Using circulating cell-free DNA to monitor personalized cancer therapy

Abstract

High-quality genomic analysis is critical for personalized pharmacotherapy in patients with cancer. Tumor-specific genomic alterations can be identified in cell-free DNA (cfDNA) from patient blood samples and can complement biopsies for real-time molecular monitoring of treatment, detection of recurrence, and tracking resistance. cfDNA can be especially useful when tumor tissue is unavailable or insufficient for testing. For blood-based genomic profiling, next-generation sequencing (NGS) and droplet digital PCR (ddPCR) have been successfully applied. The US Food and Drug Administration (FDA) recently approved the first such “liquid biopsy” test for EGFR mutations in patients with non-small cell lung cancer (NSCLC). Such non-invasive methods allow for the identification of specific resistance mutations selected by treatment, such as EGFR T790M, in patients with NSCLC treated with gefitinib. Chromosomal aberration pattern analysis by low coverage whole genome sequencing is a more universal approach based on genomic instability. Gains and losses of chromosomal regions have been detected in plasma tumor-specific cfDNA as copy number aberrations and can be used to compute a genomic copy number instability (CNI) score of cfDNA. A specific CNI index obtained by massive parallel sequencing discriminated those patients with prostate cancer from both healthy controls and men with benign prostatic disease. Furthermore, androgen receptor gene aberrations in cfDNA were associated with therapeutic resistance in metastatic castration resistant prostate cancer. Change in CNI score has been shown to serve as an early predictor of response to standard chemotherapy for various other cancer types (e.g. NSCLC, colorectal cancer, pancreatic ductal adenocarcinomas). CNI scores have also been shown to predict therapeutic responses to immunotherapy. Serial genomic profiling can detect resistance mutations up to 16 weeks before radiographic progression. There is a potential for cost savings when ineffective use of expensive new anticancer drugs is avoided or halted. Challenges for routine implementation of liquid biopsy tests include the necessity of specialized personnel, instrumentation, and software, as well as further development of quality management (e.g. external quality control). Validation of blood-based tumor genomic profiling in additional multicenter outcome studies is necessary; however, cfDNA monitoring can provide clinically important actionable information for precision oncology approaches.

Keywords:

• Genotype-directed cancer care
• liquid biopsy
• ctDNA tumor genomic profiling
• cfDNA
• chromosomal aberration pattern analysis
• immunotherapy

Disclosure statement

In accordance with Taylor & Francis policy and our ethical obligations as researchers, we are reporting all financial or business interests and all funding from any company that may be affected by the research reported in the enclosed paper. We have disclosed those interests fully to Taylor & Francis, and we have in place an approved plan for managing any potential conflicts arising from that involvement. M.O. has declared Scientific Advisory Board participation and consultancy fees from Chronix Biomedical, San José, USA, a research and development company. Chronix Biomedical was involved in cfDNA measurements (CNI score). E.S. has declared employment by Chronix Biomedical GmbH, a research and development company that was involved in cfDNA measurements (CNI score). J.B. has declared employment by Chronix Biomedical GmbH, a research and development company that was involved in cfDNA measurements (CNI score). P.K. has no conflicts of interest. N.P.P. has financial interest in Chronix Biomedical. G.J.W. has been a consultant for Pharmatech, Paradigm, Blend Therapeutics, and Viomics. He has been on the Speaker’s bureau for Medscape, Novartis, and Merck and received travel/accommodations from NantWorks. P.D.W. was previously a paid consultant to Chronix Biomedical GmbH, which owns patents on some of the technology mentioned.

Additional information

Funding

Chronix Biomedical [cfDNA measurements].