Abstract and Introduction
Study Question: Is there an increased risk of breast cancer among women after ART treatment including ovarian hormone stimulation?
Summary Answer: The risk of breast cancer was slightly increased among women after ART treatment compared to age-matched, untreated women in the background population, and the risk was further increased among women initiating ART treatment when aged 40+ years.
What is Known Already: The majority of breast cancer cases are sensitive to oestrogen, and ovarian hormone stimulation has been suggested to increase the risk of breast cancer by influencing endogenous oestrogen levels. Previous studies on ART treatment and breast cancer have varied in their findings, but several studies have small sample sizes or lack follow-up time and/or confounder adjustment. Recent childbirth, nulliparity and higher socio-economic status are breast cancer risk factors and the latter two are also associated with initiating ART treatment.
Study Design, Size, Duration: The Danish National ART-Couple II (DANAC II) cohort includes women treated with ART at public and private fertility clinics in 1994–2016.
Participants/Materials, Setting, Methods: Women with no cancer prior to ART treatment were included (n = 61 579). Women from the background population with similar age and no prior history of ART treatment were randomly selected as comparisons (n = 579 760). The baseline mean age was 33.1 years (range 18–46 years). Results are presented as hazard ratios (HRs) with corresponding CIs.
Main Results and the Role of Chance: During follow-up (median 9.69 years among ART-treated and 9.28 years among untreated), 5861 women were diagnosed with breast cancer, 695 among ART-treated and 5166 among untreated women (1.1% versus 0.9%, P < 0.0001). Using Cox regression analyses adjusted for nulliparity, educational level, partnership status, year, maternal breast cancer and age, the risk of breast cancer was slightly increased among women treated with ART (HR 1.14, 95% CI 1.12–1.16). All causes of infertility were slightly associated with breast cancer risk after ART treatment. The risk of breast cancer increased with higher age at ART treatment initiation and was highest among women initiating treatment at age 40+ years (HR 1.37, 95% CI 1.29–1.45). When comparing women with a first birth at age 40+ years with or without ART treatment, the increased risk among women treated with ART persisted (HR 1.51, 95% CI 1.09–2.08).
Limitations, Reasons for Caution: Although this study is based on a large, national cohort of women, more research with sufficient power and confounder adjustment is needed, particularly in cohorts with a broad age representation.
Wider Implications of the Findings: An increased risk of breast cancer associated with a higher age at ART treatment initiation has been shown. Ovarian stimulation may increase the risk of breast cancer among women initiating ART treatment when aged 40+ years. Age-related vulnerability to hormone exposure or higher hormone doses during ART treatment may explain the increased risk.
Study Funding/Competing Interest(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the DANAC II cohort was received from the Ebba Rosa Hansen Foundation. The authors report no conflict of interest.
Trial Registration Number: N/A.
The use of ART treatments has increased in Western countries over the last decades (De Geyter et al., 2018), and use of ovarian hormone stimulation has raised concerns. Approximately 80% of breast cancers are hormone-sensitive (Kohler et al., 2015), and whether hormonal stimulation during ART treatment has carcinogenic effects remains unclear. The risk of breast cancer relates to a number of reproductive factors. Younger age at menarche, older age at menopause, nulliparity and higher age at first birth all increase risk. The incidence of breast cancer is also associated with higher educational level and occupation (Larsen et al., 2011, Hvidtfeldt et al., 2013). Economic growth, individualisation and longer education have changed conditions of family planning. A concern is the postponement of childbearing leading to increased probability of infertility and childlessness. Female fertility starts to decline as early as 30 years of age (DeCherney and Berkowitz, 1982; Schwartz and Mayaux, 1982; van Noord-Zaadstra et al., 1991), and the use of ART treatment to overcome difficulties with conceiving has increased (De Geyter et al., 2018). Later attempts at achieving pregnancy postpones the age at which infertility is recognised and thus the age when ART treatment is undertaken. Thus, the average age of women seeking ART treatment in Danish fertility clinics has increased over the latest decades.
Previous studies examining breast cancer risk after ART treatment have found no overall association (Venn et al., 1999; Källén et al., 2011; van den Belt-Dusebout et al., 2016; Reigstad et al., 2017; Williams et al., 2018; Tsafrir et al., 2020), which was also the conclusion in two reviews and meta-analyses (Sergentanis et al., 2014; Barcroft et al., 2021). In one meta-analysis, however, the authors did find a statistically nonsignificant increased risk of breast cancer among women aged 30+ years when initiating IVF treatment (pooled effect estimate 1.64, 95% CI 0.96–2.80) (Sergentanis et al., 2014). Methodological shortcomings included little follow-up time, lack of confounder adjustment and subgroup analyses to trace potentially vulnerable groups. In 2016, a study from the Netherlands including 19 158 women in ART treatment found no overall increased risk of breast cancer after ART (van den Belt-Dusebout et al., 2016). However, they found a statistically significant, but modest, trend towards an increased risk of breast cancer with increasing age at ART treatment initiation (SIR 1.13, 95% CI 0.99–1.28 at age >35 years) compared to the general population. Similarly, a British study from 2018 including 225 786 women in ART treatment found no overall increased risk, but a non-significant modest trend towards increasing risk with higher age at treatment initiation (standardized incidence ratio (SIR) 1.09, 95% CI 0.89–1.34 at age >44 years) (Williams et al., 2018). The estimates in neither study were adjusted for socio-demographic confounders.
In the present study, we assessed the risk of breast cancer in a national cohort of women undergoing ART treatment in 1994–2016 compared with age-matched, untreated women from the background population. The aim was to determine the risk of breast cancer in women undergoing ART treatment and to assess the risk among potentially vulnerable subgroups of women treated with ART.
Hum Reprod. 2021;36(12):3152-3160. © 2021 Oxford University Press