Bevacizumab-induced Hypertension Research Articles

Bevacizumab-induced hypertension in patients with glioblastoma: a systematic review and meta-analysis

Abstract Background Bevacizumab is a monoclonal antibody medication used as standard treatment for different types of cancers, one of them is glioblastoma, which is the most common primary brain tumor. Purpose We aimed to assess bevacizumab and its effects on inducing hypertension in patients with glioblastoma. Methods PubMed, Embase and Cochrane databases were searched until February 13th, 2024 for randomized control trials (RCTs) comparing bevacizumab alone with control or bevacizumab in combination with other chemotherapies in patients with glioblastoma. Data was examined using the Mantel-Haenszel method and we computed risk ratio (RRs) for binary endpoints and 95% confidence intervals (Cls). Heterogeneity was assessed using I² statistics. Meta-regression analysis was conducted to evaluate a possible link between the occurrence of hypertension and mortality or progression-free survival. R software version 4.2.3 was used for statistical analysis. Results 5 RCTs and 1 non-randomized study were included with a total of 1402 patients, of whom 608 (43,36%) were assigned to the bevacizumab and 794(56,64%) composed the control group. Compared with bevacizumab, the control achieved statistically significant lower rates of hypertension occurrence (RR 6,31; CI: 2,13 - 18,65; p=0.000872; I²=54%). Subgroup analysis of bevacizumab alone versus bevacizumab in combination with other chemotherapies tended towards the combination group(RR 2,24; CI: 1,19 - 4,21; p= 0.012497; I² = 68%). Mortality was significantly higher in the bevacizumab group (OR 1,60; CI: 1,02 - 2,52; p=0,040443; I²= 0%). Progression-free survival did not reach a statistically significant difference between groups (OR 1,07; CI: 0,33 - 3,43; p= 0,907923; I²= 45%) and meta-regression analysis showed no significant link between hypertension and mortality or progression-free survival. Conclusion Concerning the treatment of glioblastoma, our results showed that induced hypertension is more likely to happen in patients treated with bevacizumab. Significant statistical difference in the mortality was observed between the use of bevacizumab and control. However, the current data is insufficient to determine a link between hypertension and prognostic value through meta-regression analysis.General Analysis

Bevacizumab-Induced Hypertension in Glioblastoma Patients and Its Potential as a Modulator of Treatment Response.

Glioblastoma invasion is the primary mechanism responsible for its dismal prognosis and is the direct result of interactions between glioblastoma cells and the tumor vasculature. The dysregulated microvasculature in glioblastoma tumors and vessels co-opted from surrounding brain tissue support rapid tumor growth and are utilized as pathways for invasive cancer cells. Attempts to target the glioblastoma vasculature with antiangiogenic agents (eg, bevacizumab) have nonetheless shown limited and inconsistent efficacy, and the underlying causes of such heterogeneous responses remain unknown. Several studies have identified that patients with glioblastoma who develop hypertension following treatment with bevacizumab show significant improvement in overall survival compared with normotensive nonresponders. Here we review these findings and discuss the potential of hypertension as a biomarker for glioblastoma treatment response in individual patients and the role of hypertension as a modulator of interactions between tumor cells and cells in the perivascular niche. We suggest that a better understanding of the actions of bevacizumab and hypertension at the cellular level will contribute to developing more effective personalized therapies that address glioblastoma tumor cell invasion.

Bevacizumab-Induced Hypertension as a Potential Physiological Clinical Biomarker for Improved Outcomes in Patients With Recurrent Glioblastoma Multiforme: A Systematic Review.

