Abstract
Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer.
Highlights
Androgen deprivation therapy (ADT) has been used to treat advanced prostate cancer since 1941 [1]
We examined plasma cell-free DNA (cfDNA) in advanced prostate cancer and were able to detect somatic mutations and genomic aberrations in all of the patients after accounting for constitutional genomic abnormalities
Our results suggest that somatic alterations in cfDNA may serve as sensitive biomarkers for predicting treatment response and clinical outcome in advanced prostate cancer
Summary
Androgen deprivation therapy (ADT) has been used to treat advanced prostate cancer since 1941 [1]. In 2011, more than one-third of the estimated 2.71 million prostate cancer patients in the United States received ADT (http:// seer.cancer.gov/). Response to ADT in the hormonesensitive prostate cancer (HSPC) lasts from a few months www.impactjournals.com/oncotarget to several years (median 18-30 months). After the emergence of castration-resistant prostate cancer (CRPC), several new systemic anti-cancer therapies with overall survival benefit are currently considered [2]. A biochemical response to these treatments is often estimated by PSA levels. This estimate may be unreliable due to disease heterogeneity. Development of more sensitive and specific assays to monitor the treatment response is clearly needed
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