ProspectiveFemaleAYA - Late Effects of Cancer Therapies on Gonadal Function, Fertility, Efficiency of Fertility Preservation Procedures and Pregnancy Outcomes (FemFertilAYA)

Fertility preservation (FP) and fertility counselling at the time of diagnosis and throughout follow-up are recommended to improve the quality of life of young patients diagnosed with cancer. It has been shown that gonadal function, as well as fertility capacity after treatment are crucial aspects for AYA cancer survivors . While natural conception can be possible after cancer treatment, cancer-treatment related risk factors for impaired fertility, including a drastically reduced reproductive window, have been identified.

The impact of gonadototoxic medications might also be related to genetic factors. Data on gonadotoxicity have revealed a high variance in the effect of cancer therapies on gonadal and organ function irrespective of the kind of drugs used and dosage. The high variance indicates individual risks which might be related to specific genetic variants. To better counsel on the risk of infertility and to better indicate fertility preservation (FP) measures, it would be beneficial to identify such genetic factors to develop a genetic prediction model.

FP techniques are progressing rapidly and have demonstrated their effectiveness in terms of pregnancy chances and live-birth rates. However, it remains difficult to elaborate firm and evidence-based FP strategies according to a patient's individual factors and cancer treatment. In addition, it remains crucial to carefully balance the risk-benefit of FP procedures and the potential of ovarian/fertility impairment, to examine the efficiency and safety of FP procedures and pregnancies as well as to assess patients' satisfaction regarding FP procedures. Large scale prospective and systematic short- and long-term data on the impact of specific cancer therapies on fertility based on fertility parameters such as ovarian reserve markers, sperm quality and pregnancies hardly exist. Specialized centres and joint regional and national network initiatives have started collecting such data. However, even though these initiatives are of great value and are sufficient to generate data from common cancer diseases such as breast cancer, rare cancers as well as on novel therapeutics (e.g. anti-VEGF or immune therapies) and more complex cancer treatment regimens require large scale data collection initiatives to gain in-depth robust data for appropriate individual fertility-related counselling of female and male AYA patients.

Ovarian reserve markers such as serum AMH level variations may be a direct and real-time indicator of follicular depletion and recovery during and after cancer treatment, as well as it is a non-invasive and reproducible marker. Systematic follow-up of AMH has been suggested in AYA patients with at least a measurement at baseline and within the 2 years following the end of gonadotoxic treatment. In parallel, the menstrual function pattern should be regularly analysed as a relevant clinical surrogate and independent variable to determine prevalence of cancer treatment-induced amenorrhea, its duration and hormonal and clinical signs of potential post treatment premature ovarian insufficiency (POI).

The ProspectiveFemaleAYA (FemFertilAYA) study within the PredictAYA project, therefore aim to set up a large-scale network structure of previously established data collection programs in specialized centres/networks to evaluate the ovarian toxicity, the prevalence of impaired ovarian function, its course and/or fertility impairment, POI following specific treatments, and identification of predictive markers. Furthermore, data on the use of FP and/or subsequent use of artificial reproductive treatment (ART) as well as patients' satisfaction related to these procedures in Europe will drive the understanding of patient-centered care.

A genetic database based on whole genome sequencing of selected females with evidence of impact of gonadotoxic therapies on ovarian function below and above average will be set up to identify genetic variants associated with individual risk of reproductive and organ toxicities. Whole genome sequence (WGS) data will provide an opportunity to identify and test potential genetic variants (and biomarkers) associated with chemotherapy-induced ovarian toxicity. The study will rely on WGS data and matching clinical information to develop statistical prediction models for female reproductive toxicities, as well as other toxicities when feasible. To this end, the study will systematically investigate the relationship between common genetic variation and clinically observed reproductive, cardiac, neurological, or systemic toxicities. ProspectiveFemaleAYA will identify genes and pathways that are enriched for variants associated with acquired ovarian toxicity with special focus on known pathways related to metabolism of cytotoxic drugs, DNA damage response (DDR), and other known toxicity outcome related processes as well as enrichment in other networks or pathways. Using SNVs below a data-driven minimum for the false discovery rate, will identify genes (using Burden tests) and pathways that are enriched for variants associated with the gonadal toxicity phenotypes. To further refine the variants of interest, cross-validation of SNVs will be applied and the classification technique called "random LASSO" alongside gene regulatory networks (GRNs). Machine learning modelling will be employed to propose oligo- or polygenic risk models for predicting the genotoxic effects of cancer therapy on future fertility. These data will provide a robust foundation for investigating the biological mechanisms of chemotherapy-induced gonadal toxicity and development of prediction models, enabling future targeted interventions and personalized medicine approaches to mitigate adverse effects on reproductive health.

Post-treatment sexuality, contraception and management of potential menopausal symptoms are additional relevant topics that should be addressed in counselling of patients living with and beyond cancer. ProspectiveFemaleAYA we prospectively assess both, post-treatment sexuality and contraception, in two separate sub-cohorts of patients. Additionally, the study will investigate clinical practices on menopausal symptoms management, which can significantly influence sexual dysfunction by questionnaires to the physicians.

Sexual dysfunction in any phase of the sexual response cycle, from arousal to orgasm, is widely under addressed in cancer survivors, despite being a common late effect of cancer. Experiencing sexual dysfunction following cancer may be attributable to a single cause but usually is an interplay of somatic (e.g. pelvic dysfunction), psychological (e.g. body image, reduced libido, but also depression, anxiety) and social (new roles in partnership, financial burden) factors. Literature estimates that it occurs in up to 50% of young adult cancer survivors. Despite the relevance of the issue, patients self-reported, that sexual health (SH) is rarely discussed during oncological follow ups and literature lacks in regard to the actual prevalence in the different types of cancers and protective/risk factors. In this context, the role of the oncofertility unit is shifting from an urgent pre-therapies counselling focusing only on fertility preservation procedure to a broader approach that encompasses various aspects of reproductive and sexual life.

Among these aspects, treatment-induced premature ovarian insufficiency (POI) is frequently accompanied by early menopausal symptoms with substantial impact on quality of life and long-term health outcomes. Although it has been established that hormone replacement therapy (HRT) is safe in most cancers, with few exceptions, management strategies remain variable across institutions, reflecting limited data on real-world clinical practice. For this reason, evaluating current approaches to POI and menopausal symptom management is essential to identify unmet needs and promote harmonized care pathways.

Given that a cancer diagnosis does not always coincide with the loss of reproductive function, it is also crucial to ensure cancer survivors receive complete counselling regarding safe and effective contraception options to avoid unplanned pregnancies. However, the published literature shows a suboptimal contraception use both during and after cancer treatments and an increased risk of unwanted pregnancies in these women. This concern will be also addressed in this prospective cohort. As safety of pregnancies is also related to other organ functions, counselling should, if possible, also include further health factors such as organ toxicity which might have an impact on safety of pregnancies.

The registry will focus on all different cancer diseases, including diseases which are less common such as different types of sarcoma. This will be a significant difference from other registries. By capping the number of patients per disease, it will be possible to include a sufficient number of cases of less common diseases, as the cost reimbursement quota per data record is limited.