Bevacizumab In Metastatic Breast Cancer Research Articles

Acute congestive heart failure due to Bevacizumab in metastatic breast cancer: a case report

The addition of Bevacizumab to chemotherapy has shown its first-line interest in metastatic breast cancer by improving PFS but not OS. After a certain period of exposure, the appearance of side effects such as acute Congestive heart failure (CHF) has been described during clinical trials; manifested by a drop in LVEF and clinical signs which sometimes caused a hospitalization. We report the case of a patient in whom this exposure time was rather long with a very long survival under Bevacizumab. The onset of arterial hypertension appeared after 8 months of treatment with Bevacizumab in combination with metastatic first- line chemotherapy, while acute CHF occurred after approximately 10 years of treatment, which is at the 129th treatment. The evolution of CHF was favorable after adequate treatment and discontinuation of Bevacizumab as in most cases reported in the literature.

Advocacy for a New Oncology Research Paradigm: The Model of Bevacizumab in Triple-Negative Breast Cancer in a French Cohort Study

Background: Triple-negative breast cancer remains a disease with poor prognosis and few treatment options, due to the lack of therapeutic targets. Bevacizumab, the first anti-VEGF agent approved in the treatment of cancer, has demonstrated efficacy in breast cancer in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. Despite the fact that the benefit was particularly significant for triple-negative breast cancer with its approval in 2008 by the FDA, this decision was later reversed as there was no improvement in overall survival in addition to significant costs. Objectives: The scope of the present study is to focus on the role of bevacizumab in triple-negative breast cancer through the analysis of overall survival, progression-free survival, and cost benefit among 45 patients in a French monocentric study and to discuss new paradigms of endpoints. Methods: All patients diagnosed with metastatic triple-negative breast cancer, for whom first-line treatment was bevacizumab in combination with paclitaxel between January 2011 and April 2018 were included in this single-center retrospective study, and a chart review of all recruited subjects was performed from medical records. Results: In this real-life study among 45 patients with metastatic triple-negative breast cancer, bevacizumab provided a significant benefit for a category of patients, with longer median progression-free survival and the ability of maintenance therapy associated to limited side effects. Conclusions: Beyond being the phoenix of breast oncology and a magnet of controversy, the case of bevacizumab in metastatic breast cancer highlights one of the greatest challenges in oncology, namely to balance modest clinical benefits with exponential costs. A balance needs to be found between health care affordability, high price of progress, and the best medical decision for the patients, in order to avoid the “unbreathable tipping point” we are actually dealing with.

Innovative methods for the identification of predictive biomarker signatures in oncology: Application to bevacizumab.

Current methods for subgroup analyses of data collected from randomized clinical trials (RCTs) may lead to false-positives from multiple testing, lack power to detect moderate but clinically meaningful differences, or be too simplistic in characterizing patients who may benefit from treatment. Herein, we present a general procedure based on a set of newly developed statistical methods for the identification and evaluation of complex multivariate predictors of treatment effect. Furthermore, we implemented this procedure to identify a subgroup of patients who may receive the largest benefit from bevacizumab treatment using a panel of 10 biomarkers measured at baseline in patients enrolled on two RCTs investigating bevacizumab in metastatic breast cancer. Data were collected from patients with human epidermal growth factor receptor 2 (HER2)-negative (AVADO) and HER2-positive (AVEREL) metastatic breast cancer. We first developed a classification rule based on an estimated individual scoring system, using data from the AVADO study only. The classification rule takes into consideration a panel of biomarkers, including vascular endothelial growth factor (VEGF)-A. We then classified the patients in the independent AVEREL study into patient groups according to “promising” or “not-promising” treatment benefit based on this rule and conducted a statistical analysis within these subgroups to compute point estimates, confidence intervals, and p-values for treatment effect and its interaction. In the group with promising treatment benefit in the AVEREL study, the estimated hazard ratio of bevacizumab versus placebo for progression-free survival was 0.687 (95% confidence interval [CI]: 0.462–1.024, p = 0.065), while in the not-promising group the hazard ratio (HR) was 1.152 (95% CI: 0.526–2.524, p = 0.723). Using the median level of VEGF-A from the AVEREL study to divide the study population, then the HR becomes 0.711 (95% CI: 0.435–1.163, p = 0.174) in the promising group and 0.828 (95% CI: 0.496–1.380, p = 0.468) in the not-promising group. Similar results were obtained with the median VEGF-A levels from the AVADO study (“promising” group: HR = 0.709, 95%CI: 0.444–1.133, p = 0.151; “not-promising” group: HR = 0.851, 95% CI: 0.497–1.458, p = 0.556). Our analysis shows it is feasible to employ statistical methods for empirically constructing and validating a scoring system based on a panel of biomarkers. This scoring system can be used to estimate the treatment effect for individual patients and identify a subgroup of patients who may benefit from treatment. The proposed procedure can provide a general framework to organize many statistical methods (existing or to be developed) into a coherent set of analyses for the development of personalized medicines and has the potential of broad applications.

