Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial

Khan, K. H. et al. (2018) Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial. Cancer Discovery, 8(10), pp. 1270-1285. (doi: 10.1158/2159-8290.CD-17-0891) (PMID:30166348) (PMCID:PMC6380469)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Valeri, Dr Nicola and Braconi, Professor Chiara
Authors: Khan, K. H., Cunningham, D., Werner, B., Vlachogiannis, G., Spiteri, I., Heide, T., Mateos, J. F., Vatsiou, A., Lampis, A., Damavandi, M. D., Lote, H., Huntingford, I. S., Hedayat, S., Chau, I., Tunariu, N., Mentrasti, G., Trevisani, F., Rao, S., Anandappa, G., Watkins, D., Starling, N., Thomas, J., Peckitt, C., Khan, N., Rugge, M., Begum, R., Hezelova, B., Bryant, A., Jones, T., Proszek, P., Fassan, M., Hahne, J. C., Hubank, M., Braconi, C., Sottoriva, A., and Valeri, N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:30 August 2018

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