Public Health & Health Science Division, ULAB

Estrogen receptors drive cancer cell proliferation in hormone receptor-positive cancer, which constitutes 70% of breast cancers. These require long-term endocrine therapy to suppress estrogen signaling and prevent recurrence. While these treatments significantly prolong progression-free and overall survival, the systemic depletion of estrogen and dysregulation of the HPA axis leads to severe, frequently underreported psychiatric toxicities, primarily depression and anxiety. This review evaluates the currentstandard of care and developing therapies, specifically Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), Ovarian Function Suppression (OFS), and Selective Estrogen Receptor Degraders (SERDs), and how they balance clinical efficacy against their respective neurobiological andpsychological costs. A comprehensive synthesis of primary literature, clinical trials, and case evaluations was conducted to analyze survival endpoints alongside neuropsychiatric biomarkers, neuroinflammation,and neurotransmitter pathways. It was found that SERMs like Tamoxifen and AIs (Anastrozole, Letrozole) successfully reducerecurrence risks but trigger profound mood disturbances by disrupting serotonergic pathways and neuroprotective mechanisms in the brain. Ovarian suppression significantly boosts disease-free survival inpremenopausal cohorts but incurs high psychosocial distress and premature menopausal symptoms. Emerging targeted therapies, like the oral SERD elacestrant, provide superior progression-free survival fortherapy-resistant ESR1-mutated cancers, though their long-term neuropsychiatric profiles remain a critical gap in current oncology trials. However, the field currently relies heavily on subjective, self-reportedpatient metrics that are difficult to compare across studies, highlighting an urgent need for future clinical trials to incorporate objective neuropsychiatric assessments and inflammatory biomarkers like IL-6.Ultimately, this review establishes a crucial framework and future direction for the field in order to equip oncologists to balance maximum clinical survival with preserved patient quality of life.