Clinical and metabolomic characterization of Brivanib‐Induced hypertension in metastatic colorectal cancer

Abstract

BackgroundTrials 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‐induced 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‐induced hypertension by monitoring associated changes in the circulating metabolome.Patients and MethodsClinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment‐induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography–mass spectrometry to identify treatment‐related metabolomic changes associated with TKI‐induced hypertension, compared to pre‐treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS‐DA).ResultsIn the brivanib treated group, 95 patients had treatment‐related hypertension within 12 weeks of initiating treatment. TKI‐induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression‐free 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‐induced hypertension. The OPLS‐DA model for brivanib‐induced hypertension was significant and robust (R2Y score = 0.89, Q2Y score = 0.70, CV‐ANOVA = 2.01 e‐7). Notable metabolomic features previously reported in pre‐eclampsia and associated with vasoconstriction were found.ConclusionTKI‐induced 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‐induced hypertension that may be useful in future efforts of characterizing this toxicity.

Clinical Outcome of Colorectal Cancer Patients with Concomitant Hypertension: A Systematic Review and Meta-Analysis

“…The database search yielded 802 studies for screening (PubMed (n = 425), Embase (n = 124), Web sciences (n = 107), Scopus (n = 87), Cochrane Library (n = 34), CINAHL (n = 25)), of which 298 abstracts were identified as potentially eligible and retrieved for full-text review. Finally, 16 articles met the eligibility criteria and were included in this systematic review and meta-analysis [3,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. The detailed PRISMA flowchart for study screening and selection is presented in Figure 1.…”

“…All the included articles were published between 2009 and 2023 and originated from eight countries. Among the 16 articles included in this systematic review and meta-analysis, 15 were retrospective [3,[17][18][19][20][21][22][24][25][26][27][28][29][30][31], and only 1 was a prospective study [23]. The sample size of the included articles varied from 45 to 750 participants, with a slightly higher proportion of male patients (58%).…”

“…The included studies had a median NOS score of eight, with a maximum score of nine and a minimum of six. In total, twelve articles were evaluated to be of good quality (score ≥ 7) [3,18,19,[21][22][23][24][25]27,[29][30][31], while four articles were assessed to be of fair quality (score = 6) [17,20,26,28]. Table 2 summarises the quality assessment scores for the observational studies.…”