With the advancement in medicine leading to the discovery of anti-vascular endothelial growth factor drugs, numerous oncologists are now commonly using antiangiogenic medications to improve outcomes and attain disease control. Thus, the significance of prognostic and predictive indicators in patient selection has become increasingly imperative. These biomarkers have the capacity to be highly effective and can easily be implemented in various diagnostic and therapeutic settings on a large scale. Overall, it has the potential of significantly decreasing mortality in a fatal disease and possibly achieving partial or complete remission. Many clinical trials have shown the efficacy of bevacizumab in treating malignancies. However, there are currently no known predictive or prognostic biomarkers for bevacizumab in glioblastoma multiforme (GBM). Several clinical studies have evaluated bevacizumab-induced hypertension as a potential marker in patients with different malignancies, including recurrent glioblastoma multiforme (rGBM). This systematic review was performed to determine the association of bevacizumab-induced hypertension with outcomes in patients with advanced brain cancer and to assess whether hypertension (HTN) can be used as a prognostic factor. The review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, and the databases were searched from January 2012 to June 2022. This review aimed to evaluate six published studies to investigate the relationship between hypertension and the outcomes of patients with rGBM treated with bevacizumab. Among the included publications, four out of six were retrospective and featured a positive result regarding hypertension being used as an independent predictive factor of survival outcomes in rGBM. However, two studies showed negative results. This can be attributed to the limited subsets of patients and the duration of the studies. In conclusion, bevacizumab-induced hypertension may represent a prognostic factor in patients with rGBM.

Antiangiogenic Drug-Induced Proteinuria as a Prognostic Factor in Metastatic Colorectal Cancer.

Treatment with bevacizumab is known to cause adverse events such as proteinuria and hypertension, amongst others. However, while bevacizumab-induced hypertension has been linked to increased overall survival (OS), data on proteinuria are controversial. We performed a retrospective analysis to observe the influence of adverse events developed during treatment with bevacizumab and chemotherapy on the OS in patients with metastatic colorectal cancer (mCRC). Kaplan–Meier and log-rank analyses were used to assess differences in OS, and hazard ratios (HR) were estimated using Cox models. Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Out of these, 50.7% experienced proteinuria and had reached a longer OS (40 versus 25 months, p = 0.015) and progression-free survival (15 versus 12 months, p = 0.039). The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.589; 95% CI 0.402–0.863; p = 0.007), one metastatic site (HR 0.533; 95% CI 0.363–0.783; p = 0.001), and non-metastatic stage at diagnosis (HR 0.459; 95% CI 0.293–0.720; p = 0.001). Patients with anemia and diabetes had an increased risk of death. Proteinuria emerges as a useful prognostic factor in mCRC patients undergoing bevacizumab-based systemic therapy, and it could be easily integrated into the decision-making process, thus allowing physicians to further individualize systemic treatments.

Polygenic Risk Scores for Blood Pressure to Assess the Risk of Severe Bevacizumab-Induced Hypertension in Cancer Patients (Alliance).

Hypertension is a common bevacizumab-induced toxicity. No markers are available to predict patients at risk of developing hypertension. We hypothesized that genetic risk of essential hypertension, as measured by a blood pressure polygenic risk score (PRS), would be associated with risk of severe bevacizumab-induced hypertension. PRSs were calculated for 1,027 bevacizumab-treated patients of European descent with cancer from four clinical trials (Alliance for Clinical Trials in Oncology (Alliance) / Cancer and Leukemia Group B (CALGB) 80303, 40503, 90401, 40502) using summary systolic blood pressure (SBP) and diastolic blood pressure (DBP) genome-wide association results obtained from 757,601 individuals of European descent. The association between PRS and grade 3 bevacizumab-induced hypertension (Common Toxicity Criteria for Adverse Events version 3) in each trial was performed by multivariable logistic regression. Fixed-effect meta-analyses odds ratios (ORs) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse-variance weighting. PRSs were additionally stratified into quintiles, with the bottom quintile as the referent group. The OR of the association between hypertension and each quintile vs. the referent group was determined by logistic regression. The most significant PRS (quantitative)-hypertension association included up to 67 single-nucleotide variants (SNPs) associated with SBP (P=0.0077, OR per SD=1.31, 95% confidence interval (CI), 1.07-1.60), and up to 53 SNPs associated with DBP (P=0.0209, OR per SD=1.27, 95% CI, 1.04-1.56). Patients in the top quintile had a higher risk of developing bevacizumab-induced hypertension compared with patients in the bottom quintile using SNPs associated with SBP (P=4.75×10-4 , OR=3.72, 95% CI, 1.84-8.16) and DBP (P=0.076, OR=1.83, 95% CI, 0.95-3.64). Genetic variants associated with essential hypertension, mainly SBP, increase the risk of severe bevacizumab-induced hypertension.

PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors.

No biomarkers are available to predict patients at risk of developing hypertension induced by VEGF-pathway inhibitors. This study aimed to identify predictive biomarkers of hypertension induced by these drugs using a discovery-replication approach. The discovery set included 140 sorafenib-treated patients (TARGET study) genotyped for 973 SNPs in 56 genes. The most statistically significant SNPs associated with grade ≥2 hypertension were tested for association with grade ≥2 hypertension in the replication set of a GWAS of 1039 bevacizumab-treated patients from four clinical trials (CALGB/Alliance). In the discovery set, rs444904 (G > A) in PIK3R5 was associated with an increased risk of sorafenib-induced hypertension (p = 0.006, OR = 3.88 95% CI 1.54-9.81). In the replication set, rs427554 (G > A) in PIK3R5 (in complete linkage disequilibrium with rs444904) was associated with an increased risk of bevacizumab-induced hypertension (p = 0.008, OR = 1.39, 95% CI 1.09-1.78). This study identified a predictive marker of drug-induced hypertension that should be evaluated for other VEGF-pathway inhibitors.ClinicalTrials.gov Identifier:NCT00073307 (TARGET).

Antiangiogenic drug-induced proteinuria as a predictive factor in metastatic colorectal cancer.

e15538 Background: Treatment with bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) is known to cause adverse effects such as proteinuria, hypertension, fistulas, and thromboembolic events which, in addition to chemotherapy-induced toxicity, affect the quality of life. However, while bevacizumab-induced hypertension has been linked to increased overall survival, data on proteinuria are controversial. Methods: We performed a retrospective analysis to observe the influence of adverse effects (AEs) on the results of treatment with bevacizumab and chemotherapy in patients with metastatic colorectal cancer (mCRC). Results: Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Of these, 50.7% experienced proteinuria and had reached a longer overall survival (OS, 40 versus 25 months, p = 0.015) and progression free survival (PFS, 15 versus 12 months, p = 0.039). Patients with anemia during treatment, regardless of grade, had a 20-month shorter survival. The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.630; 95% CI 0.424-0.935; p = 0.022), disease control (HR 0.436; 95% CI 0.291-0.653; p< 0.001) and non-metastatic stage at diagnosis (HR 0.477; 95% CI 0.300-0.757; p = 0.002). Anemia was a negative prognostic factor (HR 2.153; 95% CI 1.343-3.454; p = 0.001). Conclusions: Proteinuria seems to be a useful predictive factor in mCRC patients undergoing bevacizumab-based systemic therapy. Since it is already routinely assessed in this clinical setting, proteinuria could be easily integrated in the decision-making process and thus allow physicians to further individualize systemic treatments. Retrospective analyses, as our study, are setting the basis for prospective studies, required for the validation of these results.

6 Oral - Bevacizumab-induced hypertension and proteinuria: A genome-wide analysis of more than 1,000 patients

6 Oral - Bevacizumab-induced hypertension and proteinuria: A genome-wide analysis of more than 1,000 patients

118P - PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors

BackgroundHypertension is one of the major side effect of VEGF-pathway inhibitors. There are no validated biomarkers to predict which cancer patients will develop hypertension. This study aimed to identify genetic predictors of hypertension induced by VEGF-pathway inhibitors. MethodsA two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400mg twice daily) (PMID 30385613) and genotyped for 1,040 germline variants in 56 genes. The most statistically significant variant from the discovery set (chi-squared test) was tested in a validation set (cause-specific Cox model) consisting of 1,041 cancer patients treated with bevacizumab (10-15mg/kg every two-three weeks) and genotyped using GWAS microarray platforms. For both studies, grade ≥2 hypertension (CTCAE v. 3.0) was used as the endpoint. Genetic associations were adjusted for age and sex. ResultsIn the discovery set, the most statistically significant variant associated with hypertension in sorafenib-treated patients was rs444904 (G>A, P=0.006). The A allele of rs444904 (minor allele frequency, MAF 0.14) increased the risk of hypertension. In the validation set, the A allele of rs427554 (G>A, in complete linkage disequilibrium with rs444904) increased the risk of hypertension in bevacizumab-treated patients (P=0.008, MAF 0.11). rs444904 and rs427554 are intronic variants in PIK3R5. PIK3R5 encodes the regulatory subunit of PI3Kγ, which, when activated by VEGF, leads to nitric oxide (NO) production and vasodilation. These variants have been associated with decreased expression of PIK3R5 in blood (PMID 25954001), consistent with their effect in increasing the risk of hypertension. ConclusionsCommon genetic variants that could reduce PIK3R5 activity increase the risk of sorafenib- and bevacizumab-induced hypertension. In patients treated with these drugs, reduced activity or expression of PIK3R5 may lead to a reduction in NO production, resulting in vasoconstriction and hypertension. This study, for the first time, provides evidence for new predictive genetic markers of drug-induced hypertension that should be further evaluated for other VEGF-pathway inhibitors. Clinical trial identificationTARGET CALGB 80303 NCT00088894 CALGB 40503 NCT00601900 CALGB 40502 NCT00785291 CALGB 90401 NCT00110214. Legal entity responsible for the studyFederico Innocenti. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Investigation of the Pathogenesis and Treatment Efficiency of Bevacizumab-Induced Hypertension in the Rat Model

Bevacizumab is known to reduce Vascular Endothelial Growth Factor (VEGF) to undetectable levels when used in conjunction with chemotherapy. Hypertension is a frequent adverse effect of bevacizumab, although its mechanism(s) remain unclear. In this study, our aim was to examine the pathogenesis of bevacizumab-induced hypertension and to investigate the treatment efficacy of valsartan. A total of 24 Wistar Albino female rats were included in the study. Rats were divided into three groups with 8 rats in each, as follows: The control group, bevacizumab group and bevacizumab + valsartan group. Blood pressure, blood urea nitrogen and serum creatinine levels were measured, urine samples were collected for 24 hours statistical analyses were performed using IBM SPSS 20 software pack. Nephrectomy specimens in bevacizumab and bevacizumab + valsartan groups exhibited varying degrees of renal injury. Although valsartan was able to reduce the bevacizumab-induced rise in blood pressure, it could not prevent the development of nephropathy. Conclusions these findings suggest that hypertension occurring secondary to bevacizumab treatment in rats may be associated with mechanisms involving renal injury.

Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734-44. ©2018 AACR.

389P - Bevacizumab-induced hypertension correlation with survival in recurrent glioblastoma multiforme

