Dynamic changes in gene alterations during chemotherapy in metastatic castrate resistant prostate cancer

Abstract

Abstract Docetaxel chemotherapy is a standard treatment option for metastatic castrate resistant prostate cancer (mCRPC) patients. To date, the genomic perturbations underlying the emergence of resistance in mCRPC patients during chemotherapy treatment have not been fully characterized. Previous studies have established that AR, TP53, RB1 and PTEN gene alterations are frequent at this stage of progression and that TP53, RB1 and PTEN, but not AR alterations are associated with poor outcome. However, the clonal dynamics of these key driver cancer genes during chemotherapy in mCRPC patients have not been described. Toward this goal, we performed a retrospective analysis of serially profiled cell-free DNA (cfDNA) alterations in blood samples collected from mCRPC patients before and after starting chemotherapy who were followed for response and clinical outcomes. While AR alterations and measures of mutational load were significantly reduced in patients with stable or decreased PSA levels after 3 cycles of chemotherapy, reductions in RB1, TP53 and PTEN alterations were relatively modest, which may represent the persistence of a clonal signature associated with the emergence of treatment-induced lineage plasticity (TILP) underlying resistance. The ability to monitor these driver gene clonal dynamics during chemotherapy may have utility in the clinical setting.