A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR)

• Published in: ESMO open Vol. 7; no. 6; p. 100592
• Main Authors: Okamoto, W., Sakai, K., Makiyama, A., Yamamoto, Y., Shitara, K., Denda, T., Izawa, N., Nakano, Y., Nishina, T., Esaki, T., Hara, H., Miura, Y., Boku, N., Yamazaki, K., Hironaka, S., Misumi, T., Hyodo, I., Muro, K., Nishio, K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2022; Elsevier
• Subjects: Bevacizumab - pharmacology; Bevacizumab - therapeutic use; Biomarkers; circulating biomarkers; Colonic Neoplasms - drug therapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease-Free Survival; F-Box-WD Repeat-Containing Protein 7; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Humans; metastatic colorectal cancer; Original Research; pICAM-1 level; Prospective Studies; pVEGF-A short isoforms; RAS and FBXW7 mutation; Vascular Endothelial Growth Factor A - therapeutic use; pVEGF-A short isoforms; metastatic colorectal cancer; RAS and FBXW7 mutation; circulating biomarkers; pICAM-1 level
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2022.100592

The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV). Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value. The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6). The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further. •This study evaluated the associations between circulating biomarkers and outcomes in mCRC treated with BV + mFOLFOX6/XELOX.•pVEGF-Asi was not a good predictive biomarker of the efficacy of first-line BV + mFOLFOX6/XELOX.•Circulating biomarkers, such as pICAM-1 and mutant RAS and FBXW7 in ctDNA, could be clinically significant in mCRC patients.