Background: Patients with Glioblastoma multiforme (GBM) have a poor prognosis and therapeutic options are scarce after recurrence. Bevacizumab (Bv) is approved for use in this setting with proven benefits in progression-free survival (PFS) but not in overall survival (OS). Arterial hypertension (HT), a well described side effect of Bv, has been proposed as a predictive marker of clinical response in GBM as well as in other neoplasms, though conflicting data is available. This study tried to evaluate the prognostic impact of HT and other factors in recurrent GBM. Methods: Retrospective cohort of adult patients with recurrent GBM treated with a combination of Bv + Irinotecan (BvI) or Lomustine (BvL) between 01/01/2009 and 31/12/2017. Clinical records were analysed. Bv-induced HT was defined as a single evaluation ≥140/90 mmHg during first 3 months of treatment or the need to initiate or increase dose of antihypertensive drugs. OS and PFS were estimated by Kaplan-Meier method and multivariate analysis according to Cox regression; a significant level of 0.05 was chosen to assess the statistical significance. Results: 120 patients were included with male gender predominance (64.2%) and a median age at Bv onsent of 58.7 (27-78 yo). All patients were treated in first line with surgery (complete resection: 61.7%; partial resection: 38.3%) and Stupp protocol. BvI was used in 70.8% (n = 85) and BvL in 29.2% (n = 35) patients. Bv-induced HT was found in 29% of patients (n = 29) and proteinuria (PU) in 15% (n = 18). Median PFS was 4.4 months (mo) (CI 95% 3.5-5.4) and median OS was 7.8 mo (CI 95% 6.8-87). In multivariate analysis (Table), both HT and PU had an impact in PFS. OS was significantly prolonged in patients with HT and in those without corticosteroids (CCS) at Bv.Table: 389PPFS (mo)HR (CI 95%)OS (mo)HR (CI 95%)HTYes9.1HR 1.825 (1.136-2.931), p = 0.01314HR 2.726 (1.325-5.608), p = 0.006No4.17.8PUYes6.1HR 2.341 (1.282-4.275), p = 0.006--No3.9-CCS at Bv onsetYes--6.9HR 2.022 (1.059-3.860), p = 0.033No-13.4 Open table in a new tab Conclusions: In recurrent GBM patients treated with Bv combinations, HT was significantly related with prolonged PFS and OS. PU and the need for CCS also showed a significant prognostic impact. Legal entity responsible for the study: Serviço de Oncologia Médica - Centro Hospitalar de São João, EPE. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Usefulness of bevacizumab-induced hypertension in patients with metastatic colorectal cancer: an updated meta-analysis.

We tested the hypothesis that bevacizumab-induced hypertension may be a useful predictor for objective response rate, progression-free and overall survival in patients with metastatic colorectal cancer via a comprehensive meta-analysis. Search process, article selection and data extraction were independently performed by two investigators. Statistical analyses were conducted using the STATA/SE software. Fourteen independent studies and 2292 study subjects were synthesized. Overall relative risk of objective response rate for bevacizumab-induced hypertension was 2.03 (95% confidence interval [CI]: 1.18-3.48, p=0.01), with significant heterogeneity and publication bias, whereas unbiased estimate was nonsignificant after considering potentially missing studies. Overall hazard ratio for progression-free survival was 0.58 (95% CI: 0.43-0.77, p<0.001), with significant heterogeneity and publication bias, and unbiased estimate was significant (hazard ratio: 0.52, 95% CI: 0.41-0.66, p<0.001). Overall hazard ratio for overall survival was 0.51 (95% CI: 0.39-0.65, p<0.001), and this estimate was not likely confounded by heterogeneity or publication bias. Subgroup and meta-regression analyses suggested that hypertension grade of controls, sample size, age and gender were possible causes of heterogeneity. Taken together, our findings indicate that bevacizumab-induced hypertension can predict progress-free survival and overall survival in patients with metastatic colorectal cancer, whereas its prediction for objective response rate was nonsignificant.

Increased risk of adverse drug events secondary to bevacizumab treatment in patients with advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials.

BackgroundSeveral clinical trials have shown an increased risk of hypertension with bevacizumab when added to chemotherapy in different types of malignancy; however, the risks of other significant adverse events besides hypertension, specifically in breast cancer, have not been completely elucidated. This study was conducted with the aim, primarily, to assess the overall incidence and risk of common toxicities associated with bevacizumab in patients with advanced or metastatic breast cancer and, secondarily, to descriptively review study results concerning a potential correlation between bevacizumab-induced hypertension and its efficacy for breast cancer treatment.MethodsWe carried out a meta-analysis of relevant randomized controlled trials (RCTs) identified from a database search (Cochrane Library and PubMed) and, additionally, by reviewing previous reviews and meta-analyses. Overall incidence rates, odds ratios (ORs), and 95% confidence intervals (CIs) were assessed with the random- or fixed-effect models, depending on the level of heterogeneity across the included trials. The primary clinical outcomes were high-grade adverse events commonly reported with bevacizumab therapy.ResultsWe included 6,260 patients with advanced-stage breast cancer from 12 RCTs in the meta-analysis. Five types of high-grade (Grade 3 or 4) adverse drug events were identified as being correlated with bevacizumab treatment versus alternative treatment with statistical significance: hypertension (OR 5.67, 95% CI 3.02–10.65), proteinuria (OR 10.09, 95% CI 4.79–21.27), bleeding (OR 3.45, 95% CI 2.25–5.30), cardiac toxicity (OR 2.15, 95% CI 1.29–3.59), and neutropenic fever (OR 1.51, 95% CI 1.15–2.00). The prognostic value of bevacizumab-induced hypertension for its antitumor efficacy among patients with breast cancer remains controversial, with mixed results presented in the five retrospective studies that were identified from our additional literature search.ConclusionThe addition of bevacizumab to anticancer therapy was associated with a significant increase in the risk of high-grade adverse events, including hypertension, proteinuria, bleeding, cardiac toxicity, and neutropenic fever among patients with advanced-stage breast cancer. Although several retrospective studies suggested a predictive importance of hypertension secondary to bevacizumab therapy, the role of elevated blood pressure as a prognostic biomarker for its antitumor efficacy remains controversial, and further prospective trials are required to confirm such a correlation.

Early hypertension is associated with better clinical outcomes in gastric cancer patients treated with ramucirumab plus paclitaxel.

Anti-vascular endothelial growth factor (VEGF) therapeutics such as bevacizumab, which are widely used in cancer treatment, commonly leads to hypertension. Moreover, bevacizumab-induced hypertension is associated with improved clinical outcomes in several cancers. We retrospectively analyzed 89 patients with histologically confirmed advanced gastric cancer who received the human monoclonal anti-VEGF receptor-2 antibody ramucirumab plus paclitaxel at our hospital between June 2015 and October 2016 to evaluate the impact of treatment-associated hypertension occurring within the first two treatment cycles (“early hypertension”) on outcome. The objective response rate was 40%, median progression-free survival was 5.4 months, and overall survival was 10.4 months, which is similar to previous reports. Early hypertension in patients who received more than two cycles of ramucirumab + paclitaxel was associated with longer progression-free and overall survival. Objective response rates were also higher in patients with early hypertension. These data indicate that early hypertension may be predictive of better outcomes in gastric cancer patients who receive ramucirumab + paclitaxel treatment.

Genetic predisposition to bevacizumab-induced hypertension.

Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR=6.45; P=0.005; 95%CI, 1.86-22.39). We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy.

Bevacizumab-induced hypertension: Clinical presentation and molecular understanding.

Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity.

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103.

Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.

Association of hypertension and treatment outcomes in advanced stage non-small cell lung cancer patients treated with bevacizumab or non-bevacizumab containing regimens.

