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.

中文翻译：

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辅助生殖技术治疗与乳腺癌风险：基于人群的队列研究

研究问题 包括卵巢激素刺激在内的 ART 治疗后女性患乳腺癌的风险是否增加？总结答案 与背景人群中年龄匹配、未接受治疗的女性相比，接受 ART 治疗的女性患乳腺癌的风险略有增加，而 40 岁以上开始接受 ART 治疗的女性患乳腺癌的风险进一步增加。已知情况 大多数乳腺癌病例对雌激素敏感，而卵巢激素刺激可通过影响内源性雌激素水平来增加患乳腺癌的风险。先前关于 ART 治疗和乳腺癌的研究结果各不相同，但有几项研究样本量小或缺乏随访时间和/或混杂因素调整。最近分娩，未生育和较高的社会经济地位是乳腺癌的危险因素，后两者也与开始抗逆转录病毒治疗有关。研究设计、规模、持续时间 丹麦国家 ART-Couple II (DANAC II) 队列包括 1994-2016 年在公共和私人生育诊所接受 ART 治疗的女性。参与者/材料、环境、方法 ART 治疗前没有癌症的女性被纳入（n = 61 579）。随机选择年龄相近且既往无 ART 治疗史的背景人群中的女性作为比较对象（n = 579 760）。基线平均年龄为 33.1 岁（范围 18-46 岁）。结果显示为具有相应 CI 的风险比 (HR)。主要结果和机会的作用 在随访期间（ART 治疗的中位时间为 9.69 年，未治疗的中位时间为 9.28 年），5861 名女性被诊断患有乳腺癌，695 名接受 ART 治疗，5166 名未接受治疗（1.1% 对 0.9%，P < 0.0001）。使用 Cox 回归分析调整未生育、教育水平、伴侣状况、年份、母亲乳腺癌和年龄，接受 ART 治疗的女性患乳腺癌的风险略有增加（HR 1.14，95% CI 1.12-1.16）。不孕症的所有原因都与 ART 治疗后的乳腺癌风险轻微相关。ART 治疗开始时乳腺癌的风险随着年龄的增加而增加，并且在 40 岁以上开始治疗的女性中最高（HR 1.37，95% CI 1.29-1.45）。在比较 40 岁以上首次生育的​​女性接受或不接受 ART 治疗时，接受 ART 治疗的女性风险持续增加（HR 1.51，95% CI 1.09–2.08）。限制，谨慎的原因 虽然这项研究是基于一个大型的全国女性队列，但需要更多的研究，具有足够的权力和混杂因素调整，特别是在具有广泛年龄代表性的队列中。研究结果的更广泛意义 已显示乳腺癌风险增加与开始 ART 治疗时的较高年龄相关。卵巢刺激可能会增加 40 岁以上开始 ART 治疗的女性患乳腺癌的风险。ART 治疗期间与年龄相关的激素暴露或较高激素剂量的易感性可能解释了风险增加。研究资金/竞争兴趣 这项工作得到了丹麦哥本哈根大学健康与医学科学学院授予 DV 的博士资助。建立 DANAC II 队列的资金来自 Ebba Rosa Hansen 基金会。作者报告没有利益冲突。试用注册号 不适用。