Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development

• Published in: Nature reviews. Clinical oncology 2021-07, Vol.18 (7), p.454-467
• Main Authors: Pal, Abhijit, Shinde, Rajiv, Miralles, Manuel Selvi, Workman, Paul, de Bono, Johann
• Format: Article
• Language: English
• Subjects: 631/67/1059/153; 692/308/153; Antimitotic agents; Antineoplastic agents; Antitumor agents; Audit trails; Biological markers; Biomarkers; Biopsy; Cancer; Clinical trials; Deoxyribonucleic acid; Disease resistance; DNA; DNA sequencing; Drug development; Genomes; Medicine; Medicine & Public Health; Oncology; Perspective; Pharmaceutical research; Pharmacodynamics; Tumors; Whole genome sequencing
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-021-00489-x

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based ‘liquid biopsy’ approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials. In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.