Background Studies suggest that bevacizumab-induced hypertension is prognostic of better outcomes in bevacizumab-treated patients with metastatic colorectal, HER2-negative breast, kidney, and pancreatic cancer. Few have examined this correlation in metastatic non-small cell lung cancer and evaluated whether hypertension independent of bevacizumab can improve the treatment outcomes. Objectives The primary objective was to determine the effect of hypertension on the overall response of advanced non-small cell lung cancer patients from start of the first-line chemotherapy to maintenance therapy. Secondary objectives include the effect of hypertension on the overall survival in all patients and on the overall response in bevacizumab-treated patients. Methods A retrospective chart review for a single institution was conducted from 2008 to 2013 on all patients with advanced non-squamous non-small cell lung cancer who received ≥ 1 cycle of combination chemotherapy. Patients were divided into hypertension versus no hypertension and into bevacizumab versus non-bevacizumab groups. Results Of the 188 advanced non-small cell lung cancer patients evaluated, 62 were treated with bevacizumab-containing regimens. The mean age at diagnosis was 58 years in both the groups. Hypertension independent of bevacizumab did not lead to improved treatment outcomes. However, in the bevacizumab subgroup, hypertensive patients had significantly higher response rates versus non-hypertensive patients (36.7% vs. 12.5%; p = 0.02). There was no significant difference in the overall survival between hypertensive versus non-hypertensive patients. Conclusion While hypertension alone did not significantly improve the treatment outcomes, hypertension in bevacizumab-treated patients with metastatic non-small cell lung cancer led to significantly improved responses. Further prospective studies are needed to confirm the association of hypertension with improved treatment outcomes in metastatic NSCLC.

Abstract IA09: Impact of genetically determined race on outcomes in E5103

Abstract Background: African Americans (AAs) have inferior breast cancer outcomes. AAs have a higher percentage of the poor prognosis triple negative breast cancer subtype and also have inferior relative benefit from chemotherapy when compared to other races. While some of the disparity may be due to socio-economic factors, the underlying biology of the tumor may also play a pivotal role. Using ancestry informative markers, we have evaluated race-specific outcomes and various therapy-induced side effects in the adjuvant breast cancer trial, E5103. We have further explored the roles of germline genetic biomarkers to predict the increased risk for the most common chemotherapy induced toxicity; taxane-induced peripheral neuropathy (TIPN) in AAs. Methods: E5103 was a phase III adjuvant breast cancer trial that randomized 4,994 patients with node-positive or high risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for four cycles followed by 12 weeks of weekly paclitaxel alone (Arm A) or to the same chemotherapy with either concurrent bevacizumab (Arm B) or concurrent plus sequential bevacizumab (Arm C). Germline (blood) DNA and clinical data were available from 3394 patients across all arms. Genome-wide analyses were performed in these patients and race was determined by principle components analysis (PCA). Clinical outcome and the occurrence of therapy-induced toxicities were compared in genetically defined AAs against other races. Germline biomarkers were evaluated to predict the risk of TIPN in AAs through a genome wide association study (for common variants) and through whole exome sequencing (for rare variants). Results: PCA determined 386 AAs among 3394 available patients from E5103. Compared to other races, AA patients had an inferior disease free survival. AAs were also more likely to experience the most common, severe side effects from each of the agents used in E5103, including: CTCAE v 4.0 grade 3-4 TIPN (p=2.4 × 10-11; OR=2.9) and grade 3-4 bevacizumab induced hypertension (p=0.002; OR=1.6). Despite a small number of events, the same trend was observed for anthracycline induced congestive heart failure (p=0.08, OR=1.8). The genome wide study identified several germline biomarkers that impacted the risk of TIPN specific to AAs. Specifically, a SNP in FCAMR demonstrated a trend toward decreased risk of grade 2-4 TIPN in AAs (p-value=2.8 × 10-7). Whole exome sequencing revealed an association between deleterious rare variants in SET binding factor 2 (SBF2) with a marked increased risk of grade 3-4 TIPN in AAs (p-value=4.35 × 10-6). Conclusion: AA breast cancer patients had an inferior DFS and were more likely to experience bevacizumab-induced hypertension, TIPN, and anthracycline-induced congestive heart failure compared with other races in E5103. Germline biomarkers for predicting the risk of TIPN, pending validation in independent trials, can drastically impact counseling patients for the likelihood of this toxicity. Citation Format: Bryan Paul Schneider. Impact of genetically determined race on outcomes in E5103. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA09.