Journal Article

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

Starling, Naureen, Begum, Ruwaida, Khan, Khurum, Lote, Hazel, Fassan, Matteo, Valeri, Nicola, Fotiadis, Nicos, Fontana, Elisa, Bali, Maria, Cunningham, David, Vlachogiannis, George, Koh, Dow-Mu, Hedayat, Somaieh, Rugge, Massimo, Tunariu, Nina, Lampis, Andrea, Eccles, Suzanne A, Kalaitzaki, Eleftheria, Damavandi, Mahnaz Darvish, Braconi, Chiara, Marchetti, Silvia, Chau, Ian, Rata, Mihaela, Collins, David, Watkins, David, Williams, Anja, Hahne, Jens C, Eltahir, Zakaria, Temple, Eleanor, Rana, Isma, Rao, Sheela, Thomas, Jan

2018

Overview

ObjectiveRegorafenib 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.DesignPatients 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.ResultsTwenty-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).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Aged / Angiogenesis / Apoptosis / Biomarkers / Biomarkers - blood / Cancer therapies / Clinical medicine / Clinical trials / Colon / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - blood / Colorectal Neoplasms - diagnostic imaging / Colorectal Neoplasms - drug therapy / Computed tomography / Decay / Deoxyribonucleic acid / Disease control / DNA / Female / Humans / Immunohistochemistry / Inhibitor drugs / Kaplan-Meier Estimate / Magnetic Resonance Imaging / Male / Medical imaging / Medical prognosis / Metastases / Metastasis / Middle Aged / NMR / Nuclear magnetic resonance / Patients / Phenylurea Compounds - therapeutic use / Prospective Studies / Pyridines - therapeutic use / Studies / Targeted cancer therapy / Treatment Outcome / Tumors / Vascular endothelial growth factor