Moving forward, new therapies require new biomarkers for several reasons:
- Predicting response and clinical outcomes
- Monitoring response to treatment over time
- Identifying emergence of resistance mechanisms
- Ultimately guiding optimal combinations/sequencing of new drugs
Liquid biopsy from the peripheral blood represents all disease sites, is feasible at multiple time points, and allows noninvasive, repeatable mapping of disease evolution (response, resistance). This does present challenges: deciding which analytes and which phenotypes to characterize. CellSearch is an FDA approved method for counting circulating tumor cells, which is prognostic of OS in mCRPC. Across five trials, >=1 vs 0 circulating tumor cells/7.5 mL after 12 weeks of therapy has demonstrated prognostic ability. The truncated constitutively active AR-splice variant AR-V7 lacks ligand binding domain and is detectable in early disease and is higher mCRPC. More recently cell-free DNA (cfDNA) allows detection of mutations and copy number alterations in AR, BRCA2, ATM, all of which are associated with PFS and OS. Furthermore, DNA damage repair defects in cfDNA track with PARP-inhibitor response and resistance. Decreases in these alterations is associated with treatment response.
Beyond CTC counts, CTC AR-V7 and cfDNA is cell-free RNA – plasma or exosomal AR-V7, miR-1290, and miR-375 is associated with shorter PFS and OS in mCRPC and 7-month PSA response in mCSPC. This has recently been a research of Dr. Goldkorn and his group as they have developed a new capture protocol for CTC RNAseq. Their protocol involves a patient-to-RNA timeframe of 3 hours with ~30% live CTC recovery, allowing unmasking of prostate-specific genes such as AR, PSA and PSMA. They have also recently developed “multiparametric liquid biopsy” applying multiple liquid biopsy methods to generate a more comprehensive disease profile over time. Dr. Goldkorn is one of the chairs for the SWOG S1216 study:
Dr. Goldkorn concluded his talk by noting that technical novelty leads to clinical utility:
- Remarkable advances have been made in CTC counts, AR-V7, and cfDNA associated with clinical outcomes
- New technologies enable new assays, but these must be rigorously qualified
o Analyte: CTCs, plasma nucleic acids, proteins
o Phenotype: immunohistochemistry, mutations, methylation, gene expression
o Pre-Analytics: collection, workflow, handling
o Analytic Validation: accuracy, reproducibility, robustness
o Standardization: targets, cut points across various platforms
o Clinical validation: sensitivity, specificity, surrogacy as prognostic/predictive marker for a clinically relevant endpoint (response to treatment, clinical outcome)
o Clinical utility: incremental value (OS, QoL, cost) over existing standard of care
Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia @zklaassen_md at American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois