Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer

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.

Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer

“…Additionally, we found NOTCH1 locus amplification in one CRPC patients (#1014) and four HSPC patients (#1050, #1059, #1084 and #1098). Most of these abnormalities in urine cfDNAs were also observed and previously reported in the matched plasma cfDNAs [20] (Figure 2 and Table 3). …”

“…We first evaluated the urine genome abnormality (UGA) algorithm based on genome-wide copy number variation (CNVs) to determine association with treatment response and clinical outcomes in patients receiving standard advanced prostate cancer treatments. We then compared urine cfDNA-based CNVs with previously reported plasma cfDNA CNVs [20]. Our data show that urine cfDNAs may generate comparable results to plasma cfDNA in CNVs analysis and may have clinical application in predicting treatment response and clinical outcomes.…”

“…Cell free DNA (cfDNA)-based somatic aberrations in plasma of cancer patients have been extensively reported [15, 18, 19]. In advanced prostate cancer patients tumor-derived plasma cfDNA is detected in hormone sensitive and castrate resistant stages [20]. It remains unclear if genomic profiling to detect tumor cfDNA aberrations in urine is feasible and clinically relevant for developing as predictive biomarkers.…”

“…It remains unclear if genomic profiling to detect tumor cfDNA aberrations in urine is feasible and clinically relevant for developing as predictive biomarkers. To determine somatic genomic changes we performed whole-genome sequencing and analyzed copy number variations in matched urine specimens of advanced prostate cancer patients previously sequenced for plasma cfDNA [20]. We first evaluated the urine genome abnormality (UGA) algorithm based on genome-wide copy number variation (CNVs) to determine association with treatment response and clinical outcomes in patients receiving standard advanced prostate cancer treatments.…”

Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence

“…Similarly, ADT has a number of adverse side effects and, on average, is only effective for two to three years before the emergence of castration resistant prostate cancer (CRPC); an incurable and often fatal disease. There are currently no known methods to predict duration of treatment response or to identify those men who will respond most effectively (5, 6). Furthermore, due to the aforementioned issues with both screening and biopsy, overtreatment represents a significant problem in the management of prostate cancer; the majority of diagnoses will not prove fatal, but there is a subset of men with aggressive and lethal disease.…”