Oncofertility in the Age of HER2 Blockade, Immunotherapy, PARP inhibitors, CDK4/6 inhibitors and Endocrine Treatment: Unanswered Questions in Breast Cancer

OPINION STATEMENT: As survival among reproductive-age patients with breast cancer continues to improve with modern therapies, concerns regarding fertility preservation, gonadotoxicity, and pregnancy safety have become increasingly prominent. Fertility considerations are well-recognized contributors to treatment refusal and premature discontinuation, therefore, oncofertility counselling should be initiated at diagnosis and integrated into therapeutic planning. Prompt referral for fertility preservation is essential for patients who may wish to conceive, without compromising oncologic outcomes. Systemic therapy selection should remain driven by tumour biology and recurrence risk; however, when clinically equivalent regimens are available, those with lower gonadotoxic potential are preferred. Cytotoxic chemotherapy is the main determinant of permanent ovarian insufficiency, and temporary ovarian suppression during chemotherapy should be routinely considered in appropriate candidates. Endocrine therapy is not associated with irreversible ovarian damage, but its long duration necessitates individualized planning for pregnancy, including supervised treatment interruption in selected low-risk patients. HER2-monoclonal antibodies should be delivered according to standard indications, as it does not appear to confer substantial additional ovarian toxicity beyond chemotherapy; however, pregnancy must be avoided during treatment. For antibody-drug conjugates, PARP inhibitors, and CDK 4 and 6 inhibitors, the absence of prospective human fertility data supports a precautionary approach, including pre-treatment fertility preservation, effective contraception during therapy, and adherence to recommended washout periods. Given the substantial gaps in clinical evidence, transparent communication of uncertainty is essential. The integration of standardized reproductive endpoints into clinical trials, alongside the development of predictive tools is critical to support evidence-based counselling and optimize long-term survivorship outcomes.