Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Issue 8 (8th August 2017)

• Record Type: Journal Article
• Authors: Khan, Khurum; Rata, Mihaela; Cunningham, David; Koh, Dow-Mu; Tunariu, Nina; Hahne, Jens C; Vlachogiannis, George; Hedayat, Somaieh; Marchetti, Silvia; Lampis, Andrea; Damavandi, Mahnaz Darvish; Lote, Hazel; Rana, Isma; Williams, Anja; Eccles, Suzanne A; Fontana, Elisa; Collins, David; Eltahir, Zakaria; Rao, Sheela; Watkins, David; Starling, Naureen; Thomas, Jan; Kalaitzaki, Eleftheria; Fotiadis, Nicos; Begum, Ruwaida; Bali, Maria; Rugge, Massimo; Temple, Eleanor; Fassan, Matteo; Chau, Ian; Braconi, Chiara; Valeri, Nicola;
• Is Part Of: Gut. Volume 67:Issue 8(2018)
• Page Start: 1484
• Page End: 1492
• Publication Date: 2017-08-08
• Subjects: regorafenib -- anti-angiogenic treatment -- cancer therapeutics -- DCE-MRI -- liquid biopsy -- colorectal cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2017-314178
• Languages: English
• ISSNs: 0017-5749

Abstract

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 (K trans ), enhancing fraction (EF) and their product KEF (summarised median values of K trans × 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.