Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Khan, K. et al. (2018) Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Gut, 67(8), pp. 1484-1492. (doi: 10.1136/gutjnl-2017-314178) (PMID:28790159) (PMCID:PMC6204951)

Abstract

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. Design: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. Results: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06). Conclusions: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Braconi, Dr Chiara and Valeri, Dr Nicola
• Authors: Khan, K., Rata, M., Cunningham, D., Koh, D.-M., Tunariu, N., Hahne, J. C., Vlachogiannis, G., Hedayat, S., Marchetti, S., Lampis, A., Damavandi, M. D., Lote, H., Rana, I., Williams, A., Eccles, S. A., Fontana, E., Collins, D., Eltahir, Z., Rao, S., Watkins, D., Starling, N., Thomas, J., Kalaitzaki, E., Fotiadis, N., Begum, R., Bali, M., Rugge, M., Temple, E., Fassan, M., Chau, I., Braconi, C., and Valeri, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Gut
• Publisher: BMJ Publishing Group
• ISSN: 0017-5749
• ISSN (Online): 1468-3288
• Published Online: 08 August 2017
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Gut 67(8): 1484-1492
• Publisher Policy: Reproduced under a Creative Commons License