Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial
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Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial. / Seufferlein, Thomas; Lausser, Ludwig; Stein, Alexander; Arnold, Dirk; Prager, Gerald; Kasper-Virchow, Stefan; Niedermeier, Michael; Müller, Lothar; Kubicka, Stefan; König, Alexander; Büchner-Steudel, Petra; Wille, Kai; Berger, Andreas W; Kestler, Angelika M R; Kraus, Johann M; Werle, Silke D; Perkhofer, Lukas; Ettrich, Thomas J; Kestler, Hans A.
In: PLOS ONE, Vol. 19, No. 6, 2024, p. e0304324.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial
AU - Seufferlein, Thomas
AU - Lausser, Ludwig
AU - Stein, Alexander
AU - Arnold, Dirk
AU - Prager, Gerald
AU - Kasper-Virchow, Stefan
AU - Niedermeier, Michael
AU - Müller, Lothar
AU - Kubicka, Stefan
AU - König, Alexander
AU - Büchner-Steudel, Petra
AU - Wille, Kai
AU - Berger, Andreas W
AU - Kestler, Angelika M R
AU - Kraus, Johann M
AU - Werle, Silke D
AU - Perkhofer, Lukas
AU - Ettrich, Thomas J
AU - Kestler, Hans A
N1 - 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.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Humans
KW - Colorectal Neoplasms/drug therapy
KW - Bevacizumab/therapeutic use
KW - Leucovorin/therapeutic use
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Female
KW - Organoplatinum Compounds/therapeutic use
KW - Male
KW - Fluorouracil/therapeutic use
KW - Middle Aged
KW - Aged
KW - Drug Resistance, Neoplasm
KW - Prospective Studies
KW - Adult
KW - Neoplasm Metastasis
KW - Biomarkers, Tumor/blood
U2 - 10.1371/journal.pone.0304324
DO - 10.1371/journal.pone.0304324
M3 - SCORING: Journal article
C2 - 38875244
VL - 19
SP - e0304324
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 6
ER -
