues, did show increases in all types of ovarian cancer; however, those increases were limited to women with other known risk factors.

"The women showed an increased risk of ovarian cancer, but only a few extra cancers per year and only when they had known risk factors, suggesting this was not due to the IVF," senior investigator Alastair G. Sutcliffe, MD, also of UCL Great Ormond Street Institute of Child Health, told Medscape Medical News.

There was also an unexpected small increased risk of in situ breast cancer, most notably in those who had the greatest number of assisted-reproduction treatment cycles.

"The only surprise was the increase in in situ breast cancer, however it was very slight — just 1 in 50,000 women who have had an IVF cycle would have that extra risk," Sutcliffe commented.

Carcinogenicity Concerns of High Hormone Levels

The repeated exposures to high levels of hormones including estradiol, exogenous gonadotropins, and numerous punctures to the ovaries that occur with assisted reproduction have raised concerns about possible carcinogenic effects. However, findings from previous studies looking at rates of breast, endometrial, and ovarian cancers in women receiving the treatments have been inconsistent, and most studies have been relatively small.

To evaluate the risk in a larger population, Sutcliffe and colleagues studied records from 255,768 women who received assisted-reproduction treatment in Great Britain between 1991 and 2010, as documented by the Human Fertilization and Embryology Authority, and linked the information with data from national cancer records. They then compared cancer rates in those who had received IVF or other assisted-reproduction treatments with expected rates in the general population.

The average age of first assisted-reproduction treatment was 34.5 years, and the women had an average of 1.8 treatment cycles, with only 20% (50,485) having more than two stimulated cycles.

With an average follow-up of 8.8 years and a maximum follow-up of 19 years, there were no significant increases in the risk of uterine (corpus uteri) cancer (164 cancers observed vs 146.9 cancers expected in the general population; standardized incidence ratio [SIR], 1.12; 95% CI, 0.95 - 1.30).

The overall incidence of breast cancer was also not increased (2578 vs 2641.2 cases; SIR, 0.98; 95% CI, 0.94 - 1.01), nor was the incidence of invasive breast cancer (2272 vs 2371.4 cases; SIR, 0.96; 95% CI, 0.92 - 1.00).

The relatively small increased risk of in situ breast cancer (291 vs 253.5 cases; SIR, 1.15; 95% CI, 1.02 - 1.29) was primarily associated with having five or more treatment cycles (P = .03), which was uncommon, the researchers note.

The overall incidence of ovarian cancer was increased relative to the general population (SIR, 1.39; 95% CI, 1.26 - 1.53), but this higher risk was only seen in women with known risk factors for endometriosis, low parity, or both.

There were no increases in ovarian cancer rates among women who received fertility treatment only because of male factors or unexplained infertility.

Overall, the causes of infertility included having at least one female-related factor in 44% of women, only male-related factors in 33%, and in 19% of cases, the cause of infertility was unexplained.

Approximately half the study population had at least one live birth following completion of treatment.

Perplexing Findings on In Situ Breast Cancers; More Work Needed

The authors noted that the link between in situ breast cancers and treatment cycles was somewhat perplexing.

"Interpretation of these findings is challenging: the significant association with increasing number of cycles suggests a causal association, yet there was no overall increased risk of breast cancer," the authors write.

"To our knowledge, this study is the first to analyze risks of in situ and invasive breast cancers after assisted reproduction separately, so there are no previous data with which to compare."

The findings on the ovarian cancer risk meanwhile are consistent with previous studies, which have generally also shown an increased risk that lost significance after adjusting for the confounding effects of infertility.

Although this study had relatively long follow-up, the authors acknowledge they may have missed some cancers that take many years to develop.

"Our study comprised over 250,000 treated women, including almost 65,000 person-years of follow-up for at least 15 years beyond last treatment, with an average follow-up of 8.8 years and a maximum follow-up of 19 years," they explain.

"However, we cannot exclude the possibility of different risk profiles for any studied cancer on longer follow-up, at ages when most reproductive-related cancers occur."

Importantly, the wide array of factors that could play a role in infertility and important differences compared with the general population following assisted-reproduction technology require continued investigation as possible factors in the risk of cancer, the authors underscore.

"Women treated with assisted reproduction are likely to differ from the general population in their parity, age at first birth, age at menopause, and endometriosis," they stress.

"More information on these and other factors [including] socioeconomic status, oral contraceptive use, body mass index, and breastfeeding would be useful."

The study was funded by Cancer Research UK, National Institute for Health Research, Great Ormond Street Hospital for Children NHS Foundation Trust, and University College London. Sutcliffe's research was partly funded the Medical Research Council. Coauthor Ian Jacobs received funding from Breast Cancer Now.

BMJ. Published online July 11, 2018. Abstract

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