Dataset Information

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.

SUBMITTER: Xia S

PROVIDER: S-EPMC4599278 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Xia Shu S Kohli Manish M Du Meijun M Dittmar Rachel L RL Lee Adam A Nandy Debashis D Yuan Tiezheng T Guo Yongchen Y Wang Yuan Y Tschannen Michael R MR Worthey Elizabeth E Jacob Howard H See William W Kilari Deepak D Wang Xuexia X Hovey Raymond L RL Huang Chiang-Ching CC Wang Liang L

Oncotarget 20150601 18

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 t ...[more]

PMID: 25915538

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Project description:BackgroundTreatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of ≥5 cells/7.5ml are associated with poor CRPC outcome.ObjectiveTo determine the value of a ≥30% CTC decline as a treatment response indicator.Design, setting, and participantsWe identified patients with a baseline CTC count ≥5 cells/7.5ml and evaluable post-treatment CTC counts in two prospective trials.InterventionPatients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials.Outcome measures and statistical analysisThe association between a ≥30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices.ResultsOverall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count ≥5 cells/7.5ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36-0.56; p<0.001), 8 wk (HR 0.41, 95% CI 0.33-0.53; p<0.001), and 12 wk (HR 0.39, 95% CI 0.3-0.5; p<0.001) in univariable and multivariable analyses. Stable CTC count (<30% fall or <30% increase) was not associated with a survival benefit when compared with increased CTC count. The association between a 30% CTC decline after treatment and survival was independent of baseline CTC count. CTC declines significantly improved the AUC at all time-points. Finally, in the COU-AA-301 trial, patients with CTC ≥5 cells/7.5ml and a 30% CTC decline had similar overall survival in both arms.ConclusionsA 30% CTC decline after treatment from an initial count ≥5 cells/7.5ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated.Patient summaryCirculating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome.

Dataset Information

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

Publications

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

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