In the past two decades, the evidence-based knowledge on the prevalence and risk factors for gonads impairment, including infertility, following cancer and numerous cancer treatment regimen has significantly increased. However, data remains mostly insufficient for individualized prediction of (future) fertility and pregnancy potential, including the use and success of artificial reproductive technologies (ART). Furthermore, therapies have become increasingly complex as more recent treatment regimen have continuously also implemented novel treatment approaches (e.g. immune therapies such as checkpoint inhibitors) for which no comprehensive data regarding its impact on fertility and pregnancy outcomes is available, yet.

It is crucial to carefully balance risk-benefit between fertility preservation (FP) procedures and potential of gonadal function/fertility impairment, to examine the efficiency and safety, as well as to assess patients' satisfaction regarding the FP procedures. Answering these questionsis highly relevant as it has been shown that fertility capacity and post-treatment gonadal function may represent a significant part of quality of life in young cancer survivors.

The study therefore aim to set up a large-scale registry of emerging data collection programmes to evaluate the gonadotoxic risks, including the prevalence and course of ovarian dysfunction and/or fertility impairment and premature ovarian insufficiency following specific treatments, identification of further risk factors and predictive markers to enhance precision survivorship research in this field. Additionally, data on the use of fertility preservation/hormonal treatment and patients' satisfaction related to these procedures in Europe will be analysed to support patient-centric care.

Reproductive health counselling should not be limited to evaluating the risk of gonadotoxicity and offering fertility preservation to those at risk. It should also include evaluating the impact on post-treatment sexuality, menopausal symptoms management, and the counselling on contraception.

In addition to clinical information, whole genome sequence data will be generated for selected study participants with evidence of varying impact of gonadotoxic therapies on reproductive function to find genetic variants associated with risk of reproductive and organ toxicity.

The data collection will focus on all different cancer diseases, including diseases which are less common such as different types of sarcomas. This will be a significant development to the current state of information in existing registries.

The primary objectives of this prospective analysis of European ongoing adolescent and young adult (AYA) cancer patient cohorts are:

1. To establish a database with relevant clinical characteristics at time of diagnosis, cancer therapy received and post-cancer clinical and reproductive outcomes by following AYA cancer patients longitudinally.
2. To evaluate the effect of cancer therapies on ovarian function and reproductive potential.
3. To evaluate fertility preservation measures performed, their risks and efficacy.
4. To evaluate the impact of fertility preservation measures on the risk of cancer relapse.
5. To evaluate occurrence of pregnancies/live births naturally conceived (including unplanned) or through medical assistance post-cancer and the obstetrical complications and neonatal health following the use of cryopreserved oocytes or gonadal tissue.
6. To set up a genetic database based on whole genome sequencing of AYAs of the cohort. For this objective a Substudy 1 : " Development of risk prediction models based on clinical and genetic data " will be conducted.
7. To develop prediction models for organ toxicities in cancer patients (objective included in Substudy 1).
8. To evaluate the effect of cancer therapies on sexuality and quality of life. For this objective a Substudy 2 : "Sexual Health" will be conducted.
9. To evaluate the use and counselling on contraception. For this objective, a Substudy 3 : "Contraception" will be conducted.
10. To describe management of treatment-induced premature ovarian insufficiency (POI) and menopausal symptoms. For this objective a Substudy 4 "Management of POI and Menopause Symptoms" will be conducted.
11. To explore patient's satisfaction receiving counseling and/or undergoing fertility preservation. For this objective a Substudy 5 on "Satisfaction with Fertility Preservation" will be conducted.

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.

Inclusion Criteria:

• Female cancer patients aged between 15 and 39 years at diagnosis.
• Receiving a diagnosis of primary cancer 01/01/2025 or later
• Treated with chemotherapy and/or targeted therapy/immunotherapy and/or radiotherapy/ radioactive iodine therapy and/or gynaecological surgery.
• Detailed information on treatment received available.

Exclusion Criteria:

• Pre-existing known POI at cancer diagnosis.
• Treated by surgery alone (except gynaecological surgery).
• Patients with relapse or secondary malignant neoplasms at time of inclusion or having received already treatments for cancer
• Adult individuals subject of a measure of legal protection and/or patients with severe mental disorders.

Multi-center prospective cohort study of females presenting with and treated for AYA cancers at age 15-39