Evaluating Ovarian Toxicity Outcomes Following Immunotherapy in Patients With Triple-Negative Breast Cancer (TNBC)

Patients will be asked to consent to the future use of their biological samples collected during the trial. Samples will be securely stored at Peter MacCallum Cancer Centre, coded, and linked to clinical data. Patients can request sample destruction at any time, but past analyses cannot be undone.

The Sponsor or delegate will manage trial data, while sites are responsible for data entry and resolving queries. Data will be entered into REDCap, a secure system hosted by Peter MacCallum Cancer Centre. Site staff will be trained, and only authorized personnel listed on the delegation log may complete eCRFs.

Primary outcomes

• Premature Ovarian Insufficiency (POI) at 24 months after cessation of neoadjuvant chemotherapy-ICI [24 months (±12 weeks) after cessation of neoadjuvant chemotherapy-ICI]: Proportion of participants with at least one ovary in situ who meet criteria for premature ovarian insufficiency (POI), defined as amenorrhoea for ≥4 months and post-menopausal follicle-stimulating hormone (FSH) level >25 IU/L.

Secondary outcomes

• Premature Ovarian Insufficiency (POI) at 12 months after cessation of neoadjuvant chemotherapy-ICI [12 months (±12 weeks) after cessation of neoadjuvant chemotherapy-ICI]: Proportion of participants with at least one ovary in situ who meet criteria for POI, defined as amenorrhoea for ≥4 months and post-menopausal FSH level >25 IU/L.
• Change in Anti-Müllerian Hormone (AMH) Levels [Baseline; at cessation of treatment (within 12 weeks of last dose); 12 months (±12 weeks); and 24 months (±12 weeks) after cessation]: Absolute and percentage change in serum AMH levels from baseline to end of neoadjuvant chemotherapy-ICI, 12 months, and 24 months post-treatment cessation.
• Change in Menstrual Status [Baseline; at cessation of treatment; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation]: Change in menstrual pattern (including amenorrhoea, oligomenorrhoea, or regular menstruation) compared to baseline, assessed by participant report.
• Time to Return of Menses [Up to 24 months after cessation of treatment]: Time from cessation of neoadjuvant chemotherapy-ICI to first reported menstrual period in participants who experienced treatment-related amenorrhoea.
• Change in Oestradiol (E2) Levels [Baseline; at cessation of treatment; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation]: Absolute and percentage change in serum oestradiol levels from baseline to subsequent study timepoints.
• Change in Sexual Function (EORTC QLQ-SH22 Score) [Baseline; at cessation of treatment; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation]: Change from baseline in sexual function and symptom scores measured using the European Organisation for Research and Treatment of Cancer Sexual Health Questionnaire (EORTC QLQ-SH22).
• Change in Inflammatory Cytokine Levels [Baseline; at cessation of treatment; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation]: Absolute and percentage change in circulating inflammatory cytokines (TNF-α, IL-1, IL-6, IFN-γ, granzyme A and B) from baseline, and association with POI at 24 months.
• Invasive Disease-Free Survival [12 months and 24 months after cessation of treatment]: Time from cessation of neoadjuvant chemotherapy-ICI to invasive breast cancer recurrence or death from any cause.
• Pregnancy Rate and Pregnancy Outcomes [Up to 24 months after cessation of treatment]: Proportion of participants who achieve pregnancy and description of pregnancy outcomes (e.g., live birth, miscarriage, termination).
• Fertility Preservation Discussion and Uptake [Baseline (prior to commencement of neoadjuvant chemotherapy-ICI)]: Proportion of participants who report fertility preservation counselling prior to treatment initiation and proportion who undergo fertility preservation procedures.

Other outcomes

• Change in Antral Follicle Count (AFC) and Ovarian Volume [Baseline; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation of treatment]: Change from baseline in antral follicle count and ovarian volume measured by transvaginal ultrasound in consenting participants.
• Change in Endometrial Thickness [Baseline; 12 months (±12 weeks); and 24 months (±12 weeks) after cessation of treatment]: Change from baseline in endometrial thickness measured by transvaginal ultrasound in consenting participants.

Sex: Female, ages: 18 Years to 42 Years

Inclusion Criteria:

1. Patient has provided written informed consent using the FERTILE Patient Information and Consent form (PICF)
2. Early-stage TNBC (definition determined as per clinicians' discretion)
3. Female patients between 18 and 42 years of age
4. Planned to receive at least one dose of neoadjuvant chemotherapy-ICI with a PD-(L)1 inhibitor including but not limited to pembrolizumab, atezolizumab, durvalumab or nivolumab
5. Planned to receive gonadotrophin releasing hormone (GnRH) agonist with neoadjuvant chemotherapy

Exclusion Criteria:

1. Previous removal of both ovaries or ovarian ablation (such as bilateral ovarian radiotherapy)
2. Patients who have previously received immunotherapy or chemotherapy prior to registration
3. Receiving or planned to receive adjuvant endocrine therapy Note: patients using GnRH agonist for POI prevention are not excluded
4. Post-menopausal as defined by the investigator
5. Presence of any psychological, social, geographical, or other condition for which, in the opinion of the site Investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments