Dataset Information

Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer.

ABSTRACT: Treatment 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.To determine the value of a ?30% CTC decline as a treatment response indicator.We identified patients with a baseline CTC count ?5 cells/7.5ml and evaluable post-treatment CTC counts in two prospective trials.Patients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials.The 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.Overall 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.A 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.Circulating 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.

SUBMITTER: Lorente D

PROVIDER: S-EPMC5568108 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer.

Lorente David D Olmos David D Mateo Joaquin J Bianchini Diletta D Seed George G Fleisher Martin M Danila Daniel C DC Flohr Penny P Crespo Mateus M Figueiredo Ines I Miranda Susana S Baeten Kurt K Molina Arturo A Kheoh Thian T McCormack Robert R Terstappen Leon W M M LW Scher Howard I HI de Bono Johann S JS

European urology 20160609 6

<h4>Background</h4>Treatment 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.<h4>Objective</h4>To determine the value of a ≥30% CTC decline as a treatment response indicator.<h4>Design, setting, and participants</h4>We identified patients with a baseline CTC count ≥5 cells/7.5ml and evaluable post-treatment CTC counts in two prospective ...[more]

PMID: 27289566

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Project description:BackgroundSomatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer.Patients and methodsThis study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate-resistant prostate cancer) with AR alterations detected in ctDNA that underwent next-generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc., Redwood City, CA). Distribution and summary of AR alterations detected, the association of AR alterations with other genes, and a pathway analysis are reported.ResultsThe median absolute plasma copy number of AR amplifications was 3.3 (range, 1.2-165.2). Many patients had multiple AR mutations; a total of 112 unique mutations were identified in AR, including L702H (25%), T878A (14%), H875Y (11%), W742C (8%), W742L (4%), F877L (2%), and T878S (2%). Other ctDNA gene alterations in the Guardant assays included TP53 (50%), MYC (34%), BRAF (32%), PIK3CA (29%), MET (25%), CDK6 (26%), EGFR (24%), FGFR1 (21%), and APC (12%). Many of these non-AR alterations are not tissue verified in other studies. AR amplification cosegregated with alterations in MYC (p < .001), BRAF (p < .001), PIK3CA (p < .001), MET (p < .001), CDK6 (p < .001), EGFR (p < .001), FGFR1 (p = .391), and more. Alterations in APC were significantly associated with mutations in AR (p < .001).ConclusionSeveral AR alterations and concomitant non-AR alterations that associate with drug resistance were detected. These findings provide additional insights into the heterogeneity of advanced prostate cancer.Implications for practiceThe goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.

Dataset Information

Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer.

Publications

Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer.

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