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Cancer Discov. 2018 Oct;8(10):1270-1285. doi: 10.1158/2159-8290.CD-17-0891. Epub 2018 Aug 30.

Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.

Author information

1
Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.
2
Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, United Kingdom.
3
Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom.
4
Department of Radiology, The Royal Marsden NHS Trust, Londonand Sutton, United Kingdom.
5
Department of Medicine and Surgical Pathology, University of Padua, Padua, Italy.
6
Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.
7
Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, United Kingdom.
8
Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom. nicola.valeri@icr.ac.uk andrea.sottoriva@icr.ac.uk.
9
Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom. nicola.valeri@icr.ac.uk andrea.sottoriva@icr.ac.uk.

Abstract

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195.

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PMID:
30166348
PMCID:
PMC6380469
DOI:
10.1158/2159-8290.CD-17-0891
[Indexed for MEDLINE]
Free PMC Article

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