Evolutionary Dynamics of Metastatic Prostate Cancer During Serial Therapy

Treatment decisions in metastatic castration-resistant prostate cancer (mCRPC) are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. Here, we simultaneously profiled genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments (2-10 samples per patient) with androgen signaling inhibitors (ASI) and taxane chemotherapy from 60 mCRPC patients. Using the genomic data, we delineated the clonal substructure and evolutionary dynamics of each patient, and developed an evolutionary dynamic index (EDI) to measure the longitudinal changes of the tumor subclones. Treatment with ASI resulted in greater subclonal selection and population structure changes than with taxanes. The subclones that emerged in association with serial therapy resistance harbored recurrent aberrations in previously identified and new candidate genes, and particular enrichment in genes related to PI3K-AKT signaling. Our integration of detailed clinical and genomics data provides a framework for future unbiased genomic applications for ctDNA in the oncology clinic towards precision medicine.