Abstract
ABSTRACTBackgroundPlasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC).MethodsBetween 2011 and 2016, 114 sequential plasma samples from 43 mCRPC abiraterone-treated patients were collected. Targeted next-generation sequencing was performed to determine ptDNA fraction. ptDNA progressive disease was defined as a rise in the fraction compared to the pre-treatment.ResultsA ptDNA rise in the first on-treatment sample (interquartile range (IQR) 2.6–3.7 months) was significantly associated with increased risk of early radiographic or any prostate-specific antigen (PSA) rise (odds ratio (OR) = 15.8, 95% confidence interval (CI) 3.5–60.2, p = 0.0002 and OR = 6.0, 95% CI 1.6–20.0, p = 0.01, respectively). We also identified exemplar cases that had a rise in PSA or pseudoprogression secondary to bone flare but no rise in ptDNA. In an exploratory analysis, initial ptDNA change was found to associate with the duration of response to prior androgen deprivation therapy (p < 0.0001) but not to prior taxanes (p = 0.32).ConclusionsWe found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is now merited.
Highlights
Plasma tumour DNA levels on treatment are associated with response in a variety of cancers
Standard disease evaluation recommended by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines[3] specifies imaging tests and prostate-specific antigen (PSA) assessments: these guidelines highlights the need for the evaluation of progressive disease (PD) at established timepoints using liquid biopsies to better characterise disease biology and identify potential predictive molecular biomarkers
We observed that patients with an increase in Plasma tumour DNA (ptDNA) fraction had a significantly increased risk of having PD, based on 3-month early radiographic assessment (OR = 15.8, 95% confidence interval (CI) 3.5–60.2, p = 0.0002, Fig. 2a)
Summary
Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. We characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate cancer (mCRPC). CONCLUSIONS: We found that ptDNA assessment for therapy monitoring in mCRPC is feasible and provides data relevant to the clinical setting. Prospective evaluation of these findings is merited. Standard disease evaluation recommended by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines[3] specifies imaging tests and prostate-specific antigen (PSA) assessments: these guidelines highlights the need for the evaluation of progressive disease (PD) at established timepoints using liquid biopsies to better characterise disease biology and identify potential predictive molecular biomarkers. Its promise as a minimally invasive biomarker is supported by the high concordance of detected genomic alterations with matched metastatic biopsies.[5,6]
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