Tumor fraction in circulating free DNA as a biomarker of disease dynamics in metastatic prostate cancer.

Abstract

195 Background: Quantification of circulating free DNA (cfDNA) has been proposed both as a prognostic biomarker and as a biomarker of response and resistance to therapy. However, dynamics of cfDNA derived from both tumor and non-cancerous tissues through dense longitudinal monitoring over the course of treatment with multiple therapeutic modalities have not been well described. Methods: CfDNA isolated from banked and prospectively collected plasma samples from pts with metastatic castration-resistant prostate cancer (mCRPC) was subject to ultra-low pass (~0.1x coverage) whole genome sequencing (ULP-WGS). The fraction of cfDNA derived from tumor rather than non-cancerous tissues (i.e. the tumor fraction, or TFx) in each sample was estimated using a novel computational tool called ichorCNA, and was correlated with clinical features and response to therapy. Results: 663 plasma samples from 140 pts were included (median 3 samples/pt; range 1-20). TFx was correlated with the number of bone metastases (median TFx = 0.014 with no bone mets, 0.047 with 1-3, 0.190 for 4+), and with the presence of distant visceral mets (p < 0.0001). In multi-variate analysis, TFx was positively correlated with Alk Phos (p = 0.0227) and negatively correlated with Hgb (p < 0.001), but was not correlated with PSA (p = 0.75). All new treatment starts leading to > = 30% PSA decline at > = 6 weeks were associated with a decline in TFx from baseline when baseline TFx was > 7% (median TFx change -92.2%, range -70.3% to -100%); however, TFx in patients being subsequently maintained on secondary hormonal therapy without radiographic progression was quite dynamic. The total yield of cfDNA derived from both tumor and non-cancerous tissues tracked closely with TFx, and did not markedly change with initiation of therapies expected to lead to generalized tissue damage, such as chemotherapy and radiation, over the time scales examined. Conclusions: Decline in TFx is a promising biomarker for initial response to therapy, but subsequent temporary rises in TFx do not necessarily indicate the cessation of clinical benefit from secondary hormonal therapies. Analysis of cfDNA may allow a window into short-term tumor dynamics not easily assayed through other methods.