Chemotherapy in combination with bevacizumab in breast cancer. Results of the observational study in daily clinical practice

In metastatic breast cancer (MBC) the combination of Bevacizumab (Avastin) and chemotherapy (CT) failed to demonstrate an increase in overall survival with a significant improvement of the objective response rate and progression-free survival (PFS) in randomized trials of the 3d phase. Nevertheless, observational studies in the daily clinical practice for the use of Bevacizumab in MBC continue in the world. We present the results of our own observational study, which goal is to assess the efficacy and tolerability of Bevacizumab in combination with CT in patients with HER/2-negative metastatic and locally advanced breast cancer. The study included 34 patients with breast cancer (6-locally advanced, 28-metastatic) at the age of 29 to 66 years (mean – 49.5). Bevacizumab was administered at a dose of 7.5 to 15 mg/kg every 3 weeks in combination with CT. In total, the patients received 294 doses of Bevacizumab (median – 10). All patients with locally advanced breast cancer were operated on after the treatment completion, a pathologic complete response was registered in 33.3%. In MBC, the objective response was registered in 46,4%, tumor growth control in 89.3%, median PFS – 10 months. Typical for Bevacizumab adverse events, such as hypertension, proteinuria, were moderate and were met respectively in 14.7% and in 5.9% cases. In 1 (2.9%) patient the treatment was complicated by deep vein thrombosis and PE due to disease progression. Conclusion. Bevacizumab in combination with CT in breast cancer treatment can achieve high rates of objective response and PFS independent of the treatment line

Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study

Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination. This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively. From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601-0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case-control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672-0.813; 8.1 versus 6.4 months). In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.

Is there room for bevacizumab in metastatic breast cancer?

Is there room for bevacizumab in metastatic breast cancer?

Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer.

Biomarkers for bevacizumab efficacy in metastatic breast cancer (MBC) are of urgent need. The genetic variability of genes involved in angiogenesis could explain the interpatient variability of drug effects. For this biomarker study DNA was extracted from tumor blocks or blood samples of patients with human epidermal growth factor receptor 2 (HER2)-negative MBC treated with bevacizumab in combination with chemotherapy (bevacizumab cohort, 163 patients) or chemotherapy only (control cohort, 105 patients). We assessed the correlation of 10 single-nucleotide polymorphisms (SNPs) in genes modulating angiogenesis (vascular endothelial growth factor-A (VEGF-A), VEGF receptor 1 (VEGFR-1), serine threonine kinase 39 (STK39)) or hypertension (endothelin-1 and uromodulin) with outcome and toxicity. In the bevacizumab cohort, the SNP rs5370-TT in endothelin-1 (EDN1) showed a significantly shorter median overall survival (OS, 6.3 vs 21.3 months; hazard ratio (HR) 2.89, 95% confidence interval (CI) 1.34-6.26; log-rank P=0.0069) and a trend toward worse median progression-free survival (3.5 vs 7.9 months; HR 2.05, 95% CI 0.96-4.39; log-rank P=0.065) compared with the alternate genotypes combined. Similarly, patients harboring the VEGF-936 (rs3025039) TT alleles showed a significantly shorter median OS than patients with VEGF-936 CC or CT (14.9 vs 21.3 months; HR 2.37, 95% CI 1.09-5.13; P=0.0286). In multivariate analysis including important clinical parameters like disease-free survival (DFS), adjuvant chemotherapy, ECOG (Eastern Cooperative Oncology Group) performance score, histologic subtype, grade, hormone receptor status, visceral metastases and treatment line, only the association of rs5370 (EDN1) with OS was still statistically significant (P=0.012). In the control cohort, no association of the EDN1 genotype with outcome was seen, suggesting a predictive value for bevacizumab. In conclusion, the SNP rs5370 in endothelin-1 could help identifying patients who unlikely gain any benefit from bevacizumab.

