mFAST-SeqS based aneuploidy score in circulating cell-free DNA and role as early response marker in patients with metastatic prostate cancer treated with androgen receptor signaling inhibitor.
Authors: Isebia Khrystany T. , de Jong Anouk , de Weerd Vanja , Beaufort Corine , Hamberg Paul , Lolkema Martijn P. , Wilting Saskia M , De Wit Ronald , Martens John W.M. , Jansen Maurice P. H. M. 
Published: June 2023

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Background: Several treatment modalities in metastatic castration resistant prostate cancer (mCRPC) are available to prolong progression-free and overall survival. With the arrival of additional treatment modalities, the need for accurate monitoring of treatment response is becoming more eminent and research for biomarkers pivotal. Cell-free circulating tumor DNA (ctDNA) has emerged as a promising prognostic and predictive biomarker. Several techniques have been employed for the detection and characterization of ctDNA within the total pool of cell-free DNA (cfDNA), one of which is the modified Fast Aneuploidy Screening Test-Sequencing System (mFAST-SeqS). This affordable and robust assay enables the quantitation of a sample’s ctDNA using a genome-wide aneuploidy score (GWA). Our aim was to investigate whether estimation of the GWA by mFAST-SeqS can be used to evaluate early response to treatment and predict response to treatment at baseline in patients with mCRPC. Methods: We prospectively enrolled mCRPC patients before start of treatment with androgen receptor signaling inhibitor (ARSI) abiraterone or enzalutamide. Blood samples were collected at baseline before start of treatment (BL, n= 134) and at an early treatment time point during treatment (ET, n= 20). We isolated cfDNA from plasma collected at both time points using the QiaSymphony or Maxwell system, and performed mFAST-SeqS on 1 ng cfDNA by amplifying and sequencing long interspaced nuclear elements (LINE-1) throughout the genome. The GWA-scores were calculated by taking the summed square of individual Z scores per chromosome arm relative to healthy controls. GWA-score was dichotomized in high (GWAhigh) and low (GWAlow), based on the previously described cut-off of 5. Clinical outcome, defined as treatment duration with ARSI, was compared for patients with a GWAhigh and GWAlow score at baseline and at an early time point. In addition, conversion of GWA score from baseline to early time point was explored. Results: Median age at start of treatment was 68.5 years (inter-quartile range (IQR): 63-73). Median time between start treatment and blood draw at BL and ET was 3 (IQR: 0-10 days before treatment) and 28 (IQR: 18-62 days during treatment) days, respectively. Median number of prior therapy lines was 1 (IQR: 0-10). Treatment duration was significantly shorter in the GWAhigh group versus the GWAlow group both at BL and at ET in patients treated with ARSI (BL: p<0.001, log-rank test, median 221 and 82 days; ET: p<0.01, log-rank test, median 123 and 42 days). Conclusions: The genome-wide aneuploidy score, based on mFAST-SeqS of cfDNA, is a useful tool to predict response to ARSI in patients with mCRPC. The current dataset will be extended to 199 samples at baseline and 78 samples at early time point, and also include mCRPC patients treated with taxanes. Clinical trial information: NCT01855477 , NTR732 .