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Integration of Liquid Biopsies in Clinical Management of Metastatic Prostate Cancer - Beyond the Abstract

The term “liquid biopsy” encompasses circulating tumor cells (CTCs), cell-free nucleic acids (circulating tumor DNA or RNA), and extracellular vesicles (EVs) found in peripheral blood which is reflective of active metastatic sites. This minimally invasive technique throughout a treatment course would allow for sequential profiling to monitor clinical response in real time. We review the current data on the use of liquid biopsies in metastatic prostate cancer with a specific focus on evidence supporting their use in clinical decision-making.


CTC capture is accomplished using various methods including immunomagnetic enrichment, microfluidic sorting, and high content scanning.1-4  The number of CTCs is representative of disease burden and serves as a biomarker for prognosis and response to therapy. In some studies, CTC kinetics on treatment were superior to PSA change in predicting overall survival.5,6  CTC molecular phenotypes are also informative: For example, the AR-V7 splice variant of the androgen receptor, which is associated with therapy resistance, can be detected in CTCs by immunofluorescent staining using a monoclonal anti-AR-V7 antibody as well as by qPCR amplification of mRNA from immunomagnetically enriched CTCs.7,8

Cell-free DNA (cfDNA) analysis is accomplished through digital droplet PCR, beads, emulsions, amplification, and magnetics (BEAM), whole exome sequencing, or targeted sequencing libraries.9  Guardant360 CDx and FoundationOne Liquid CDx are FDA approved for comprehensive analysis of cfDNA.10,11

cfDNA can be used to detect clinically relevant DNA alterations in prostate cancer, such as homologous recombination deficiency (HRD) mutations. HRD mutations suggest a poor response to ARPIs as well as poor cancer-specific survival.12  Conversely, they predict response to poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) treatment; therefore determining HRD mutation status is clinically imperative in those with metastatic disease.10  Serial cfDNA is also useful in monitoring disease response as well as development of resistant as HRD reversion mutations have been identified in patients with progression on PARPi treatment.13 

Based on the evidence provided by a number of phase 3 trials supporting the clinical validity of liquid biopsies as biomarkers for prognosis and treatment response, we propose an algorithm for incorporating the use of liquid biopsies in the treatment of metastatic prostate cancer, summarized in the diagram below (Figure 1).

Liquid_Biopsies_BTA.png
Liquid biopsy approaches are rapidly evolving, with new capabilities such as highly multiplexed protein profiling enabled by technologies like single cell mass cytometry and evaluation of DNA methylation patterns by whole genome sequencing of bisulfite converted cfDNA.14-16  Combination of multiple liquid biopsy techniques may provide a more comprehensive and nuanced molecular picture of an individual’s disease.17  Our understanding of the potential utility of liquid biopsies continues to evolve, and with further clinical validation liquid biopsies will become an integral tool in the standard of care treatment of metastatic prostate adenocarcinoma.

Written by: Varsha Tulpule, Gareth J. Morrison, Mary Falcone, David I. Quinn, Amir Goldkorn

Division of Medical Oncology, Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

References:

  1. Miller MC, Doyle GV, Terstappen LW. Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol 2010;2010:617421.
  2. Xu L, Mao X, Imrali A, Syed F, Mutsvangwa K, Berney D, et al. Optimization and Evaluation of a Novel Size Based Circulating Tumor Cell Isolation System. PLoS One 2015;10:e0138032.
  3. Scher HI, Armstrong AJ, Schonhoft JD, Gill A, Zhao JL, Barnett E, et al. Development and validation of circulating tumour cell enumeration (Epic Sciences) as a prognostic biomarker in men with metastatic castration-resistant prostate cancer. Eur J Cancer 2021;150:83-94.
  4. Kaldjian EP, Ramirez AB, Sun Y, Campton DE, Werbin JL, Varshavskaya P, et al. The RareCyte(R) platform for next-generation analysis of circulating tumor cells. Cytometry A 2018;93:1220-5.
  5. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008;14:6302-9.
  6. Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 2009;10:233-9.
  7. Lu D, Krupa R, Harvey M, Graf RP, Schreiber N, Barnett E, et al. Development of an immunofluorescent AR-V7 circulating tumor cell assay - A blood-based test for men with metastatic prostate cancer. J Circ Biomark 2020;9:13-9.
  8. Lokhandwala PM, Riel SL, Haley L, Lu C, Chen Y, Silberstein J, et al. Analytical Validation of Androgen Receptor Splice Variant 7 Detection in a Clinical Laboratory Improvement Amendments (CLIA) Laboratory Setting. J Mol Diagn 2017;19:115-25.
  9. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008;14:985-90.
  10. FDA approves liquid biopsy NGS companion diagnostic test for multiple cancers and biomarkers.
  11. FDA Approves First Liquid Biopsy Next-Generation Sequencing Companion Diagnostic Test.
  12. Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer. Cancer Discov 2018;8:444-57.
  13. Quigley D, Alumkal JJ, Wyatt AW, Kothari V, Foye A, Lloyd P, et al. Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors. Cancer Discov 2017;7:999-1005.
  14. Gerdtsson E, Pore M, Thiele JA, Gerdtsson AS, Malihi PD, Nevarez R, et al. Multiplex protein detection on circulating tumor cells from liquid biopsies using imaging mass cytometry. Converg Sci Phys Oncol 2018;4.
  15. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjostrom M, et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet 2020;52:778-89.
  16. Wu A, Cremaschi P, Wetterskog D, Conteduca V, Franceschini GM, Kleftogiannis D, et al. Genome-wide plasma DNA methylation features of metastatic prostate cancer. J Clin Invest 2020;130:1991-2000.
  17. Hodara E, Morrison G, Cunha A, Zainfeld D, Xu T, Xu Y, et al. Multiparametric liquid biopsy analysis in metastatic prostate cancer. JCI Insight 2019;4.

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