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

Nature Reviews Clinical Oncology volume 18, pages 454–467 (2021)Cite this article

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Abstract

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.

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Fig. 1: Liquid biopsies can be used at multiple steps of the PhAT.
Fig. 2: Liquid biopsy analyses can serve multiple functions in drug development.
Fig. 3: Demonstration of intrapatient heterogeneity through single-cell genomic analysis of CTCs.
Fig. 4: Example of the power of single-cell analysis of CTCs in fully understanding the heterogeneity of tumour biology and evolution.
Fig. 5: Serial analysis of cfDNA with LPWGS.
Fig. 6: LPWGS of cfDNA can provide insights into tumour biology and provide new biomarkers.

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Acknowledgements

P.W. acknowledges funding from Cancer Research UK (C309/A11566 and C35696/A23187), Wellcome (212969/Z/18/Z) and the Mark Foundation and the Chordoma Foundation. J.d.B. acknowledges funding support from Cancer Research UK through The ICR Cancer Centre Grant, from an Experimental Cancer Medicines Centre grant funded by Cancer Research UK and the Department of Health to The Institute of Cancer Research and Royal Marsden, from Movember to the London Prostate Cancer Centre of Excellence programme, and from Prostate Cancer UK and the Prostate Cancer Foundation.

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  1. These authors contributed equally: Abhijit Pal, Rajiv Shinde

Authors and Affiliations

  1. The Institute of Cancer Research, London, UK

    Abhijit Pal, Rajiv Shinde, Manuel Selvi Miralles, Paul Workman & Johann de Bono

  2. The Royal Marsden NHS Foundation Trust, London, UK

    Abhijit Pal, Rajiv Shinde, Manuel Selvi Miralles & Johann de Bono

  3. Cancer Research UK Cancer Therapeutics Unit, The Institute for Cancer Research, London, UK

    Paul Workman

  4. CRUK Convergence Science Centre, The Institute of Cancer Research and Imperial College, London, UK

    Paul Workman

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Competing interests

M.S.M. has become an employee of AstraZeneca since this manuscript was initiated, and is a current shareholder of this company; however, this affiliation does not lead to a direct conflict of interest with the presented work. P.W. is a consultant and/or scientific advisory board member for Astex Pharmaceuticals, Black Diamond Therapeutics, CV6, NextechInvest and Storm Therapeutics, and holds stock in Black Diamond Therapeutics, Chroma Therapeutics, NextechInvest and Storm Therapeutics; he is also a former employee of AstraZeneca and a Non-Executive Director of Storm Therapeutics and the Royal Marsden NHS Trust, and is an Executive Director of the non-profit Chemical Probes Portal. P.W. has received research funding from CRT Pioneer Fund/6th Element Capital and Merck. J.d.B. has served on advisory boards for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi-Aventis, Sierra Oncology, Taiho and Vertex Pharmaceuticals. He is an employee of The Institute of Cancer Research, which has received funding or other support for his research work from Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini Silicon Biosystems, Orion, Pfizer, Sanofi-Aventis, Sierra Oncology, Taiho and Vertex. The Institute of Cancer Research also has a commercial interest in abiraterone, PARP inhibition in DNA repair-defective cancers and PI3K/AKT pathway inhibitors (which provide no personal income to J.d.B.). J.d.B. is named as an inventor, with no financial interest, on US patent 8,822,438. A.P. and R.S. declare no competing interests.

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Nature Reviews Clinical Oncology thanks J.-Y. Pierga, C. Rolfo, A. Sartore-Bianchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Pal, A., Shinde, R., Miralles, M.S. et al. Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development. Nat Rev Clin Oncol 18, 454–467 (2021). https://doi.org/10.1038/s41571-021-00489-x

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