• Cancer
• Hypertension
• Tyrosine kinase inhibitors
• Vascular endothelial growth factor receptor inhibitors
• Vascular endothelial growth factor signaling pathway

• Humans
• Hypertension/chemically induced
• Hypertension/physiopathology
• Hypertension/therapy
• Hypertension/drug therapy
• Neoplasms/drug therapy
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/physiopathology
• Antineoplastic Agents/adverse effects
• Vascular Endothelial Growth Factor A
• Signal Transduction/drug effects

• Cardiovascular Toxicity
• Renin–angiotensin–aldosterone System

• Humans
• Renin-Angiotensin System/drug effects
• Neoplasms/drug therapy
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/prevention & control
• Angiotensin-Converting Enzyme Inhibitors/therapeutic use
• Molecular Targeted Therapy/adverse effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/adverse effects
• Disease Susceptibility
• Disease Management
• Treatment Outcome
• Angiotensin Receptor Antagonists/therapeutic use

• Angiogenesis
• Carcinogenesis
• Prognosis
• Renin-angiotensin-aldosterone system
• Risk
• Variants

• Humans
• Renin-Angiotensin System/genetics
• Prognosis
• Blood Pressure/physiology
• Aldosterone
• Neoplasms/drug therapy
• Neoplasms/genetics

• AGT1 (rs699)
• AGT2 (rs4762), Tyrosine kinase inhibitors
• Early DAE
• HCC
• Single-nucleotide polymorphisms

Molecular biology knowledge has enabled the incorporation of targeted therapies, such as the anti-angiogenic drug bevacizumab, into combined chemotherapy regimens for the treatment of metastatic colorectal cancer. However, to date, there are no reliable useful biomarkers to predict the efficacy of this anti-angiogenic therapy. The objective of this prospective study was to evaluate potential circulating plasma biomarkers in mCRC patients prior to the start of first-line treatment with chemotherapy plus bevacizumab. We found that high VEGF-A and low ACE plasma levels were associated with poor OS after treatment. Moreover, a simple scoring system combining both biomarkers efficiently stratified patients into high- or low-risk groups, which allows the selection of patients for anti-angiogenic therapy.

The identification of factors that respond to anti-angiogenic therapy would represent a significant advance in the therapeutic management of metastatic-colorectal-cancer (mCRC) patients. We previously reported the relevance of VEGF-A and some components of the renin–angiotensin-aldosterone system (RAAS) in the response to anti-angiogenic therapy in cancer patients. Therefore, this prospective study aims to evaluate the prognostic value of basal plasma levels of VEGF-A and angiotensin-converting enzyme (ACE) in 73 mCRC patients who were to receive bevacizumab-based therapies as a first-line treatment. We found that high basal VEGF-A plasma levels were significantly associated with worse overall survival (OS) and progression-free survival (FPS). On the other hand, low ACE levels were significantly associated with poor OS. Importantly, a simple scoring system combining the basal plasma levels of VEGF-A and ACE efficiently stratified mCRC patients, according to OS, into high-risk or low-risk groups, prior to their treatment with bevacizumab. In conclusion, our study supports that VEGF-A and ACE may be potential biomarkers for selecting those mCRC patients who will most benefit from receiving chemotherapy plus bevacizumab treatment in first-line therapy. Additionally, our data reinforce the notion of a close association between the RAAS and the anti-angiogenic response in cancer.

• colorectal cancer
• combination drug therapy

• anti-angiogenic therapy
• drug repurposing
• epithelial ovarian cancer
• nanocarriers
• non-coding RNAs

• angiogenesis
• angiotensinogen
• bladder cancer
• renin-angiotensin system
• single nucleotide polymorphisms

• Angiotensinogen/genetics
• Female
• Genetic Predisposition to Disease
• Humans
• Male
• Polymorphism, Single Nucleotide/genetics
• Renin-Angiotensin System/genetics
• Urinary Bladder Neoplasms/genetics

• ACEIs
• ARBs
• Renin–Angiotensin System
• postsurgical adhesion

• breast cancer
• chemo resistance
• drug response
• prognostic marker

• ACE inhibitors
• AT1R
• AT1R blockers
• Angiotensin II
• Cancer
• Immunotherapy

