Case Report: Clinicopathologic and molecular characteristics of prostate adenocarcinoma brain metastases despite disproportionately low PSA levels: a four-patient case series and narrative review

Brain metastases (BM) from prostate cancer (PCa) are rare, typically occurring in a small subset of patients with advanced disease or tumors with neuroendocrine differentiation. Diagnosis can be particularly challenging when prostate-specific antigen (PSA) levels remain low or undetectable. We describe four patients with prostate adenocarcinoma who developed brain metastases despite low or modestly elevated PSA levels relative to disease burden(<0.01 to 6.5 ng/ml). All patients underwent surgical resection followed by focal stereotactic radiosurgery and androgen deprivation therapy, with androgen receptor pathway inhibitors used in selected cases. Molecular profiling was available for three patients and demonstrated heterogeneous genomic findings, including PTEN alteration (Case 1), CDK4 amplification (Case 2), and an ATM mutation (Case 3), while testing was unavailable in Case 4. No pathogenic TP53 or RB1 alterations were identified in the profiled tumors. Two patients achieved durable biochemical and radiographic complete remission, one remained in remission before dying of an unrelated cause, and one developed biochemical recurrence without radiographic progression. These findings highlight the biological heterogeneity of central nervous system involvement in prostate cancer and emphasize that brain metastases should be considered even in patients with low PSA levels. Further studies are needed to better define the molecular determinants and biomarkers associated with this uncommon presentation.