Abstract P3-07-43: DNA methylation patterns correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer

Abstract Background: Biomarkers predicting response to bevacizumab containing therapy in breast cancer are of urgent need for a personalized treatment approach. DNA methylation is involved in regulation of angiogenesis and development of treatment resistance and could therefore provide predictive information for bevacizumab efficacy. Patients and methods: A genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in FFPE specimen of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (discovery set). Twenty-eight (78%) samples came from primary tumor and 8 (22%) from metastasis (2 lung mets., 1 pleural met., 1 liver met., 2 soft tissue mets., 1 ovarial met, 1 bone marrow infiltration). Based on progression-free survival (PFS) and breast cancer subtype (ER+ vs. triple-negative) patients were divided in responder (R) and non-responder (NR). By biostatistical methods differences in the methylation pattern between R and NR were detected. The 48 most interesting genes (e.g. because of there involvement in angiogenesis or carcinogenesis) showing a differential methylation status between R and NR are currently validated in two further metastatic breast cancer cohorts treated with (main set) and without bevacizumab (validation set), respectively. These validated results will be presented at the meeting. Citation Format: Gampenrieder SP, Rinnerthaler G, Weinhäusel A, Pulverer W, Hugnagl C, Hackl H, Romeder F, Monzo Fuentes C, Hauser-Kronberger C, Mlineritsch B, Greil R. DNA methylation patterns correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-43.

WS1-5 - How to manage bevacizumab for metastatic breast cancer?

WS1-5 - How to manage bevacizumab for metastatic breast cancer?

Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis.

The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.

Abstract P4-07-03: MicroRNAs correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer

Abstract Background: Biomarkers predicting response to bevacizumab containing therapy in breast cancer are of urgent need. MiRNAs, small non-coding RNAs, can be involved in tumor evolution including regulation of angiogenesis and development of treatment resistance. Therefore, miRNAs can provide both prognostic and predictive information in different cancer entities. Patients and methods: A genome-wide miRNA profiling using high-throughput TaqMan® Array Human MicroRNA Cards enabling quantification of 754 unique human miRNAs was performed. Formalin-fixed paraffin-embedded specimens from 60 patients treated with bevacizumab as first-line therapy at our institution were analyzed. Based on the median overall progression-free survival (PFS) patients were divided into a responder (G1) and a non-responder group (G2). Differentially expressed miRNAs were selected considering a more than two-fold change and a false discovery rate (FDR) < 10% as significant. Further interesting miRNAs were selected by a multivariate logistic regression approach using LASSO (Least Absolute Selection and Shrinkage Operator) regularization. Results: Overall median PFS was 9.3 months with a median PFS of 17.5 and 5.0 months in G1 and G2, respectively. Eight miRNAs (miR-19b-3p, miR-21-5p, miR-9-5p, miR-590-5p, miR-106b-5p, miR-20a-5p) were significantly differentially expressed between these groups (FDR < 10%). Their expression levels were all negatively associated with G1. Additionally, four miRNAs (miR-210-3p, miR-224-5p, miR-155-5p, miR-28-5p) might be interesting predictive biomarkers as they were included in a logistic regression classification model providing an optimal separation between responder and non-responder group (evident from the area under curve [AUC] and 100 x 5-fold cross validation). Currently these data is being validated in a patient cohort not treated with bevacizumab in order to detect the predictive value of these miRNAs for a bevacizumab-based treatment. These validated results will be presented at the meeting. Conclusion: Twelve miRNAs in breast cancer tissue could be identified showing promising predictive value for bevacizumab-based therapy. Although these data need to be confirmed, differences in miRNA expression could help identifying patients with greater benefit from anti-VEGF agents. Citation Format: Simon P Gampenrieder, Frank Hamacher, Gabriel Rinnerthaler, Clemens Hufnagl, Hubert Hackl, Franz Romeder, Claudia Muß, Cornelia Hauser-Kronbeger, Brigitte Mlineritsch, Richard Greil. MicroRNAs correlating with outcome in patients treated with first-line bevacizumab for metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-07-03.

