P-365 High Impact of Chemotherapy on Ovarian Reserve in Breast Cancer Survivors of Reproductive Age: A Systematic Review and Meta-Analysis

Abstract Study question What is the prevalence of clinically relevant reduced ovarian reserve defined by low anti-Mullerian hormone (AMH) in breast cancer (BC) survivors ≤40 years after chemotherapy? Summary answer The overall prevalence of clinically relevant reduced ovarian reserve in breast cancer survivors ≤40 years is 58% (95% CI 46-70%) 1-2 years following chemotherapy. What is known already Risk of infertility after BC therapies is of major clinical relevance for women of reproductive age with open family planning. Precise estimation of infertility after oncological treatment is required for counselling on fertility and fertility preservation measures. However, estimation of infertility based on the rate of amenorrhoea is almost impossible in BC due to endocrine treatments following chemotherapy. AMH is used as an indirect fertility marker to estimate gonadotoxicity. However, the influence of chemotherapy on the ovarian reserve in a defined group of BC survivors with AMH measurements before and after oncological therapy has not yet been systematically analysed. Study design, size, duration The systematic review and meta-analysis was performed on all published studies since 2000 that have reported pre- and post-treatment AMH measurements in BC survivors of reproductive age after chemotherapy. The study is part of the FertiTOX project (www.fertitox.com) which aims to close the gap of data regarding gonadotoxicity of cancer therapies to enable more accurate counselling regarding fertility and fertility preservation. Participants/materials, setting, methods A systematic literature search was performed in PubMed, Embase and Cochrane Library databases. Studies reporting on AMH levels in women ≤40 years of age before and 1-2 years after completing chemotherapy for BC were included. Prevalence of reduced AMH (< 1 and < 0.5 ng/ml) and treatment effect on AMH levels were calculated in each study and pooled using random-effects meta-analysis. Study quality was assessed according to the PRISMA guidelines using the Newcastle-Ottawa scale. Main results and the role of chance A total of 10 studies comprising 860 BC survivors fulfilled the inclusion criteria and remained in the qualitative and quantitative synthesis. The sample size of each study ranged from 3 to 193 participants with a follow-up period from 1 to 5 years. Nine studies included BC survivors with newly diagnosed BC FIGO stages I-III. Only 2.2% of the study population had FIGO IV tumour stage. Of the studies reviewed, one was a randomized-controlled trial with 101 participants; the remaining studies were prospective cohort studies. Chemotherapy treatments comprised antracyclines (97%), alkylants (98%), taxanes (80%), antimetabolites (43%) and platinum derivatives (1%). Most studies were rated as having good methodological quality (n = 9). A quantitative synthesis was performed in all 10 studies. A statistically significant decline of − 1.73 (95% CI: −2.54; −0.91) in mean AMH concentration was identified after chemotherapy, leading to a pooled prevalence of reduced (AMH < 1 ng/ml) and very reduced (AMH < 0.5 ng/ml) ovarian reserve (95% CI) in 58% (46-70%) and 53% (41-64%) of the study population. Significant heterogeneity was observed between studies (I² > 80%). Limitations, reasons for caution First, the majority of the studies was based on observational data with inherent confounding and bias. Second, further subgroup analysis based on chemotherapy regimens was not possible due to predominantly mixed treatments within the study cohorts. Third, reduced ovarian reserve might have occurred due to factors besides the oncological therapy. Wider implications of the findings More than half of BC survivors had significantly and clinically relevant reduced ovarian reserve, which is likely to be associated with a shortened fertile window and a significantly increased risk of premature ovarian failure. These findings highlight the need for counselling on fertility preservation strategies before BC therapy. Trial registration number No