Circulating tumor cell genomic evolution and hormone therapy outcomes in men with metastatic castration-resistant prostate cancer (mCRPC).
Men with circulating tumor cell (CTC) AR-V7 positive mCRPC have worse outcomes when treated with enzalutamide/abiraterone. However, most men lack CTC AR-V7 detection, and additional predictive-biomarkers are needed. We conducted a retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men with mCRPC undergoing treatment with enzalutamide/abiraterone, analyzing pooled CTC and germline DNA for whole-genome copy number alterations (CNAs) in 73 samples from 48 men over time along with pooled CTC and germline whole-exome sequencing (WES) on 22-paired samples before and following progression on AR inhibitor therapy to identify somatic genomic alterations associated with acquired resistance. We observed broad inter-patient and longitudinal CTC genomic heterogeneity from AR-V7 negative men with mCRPC, including common gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN. Men who had progression-free survival of <=3 months despite enzalutamide/abiraterone treatment were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC. After progression on abiraterone/enzalutamide, we observed clonal-evolution of CTCs harboring TP53 mutations and gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2. CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). Implications: We identified common and reproducible genomic alterations in CTCs from AR-V7 negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.
Gupta, S; Halabi, S; Kemeny, G; Anand, M; Giannakakou, P; Nanus, DM; George, DJ; Gregory, SG; Armstrong, AJ
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