Cell-Free DNA and Neuromediators in Detecting Aggressive Variant Prostate Cancer

Abstract

Background: Aggressive variant transformation in metastatic castration-resistant prostate cancer (mCRPC) represents an under-recognized phenomenon. There is an urgent need for non-invasive biomarkers to detect these variants and identify treatment alternatives. Methods: A prospective observational pilot study in mCRPC patients receiving treatment with cabazitaxel (CAB) was conducted. Neuromediators were sequentially evaluated and their impact on disease endpoints calculated. Targeted next-generation sequencing (NGS) of cell-free DNA (cfDNA) was also performed in a highly pretreated subset of patients. Results: 23 patients were included. Estimated effects indicate that neuron-specific enolase (NSE) levels at baseline may be correlated with overall survival (NSE unit 18.3 ng/ml: HR1.262 (95% confidence interval (CI) 0.985-1.616)) and that chromogranin A (CGA) may be correlated with progression-free survival (CGA unit 98.1 ng/ml: HR1.341 (95% CI 1.011-1.778)). cfDNA analysis revealed mutations annotated in prostate cancer (PCA) and small cell cancers (SCC). 1 patient showed elevated neuromediators along with annotated mutations in PCA and SCC, potentially indicating aggressive variant cancer. In 3 patients KIT mutations (e.g. pM541L, pV654A) known to be tissue-based biomarkers with level 1 evidence for the treatment with imatinib and sunitinib were found. Conclusions: Sequential analysis of neuromediators and targeted NGS of cfDNA provide insight for the estimation of tumor heterogeneity under therapy with CAB.

Neuroendocrine and Aggressive-Variant Prostate Cancer

“…Serum NE markers such as NSE and CgA have been reported to be prognostic in patients with mCRPC [61,[91][92][93][94][95][96][97][98]. Their role as predictors of response in unselected mCRPC patients is still under investigation, with some reports suggesting such a role [93].…”

“…For instance, CgA rise and velocity have been reported to be associated with androgen-independent progression under hormonal therapy [99], while CgA and NSE elevation during the first months of treatment with abiraterone was found to be associated with worse treatment outcome [98]. With regard to chemotherapy, baseline CgA levels and early high CgA rise were shown to be associated with outcome during treatment with taxanes [97,100]. Currently, a prospective cohort study (NCT03017794) is investigating the role of CgA as a predictor of recurrence after primary radiation to the prostate, hypothesizing that radiation-induced NE differentiation is a driver of progression.…”