Abstract OT1-2-03: A prospective randomized phase II study to identify predictive biomarkers and mechanisms of resistance in patients with HER2-negative metastatic breast cancer treated with the combination of bevacizumab and paclitaxel

Abstract Background Several phase III trials have evaluated the combination of bevacizumab and chemotherapy in patients with metastatic breast cancer (MBC). These individual studies as well as a meta-analysis indicate high response rates (RR) and increased progression-free survival (PFS), however no significant gain of overall survival (OS) by the addition of bevacizumab to chemotherapy. To date, there are no methods to reliably select patients with MBC that benefit from treatment with bevacizumab. Trial design This project is a prospective, randomized, 2-arm, open-label, single-center, phase II trial aiming to identify predictive markers and mechanisms of resistance to bevacizumab in MBC by longitudinal biopsies and functional imaging. The study will be initiated with a non-randomized, feasibility stage including ten patients who will be treated with bevacizumab and paclitaxel, in order to determine the safety of metastatic tumor biopsies during therapy with bevacizumab. In a second phase, 20 patients will be randomized (1:1) between two treatment arms: Paclitaxel 80 mg / m2 weekly with or without bevacizumab 15 mg / kg every 3 weeks. Mandatory, repeated peripheral blood sampling and fine needle aspiration biopsies (FNAB) will be collected at baseline, at day 4 after the first cycle and at progression. At baseline, a core biopsy will be obtained as well. Patients will also undergo two 18F]-fluoro-L-thymidine (FLT) Positron Emission Tomography (PET)/CT scans (18F-FLT PET/CT), at baseline and at day 4 after the first cycle. Eligibility criteria Eligible are patients aged 18-70 years, with newly diagnosed HER2-negative MBC (stage IV or recurrent) that are candidates for chemotherapy (ECOG 0-2), with measurable disease and at least one lesion that is accessible for biopsy. Adequate bone marrow, hepatic and renal function are required, as well as absence of thromboembolic disease, bleeding diathesis or second concurrent malignancy. No previous systemic treatment for MBC is allowed. Specific aims 1. To assess early therapeutic response to bevacizumab in MBC by whole-exome sequencing and gene expression of serial metastatic biopsies and functional imaging. 2. To identify potential biomarkers present in plasma that can be used for patient selection or for monitoring therapy with bevacizumab in MBC. 3. To explore mutations and gene expression alterations as mechanisms of resistance to bevacizumab in MBC. Statistical methods The main objective of the study is exploratory. For most of the planned analyses, each patient will serve as her own control and baseline values of potential biomarkers will be compared in pairs with intra-patient, longitudinal samples, which significantly increases the statistical power. For the identification of biomarkers, the results of the molecular analyses will be correlated with clinical outcome measurements including RR, PFS, and OS. Present accrual and target accrual. The trial was opened for inclusion in May 2013 and one patient has been accrued by June 1st 2013. A total of 30 patients will be included during a period of 2 years. Contact: Principal Investigator: Theodoros.Foukakis@ki.se; Study Director: Jonas.Bergh@ki.se. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-2-03.

Abstract P1-08-32: Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer

Abstract Background: Biomarkers predicting response or toxicity of bevacizumab containing therapy in breast cancer are of urgent need. The genetic variability of VEGF, its receptor or other genes involved in angiogenesis could explain the inter-patient variability of drug effects and treatment resistance. Patients and methods: DNA was extracted from 180 paraffin-embedded tumor tissue blocks of patients with locally advanced or metastatic breast cancer treated with bevacizumab in combination with chemotherapy at our institution. We assessed the correlation of 11 SNPs in VEGF-A, VEGFR-1, STK39, endothelin-1 and uromodulin with outcome and toxicity. Results: Only one SNP in endothelin-1 (rs5370 TT) was significantly associated with worse median progression-free survival (HR 2.13, 95% CI 1.04 to 4.35, P = .038) and median overall survival (HR 2.88, 95% CI 1.40 to 5.93, P = .0042) compared with the alternate genotypes combined. One VEGF genotype (VEGF-634 GG) was associated with a significantly higher rate of treatment-induced hypertension when compared with the alternate genotypes combined (P = .048). Conclusion: Although these data need to be confirmed in larger trials, germline polymorphisms could help identifying patients who do not gain any benefit from anti-VEGF agents or who are at high risk of toxicity. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-32.

