This study describes the ProspectiveMaleAYA cohort, a multicentre, prospective, longitudinal European study designed to investigate the long-term impact of cancer and cancer treatments on reproductive and endocrine health in adolescent and young adult (AYA) male cancer patients. Addressing major gaps in standardized prospective data, particularly for long-term fertility, hypogonadism, and the effects of newer systemic therapies, the study will harmonize data collection across centres and follow patients from diagnosis through post-treatment survivorship.

Comprehensive clinical, oncologic, reproductive, hormonal, biological, and patient-reported outcomes will be collected at predefined intervals to evaluate testicular dysfunction, fertility impairment, oligo/azoospermia, sexual health, and quality of life. Sub-cohorts will enable focused analyses of genetic and epigenetic sperm changes, whole-genome sequencing to identify susceptibility to reproductive and organ toxicity, accelerated aging markers following specific treatments, access to and satisfaction with fertility counselling, and sexual health dysfunctions. The overarching aim is to identify risk factors and predictive markers, develop individualized risk stratification and prediction models, and support precision, patient-centred survivorship care for male AYA cancer survivors.

In the past two decades, knowledge regarding the gonadotoxicity of cancer treatments and their impact on fertility and pregnancy outcomes has expanded. However, prospective, standardized, longitudinal data remain largely unavailable, particularly for:

• long-term endocrine and reproductive outcomes,
• effects of novel systemic therapies (e.g., immunotherapy, targeted therapies)

To address this gap, we will conduct a prospective, multicentre, longitudinal cohort study (ProspectiveMaleAYA cohort) in adolescent and young adult (AYA) male cancer patients.

Participants will be enrolled for this study after having received a diagnosis of primary cancer (no relapse or secondary cancers) and if they will receive or are already receiving oncological treatment. Clinical, oncologic, reproductive, endocrine, biological and patient-reported data will be collected at predefined follow-up intervals. Substudies including analyses of biological materials will be conducted in sub-cohorts.

The study aims to harmonize data collection across participating European centres and to set up a large-scale network structure of emerging data collection programmes to evaluate the gonadotoxic risk, including the prevalence and course of testicular dysfunction and/or fertility impairment and oligo/azoospermia following specific treatments, identification of further risk factors and predictive markers to enhance precision survivorship research in this field. In addition to clinical information, whole genome sequencing data will be generated for selected individuals with evidence of varying impact of gonadotoxic therapies on reproductive function. The aim is to find genetic variants associated with risk of reproductive and organ toxicity, and to build and enhance individual predictive risk models for gonadotoxic therapies. Additionally, data on sexual health, quality of life and subjective health status shall be analysed to support patient-centric care.

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

• Establish harmonized prospective databases with relevant clinical characteristics at time of diagnosis, cancer therapy received and post-cancer clinical and reproductive outcomes by following AYA cancer patients longitudinally.
• Evaluate the impact of cancer treatment on long-term fertility according to cancer type, patient characteristics (pre- and post-treatment) and treatment modalities in a male AYA population
• Establish predictive parameters for the recovery of spermatogenesis and for the later development of hypogonadism
• Classification of patients into low-, medium- and high-risk groups for the development of hypogonadism and infertility.

For specific sub-cohorts, the following objectives are planned:

• Sub-cohort 1: Determine the duration of genetic/epigenetic alterations in spermatozoa to define the minimum time-period after AYA cancer treatment to attempt safe conception.
• Sub-cohort 2: i) To set up a genetic database based on whole genome sequencing of AYAs of the cohort; ii) To evaluate the role of genetic background on determining persistent damage to testicular function (reproductive and endocrine); iii) To develop prediction models for organ toxicities in cancer patients.
• Sub-cohort 3: i) To test and evaluate the magnitude of accelerated aging following oncological treatments BEP (testicular cancer) or ABVD (Hodgkin lymphoma) through epigenetic clock and mosaic Y chromosome loss (mLoY); ii) To assess the role of clinical and the genetic factors in accelerated aging following oncological treatments.
• Sub-cohort 4: Evaluate the frequency and entity of sexual health dysfunctions in male cancer survivors, according to the disease and treatment.
• Sub-cohort 5: Mapping access and barriers to reproductive counseling and FP, and evaluating the satisfaction with these programs.

Inclusion Criteria:

• Subjects with male internal and external genitalia
• Age at cancer diagnosis 15-39 years old
• Subjects planned to or having received oncologic treatment
• Subjects able to provide semen sample
• Information available on cancer treatment and medical history
• Patients (or parents in case of minors) who signed informed consent

Exclusion Criteria:

• individuals presenting with relapse or secondary cancers at time of inclusion
• subjects who were not treated with oncological treatment
• subjects who underwent bilateral orchiectomy
• patients with a diagnosis of azoospermia or testicular failure previously to cancer diagnosis

Multi-center study on European AYA patient cohorts.

Prospective observational multicohort study including male AYA cancer patients enrolled after a diagnosis of primary cancer and followed at 1, 2 and 3 years post diagnosis.

The cohort database will be maintained to allow additional follow-up >3 years after reconsent to allow for further longitudinal research.

The subjects will be recruited at ~16 European Centres with expertise in oncofertility.

Upon new ethical approval of additional research, sharing of the study cohort can be allowed.