• Angiotensin Receptor Antagonists/pharmacology
• Angiotensin-Converting Enzyme Inhibitors
• Animals
• Antineoplastic Agents/pharmacology
• Drug Repositioning
• Humans
• Neoplasms/drug therapy
• Neoplasms/pathology
• Renin-Angiotensin System/drug effects

• Angiotensin Receptor Antagonists/pharmacology
• Angiotensin-Converting Enzyme Inhibitors/pharmacology
• Capillary Permeability/drug effects
• Cells, Cultured
• Diabetic Retinopathy/metabolism
• Endothelial Cells/metabolism
• Humans
• Renin-Angiotensin System/physiology
• Retina/metabolism
• Retinal Vessels/drug effects
• Retinal Vessels/metabolism
• Vascular Endothelial Growth Factor A/metabolism

• R01 EY031350 NEI NIH HHS
• UL1 TR002003 NCATS NIH HHS

This study postulated that antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibition may mitigate vascular endothelial growth factor inhibitor (VEGFi)–mediated increases in blood pressure more effectively than other antihypertensive medications in patients receiving VEGFi therapy.

VEGFi therapy is commonly used in the treatment of cancer. One common side effect of VEGFi therapy is elevated blood pressure. Evidence suggests that the RAAS may be involved in VEGFi-mediated increases in blood pressure.

This retrospective cohort analysis was performed using a de-identified version of the electronic health record at Vanderbilt University Medical Center in Nashville, Tennessee. Subjects with cancer who were exposed to VEGFi therapy were identified, and blood pressure and medication data were extracted. Changes in mean systolic and diastolic blood pressure in response to VEGFi therapy in patients receiving RAAS inhibitor (RAASi) therapy before VEGFi initiation were compared with changes in mean systolic and diastolic blood pressure in patients not receiving RAASi therapy before VEGFi initiation.

Mean systolic and diastolic blood pressure rose in both groups after VEGFi use; however, patients who had RAASi therapy before VEGFi initiation had a significantly lower increase in systolic blood pressure as compared with patients with no RAASi therapy (2.46 mm Hg [95% confidence interval: 0.7 to 4.2] compared with 4.56 mm Hg [95% confidence interval: 3.5 to 5.6], respectively; p = 0.034).

In a real-world clinical population, RAASi therapy before VEGFi initiation may ameliorate VEGFi-mediated increases in blood pressure. Randomized clinical trials are needed to further our understanding of the role of RAASi therapy in VEGFi-mediated increases in blood pressure.

• VEGF
• VEGF inhibitors
• cancer
• hypertension
• renin-angiotensin-aldosterone
• vascular endothelial growth factor

• Bevacizumab
• biomarker
• breast cancer
• efficacy

• Angiotensinogen
• Brain tumor
• Cancer
• Glioblastoma
• Glioma
• Gliomagenesis
• Renin-angiotensin system

• bevacizumab
• inflammation
• metastatic colorectal cancer
• predictive biomarkers
• vasculature

• Alcohol use
• HER2 inhibitors
• Resveratrol
• SNP
• Tobacco use

To investigate the association between 16 insertion-deletions (INDEL) polymorphisms, colorectal cancer (CRC) risk and clinical features in an admixed population.

One hundred and forty patients with CRC and 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. Clinicopathological data were obtained by consulting the patients’ clinical charts, intra-operative documentation, and pathology scoring.

Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis (TNM) stage risk, the Ins alleles of ACE, HLAG and TP53 (6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.

The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.

• Colorectal cancer
• Ins-del polymorphism
• Admixed population
• Potential biomarker
• Diagnostic
• Risk stratification
• Prognostic
• Clinical features

• Adult
• Aged
• Aged, 80 and over
• Brazil/epidemiology
• Case-Control Studies
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/genetics
• Electrophoresis, Capillary
• Female
• Genetic Predisposition to Disease
• Genotype
• Genotyping Techniques/instrumentation
• Genotyping Techniques/methods
• Humans
• INDEL Mutation/genetics
• Incidence
• Male
• Middle Aged
• Polymorphism, Genetic/genetics
• Risk Factors