Cell-free DNA aneuploidy score as a dynamic early response marker in prostate cancer

Abstract

Cell-free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration-resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), a quick, tumor-agnostic and affordable ctDNA assay that requires a small input of DNA, to generate a genome-wide aneuploidy (GWA) score in mCRPC patients, and correlated this to matched metastatic tumor biopsies. In this prospective multicenter study, GWA scores were evaluated from blood samples of 196 mCRPC patients prior to treatment (baseline) with taxanes (docetaxel and cabazitaxel) and androgen receptor signaling inhibitors (ARSI; abiraterone and enzalutamide), and from 74 mCRPC patients at an early timepoint during treatment (early timepoint; median 21 days). Z-scores per chromosome arm were tested for their association with tumor tissue genomic alterations. We found that a high tumor load in blood (GWA^high) at baseline was associated with poor response to ARSI [HR: 2.63 (95% CI: 1.86-3.72) P < 0.001] but not to taxanes. Interestingly, GWA^high score at the early timepoint was associated with poor response to both ARSIs [HR: 6.73 (95% CI: 2.60-17.42) P < 0.001] and taxanes [2.79 (95% CI: 1.34-5.78) P = 0.006]. A significant interaction in Cox proportional hazards analyses was seen when combining GWA status and type of treatment (at baseline P = 0.008; early timepoint P = 0.018). In summary, detection of ctDNA in blood by mFast-SeqS is cheap, fast and feasible, and could be used at different timepoints as a potential predictor for outcome to ARSI and taxane treatment in mCRPC.

Keywords: abiraterone; cabazitaxel; ctDNA; docetaxel; enzalutamide; prostate cancer.

Fig. 1

Schematic overview of mCRPC‐patient inclusion within the CPCT‐02 and CIRCUS study. Overview of metastatic castration resistant prostate cancer (mCRPC)‐patient enrollment into the CPCT‐02 and CIRCUS studies and subsequent analyses performed. In total, 196 patients were enrolled prior to a new treatment line with androgen receptor signaling inhibitor (ARSI) or taxanes. Patients could be included multiple times, depending on whether they received multiple new treatment lines. Of the 196 patients, we had 153 unique tissue biopsies available for WGS.

Fig. 2

Correlation between GWA score of cfDNA and tumor tissue aneuploidy. Spearman correlation coefficient between tissue‐based copy number alterations (CNA) per chromosome arms derived from WGS (x‐axis) and the aneuploidy scores per chromosome arms in cell‐free DNA (cfDNA) derived from mFast‐SeqS data (y‐axis). The relative deviation of CNA from the expected normal CNA was calculated and log₂ transformed and the results are shown per sample. The graphs represent matched samples ordered according to the genome‐wide aneuploidy (GWA) score.

Fig. 3

Genomic landscape of included patients (oncoplot), ordered by dichotomized GWA. Overview of genome‐wide tumor tissue characteristics of the cohort (CPCT‐02; n = 153) ordered by dichotomized genome‐wide aneuploidy (GWA) derived from cfDNA. From top to bottom, the tracks represent: Dichotomized GWA score in blood; GWA score in blood; type of treatment, if known; response to treatment category; genome‐wide tumor mutational burden (mutations per megabase); the relative contribution of Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures (v3.3), grouped per proposed etiology; absolute frequency of structural variants; relative frequency of structural variants; tumor purity; genome ploidy; genome duplication detected; microsatellite‐instability (MSI) status; homologous recombination (HR) status as detected by Classifier of HOmologous Recombination Deficiency (CHORD) [25]; presence of chromothripsis; generalized biopsy location; overview of detected somatic mutations in driver genes estimated by dNdScv [26] and GISTIC2 [27].

Fig. 4

Blood GWA and treatment response. Kaplan Meier curves of failure‐free survival (FFS) were grouped by type of treatment [androgen receptor signaling inhibitor (ARSI) or taxanes] and dichotomized based on blood GWA score. This was done for at baseline timepoint samples, early time point samples and longitudinal timepoint (combined baseline and early on treatment timepoint). Groups based on genome‐wide aneuploidy (GWA) scores were compared using a Log‐Rank test.