{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T10:16:35Z","timestamp":1773483395966,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T00:00:00Z","timestamp":1686960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI\u2010induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI\u2010induced hypertension by monitoring associated changes in the circulating metabolome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab\u2009\u00b1\u2009the TKI brivanib (<jats:italic>N<\/jats:italic>\u2009=\u2009750). Outcomes were evaluated as a function of treatment\u2010induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12\u2009weeks after treatment initiation. Samples were submitted to gas chromatography\u2013mass spectrometry to identify treatment\u2010related metabolomic changes associated with TKI\u2010induced hypertension, compared to pre\u2010treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS\u2010DA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the brivanib treated group, 95 patients had treatment\u2010related hypertension within 12\u2009weeks of initiating treatment. TKI\u2010induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression\u2010free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI\u2010induced hypertension. The OPLS\u2010DA model for brivanib\u2010induced hypertension was significant and robust (R<jats:sup>2<\/jats:sup>Y score\u2009=\u20090.89, Q<jats:sup>2<\/jats:sup>Y score\u2009=\u20090.70, CV\u2010ANOVA\u2009=\u20092.01 e\u20107). Notable metabolomic features previously reported in pre\u2010eclampsia and associated with vasoconstriction were found.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TKI\u2010induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib\u2010induced hypertension that may be useful in future efforts of characterizing this toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.6248","type":"journal-article","created":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T08:14:07Z","timestamp":1686989647000},"page":"16019-16031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Clinical and metabolomic characterization of <scp>Brivanib\u2010Induced<\/scp> hypertension in metastatic colorectal cancer"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5291-7254","authenticated-orcid":false,"given":"Jodi I.","family":"Rattner","sequence":"first","affiliation":[{"name":"Cumming School of Medicine Arnie Charbonneau Cancer Institute, University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen A.","family":"Kopciuk","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, Faculty of Science University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans J.","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department Biological Sciences, Faculty of Science University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia A.","family":"Tang","sequence":"additional","affiliation":[{"name":"Cumming School of Medicine Arnie Charbonneau Cancer Institute, University of Calgary  Calgary Alberta Canada"},{"name":"Department of Surgery and Oncology, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy D.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Carbini Hospital  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Community Health &amp; Epidemiology Queens University  Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek J.","family":"Jonker","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology Ottawa Hospital Cancer Centre  Ottawa Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lillian L.","family":"Siu","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology and Hematology Princess Margaret Cancer Centre  Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris J.","family":"O'Callaghan","sequence":"additional","affiliation":[{"name":"Department 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