Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial.

Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab.
Patients and Methods: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM).
Results: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity.
Conclusions: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
Competing Interests: “•Thomas Seufferlein reports research funding to the institution from Sanofi during the conduct of the study; honoraria from Lilly, Pierre Fabre, BMS, MSD; advisory/consultancy roles with Amgen, Lilly, BMS, MSD, Pierre Fabre, Servier, Immodulon, Biontech, Mirati, Boehringer; Travel expenses from Takeda • Stefan Kasper discloses honoraria (self) from Merck, Amgen, Roche, Sanofi-Aventis, Servier, and Lilly; honoraria (institution) from Merck, Amgen, Roche, and Lilly; advisory/consultancy roles with Merck, BMS, Amgen, Roche, MSD, Sanofi-Aventis, Servier, and Lilly; research grants/funding (self) from Merck, Roche, BMS and Lilly; research grants/funding (institution) from Merck, Roche, BMS and Lilly; travel/accommodation expenses from Merck, Amgen, BMS, Roche, Sanofi, Aventis, Servier, and Lilly. • Thomas J. Ettrich reports honoraria from Roche, Sanofi; advisory/consultancy roles with Roche, Sanofi; research funding from Servier. • All other authors declare to have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials”.
(Copyright: © 2024 Seufferlein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)