Comment on ‘The efficacy and toxicity of gemcitabine, carboplatin and bevacizumab in metastatic breast cancer‘

Comment on ‘The efficacy and toxicity of gemcitabine, carboplatin and bevacizumab in metastatic breast cancer‘

Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel versus carboplatin/docetaxel in initial treatment of metastatic Her-2-negative breast cancer

In view of the previous reports demonstrating the positive outcome of bevacizumab in metastatic breast cancer, we aimed at comparing the role of bevacizumab-based metronomic combination with taxane (paclitaxel) versus a different taxane (docetaxel)-based regimen in addition to carboplatin as initial treatment for metastatic Her-2-negative breast cancer. This is a randomized Phase III study comparing the progression-free survival (PFS) and safety in Her-2-negative female patients with initial diagnosis of metastatic breast cancer with World Health Organization performance status of 0-II. Forty-one patients were randomized from September 2008 to July 2009 to receive either; (1) bevacizumab 5 mg/kg day 1 and day 15, carboplatin area under the curve (AUC)-2 day 1, day 8, and day 15, and paclitaxel 60 mg/m(2) day 1, day 8, and day 15 (arm-I); or (2) carboplatin AUC-5 day 1, docetaxel 75 mg/m(2) day 1 (arm-II). The Kaplan-Meier method was used for estimating survival; log-rank test for comparing survival curves. The primary end point was PFS, and secondary end points were overall survival (OS) and safety. PFS was 10 months in arm I versus 10.2 months in arm II (P = 0.9). The OS rate was similar in both arms: 37.6 months for arm I versus 37.4 months for arm II (P = 0.92). The toxicity revealed higher incidence of hypertension and proteinuria in arm I; however, with higher incidence of grade III-IV neutropenia and neutropenic fever in arm II. No treatment-related mortality was recorded. Bevacizumab/carboplatin/paclitaxel and carboplatin/docetaxel show comparable PFS and OS with different toxicity profiles.

Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety

This study sought to examine the effects and underlying mechanisms of systemic VEGF inhibition in experimental atherosclerosis and aortic endothelial cells. Pharmacological inhibition of vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, has become a widely applied treatment of certain cancers and multiple ocular diseases including age-related macular degeneration. However, recent clinical trials raise concern for systemic vascular adverse effects, prompting the Food and Drug Administration to revoke the approval of bevacizumab for metastatic breast cancer. Eight-week old apolipoprotein E knockout mice received a high-cholesterol diet (1.25% cholesterol) for 24 weeks and were exposed to a systemic pan-VEGF receptor inhibitor (PTK787/ZK222584, 50mg/kg/d) or placebo (gavage) for the last 10 weeks. Atherosclerotic lesions were characterized in thoraco-abdominal aortae and aortic arches. Mechanistic analyses were performed in cultured human aortic endothelial cells. Systemic VEGF inhibition increased atherosclerotic lesions by 33% whereas features of plaque vulnerability (i.e. necrotic core size, fibrous cap thickness) remained unchanged compared with controls. Aortic eNOS expression was decreased (trend). In human endothelial cells VEGF inhibition induced a dose-dependent increase in mitochondrial superoxide generation with an uncoupling of eNOS, resulting in reduced NO availability and decreased proliferation. Systemic VEGF inhibition disrupts endothelial homeostasis and accelerates atherogenesis, suggesting that these events contribute to the clinical cardiovascular adverse events of VEGF-inhibiting therapies. Cardiovascular safety profiles of currently applied anti-angiogenic regimens should be determined to improve patient selection for therapy and allow close monitoring of patients at increased cardiovascular risk.

GRP-177 The Use of Bevacizumab in Metastatic Breast Cancer

BackgroundMany drugs are prescribed outside the terms of the marketing authorization (off-label), especially in oncology.PurposeTo describe the use of bevacizumab in metastatic breast cancer (MCB), evaluating its suitability after the...

CPC-044 Effectiviness and Safety of Bevacizumab in Metastatic Breast Cancer in Clinical Practise

BackgroundNew data released by clinical trials AVADO and RIBBON have questioned the use of Avastin in metastatic breast cancer (MBC). EMA keeps the indication of first line in combination with...

