Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Circulating tumor cell heterogeneity in neuroendocrine prostate cancer by single cell copy number analysis.

Neuroendocrine prostate cancer is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. The combined loss of tumor suppressors RB1, TP53, and PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with a phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer.

SLFN11 Expression in Advanced Prostate Cancer and Response to Platinum-based Chemotherapy.

Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.