Two Decades of Disease Evolution and Biomarker-Guided Clinical Decision Making in Metastatic Prostate Cancer

Abstract

Despite significant advances in prostate cancer treatment over the past two decades, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. We present the case of a patient with aggressive prostate cancer diagnosed 20 years ago, underscoring the value of longitudinal genomic profiling and advanced imaging to guide clinical decisions. After multiple treatment failures, genomic analyses of tissue and liquid biopsies revealed dynamic changes in tumor biology and the emergence of resistance mechanisms, particularly AR amplification, identified with a liquid biopsy test and validated by [¹⁸F]-FDHT PET scan. This finding guided treatment with bipolar androgen therapy (BAT), which achieved a dramatic clinical response, reduced AR expression, improved symptoms, and restored sensitivity to enzalutamide. This case exemplifies the utility of serial liquid biopsies in uncovering mechanisms of tumor evolution and resistance, and the crucial role of cutting-edge diagnostics in personalized cancer treatment.

Keywords: AR amplification; bipolar androgen therapy (BAT); liquid biopsy; longitudinal genomic profiling; metastatic castration-resistant prostate cancer (mCRPC); tumor evolution.

Figure 1

PSA kinetics throughout the patient’s clinical course and therapeutic interventions. PSA levels over time in relation to disease progression and sequential treatment regimens: ARSi (androgen receptor signaling inhibitor, turquoise), ADT (androgen deprivation therapy, purple), RT (radiotherapy, pink), targeted therapy (gray), theranostics (yellow), chemotherapy (orange), and BAT (red).

Figure 2

Longitudinal molecular profiling and mutation analysis over two decades of disease course using the MSK-IMPACT, MSK-ACCESS, and Guardant360 platforms. (A) Schematic illustrating the origin of samples collected at multiple time points throughout the course of the disease. Created in BioRender (https://app.biorender.com/, accessed on 3 August 2025). (B) Comprehensive genomic profiling. The upper panel shows the origin, year of collection, and clinical event associated with each biopsy. Tissue biopsies were analyzed using MSK-IMPACT (green dashes) and cfDNA was assessed via MSK-ACCESS (red dashes) or the Guardant360 assay (purple dashes). Second panel: copy number alterations (CNAs) are depicted with gene amplifications in blue and deletions in red. Third panel: variant allele frequencies (VAFs) of 14 unique mutations identified at different sampling sites are also shown. The bottom panel presents a mutational signature analysis demonstrating enrichment of pathways, including homologous recombination deficiency (HRD), DNA mismatch repair deficiency (dMMR), and nucleotide excision repair (NER), that correlate with changes in cancer biology.

Figure 3

Multi-modal PET imaging demonstrates the therapeutic response to BAT. (A) Baseline [¹⁸F]-FDHT PET scan (left) demonstrates high AR expression in multiple metastatic lesions. Follow-up [¹⁸F]-FDHT PET scans at cycle 3 (11 weeks, center) and cycle 4 (19 weeks, right) of BAT treatment showing near complete resolution of previously identified metastatic lesions. (B) Serial FDG PET-CT scans showing response to BAT. Baseline pre-treatment FDG PET scan showing increased FDG uptake in multiple bones and thoracic nodes. Follow-up FDG PET-CT scans at the second cycle (7 weeks), third cycle (11 weeks), and fourth cycle (19 weeks) of BAT treatment, respectively, showing significantly lower FDG uptake compared to the pre-treatment scan, confirming continued treatment response.