Abstract P1-06-01: Upregulation of metabolism as a potential resistance mechanism to bevacizumab in primary breast cancer

Abstract Background: Recently the FDA has withdrawn the indication for bevacizumab in metastatic breast cancer after several clinical studies failed to demonstrate an overall survival benefit. These studies however did report an increase in response rates to chemotherapy and improvement in progression free survival, suggesting a pattern of response to the drug followed by the development of resistance. We have little knowledge of the molecular mechanisms driving the development of resistance to bevacizumab. To better understand these mechanisms, we have conducted a window of opportunity study using a single cycle of bevacizumab with detailed pharmacodynamic assessments using gene expression arrays and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods: After ethical approval, 47 newly diagnosed locally advanced breast cancer patients were prospectively enrolled in this trial. Patients received single dose bevacizumab (15mg/ kg) 2 weeks prior to neoadjuvant chemotherapy and underwent core biopsies for gene expression and immunohistochemistry analysis and DCE-MRI scans before and 2 weeks after bevacizumab. 35 patients who had invasive ductal carcinoma together with good quality MRI scans and core biopsies before and after bevacizumab were included in this analysis. Pharmacokinetic (PK) modelling techniques were used to quantify PK parameters (Ktrans, kep, ve) from the DCE-MRI data. Gene expression profiling was performed using the Affymetrix Human Exon 1.0 ST arrays. Results: The majority of patients (28/35) showed a significant reduction in vessel permeability and blood flow of at least 30% following bevacizumab, with a mean decrease in the forward transfer constant (P < 0.0001) and the reverse rate constant kep (P < 0.0001). From gene expression and immunohistochemistry analyses, we identified several key metabolism-related genes that are significantly up-regulated after bevacizumab treatment, including pyruvate dehydrogenase kinase isozyme 1 (PDK1) (fig.1) and carbonic anhydrase 9 (CA9). In addition, we found a number of interesting genes that are down-regulated after bevacizumab treatment, including sulfatase-1 (SULF1), and cyclin E1 (CCNE1). Discussion: This study highlights that the combination of DCE-MRI and gene expression arrays can lead to an improved understanding of the molecular mechanisms governing response and resistance to anti-angiogenic therapy. Heterogeneity of response to bevacizumab was demonstrated, with some tumours showing increases or no change in Ktrans and others marked reductions, which may be of value in early stratification for therapy maintenance. Furthermore, the gene expression analysis showed activation of pathways, which could contribute to the development of resistance. For example, we observed significant up regulation of genes involved in regulating the switch from mitochondrial metabolism to glycolysis, such as PDK1. This suggests that using bevacizumab with the other targeted agents such as Dichloroacetate, a PDK1 inhibitor might be helpful in overcoming the development of resistance and ultimately lead to improved patient survival. Our preclinical studies strongly support this possibility. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-06-01.

Pharmacokinetic and Pharmacodynamic Analysis of Circulating Biomarkers of Anti-NRP1, a Novel Antiangiogenesis Agent, in Two Phase I Trials in Patients with Advanced Solid Tumors

MNRP1685A is a monoclonal antibody to neuropilin-1 (NRP1). We evaluated blood-based pharmacodynamic biomarkers of MNRP1685A in two phase I studies to assess exposure/response relationships to inform target dose and regimen selection. The phase I studies evaluated escalating doses of MNRP1685A as a single agent or in combination with bevacizumab. Plasma placental growth factor (PlGF), VEGF, and circulating NRP1 (cNRP1) were evaluated at multiple time points using meso-scale discovery (MSD) assays and ELISA, respectively. Plasma PlGF was also measured in a phase I/II trial of bevacizumab in metastatic breast cancer (AVF0776). The association between PlGF and MNRP1685A dose was described by a sigmoid E(max) model. cNRP1 and MNRP1685A PK profiles were described using a two-target quasi-steady state (QSS) model. A dose- and time-dependent increase in plasma PlGF and cNRP1 was observed in all patients treated with MNRP1685A. PK/PD analysis showed that bevacizumab and MNRP1685A had an additive effect in elevating PlGF. Predictions based on the two-target QSS model showed that the free drug concentration to maintain greater than 90% saturation of membrane NRP1 (mNRP1) and cNRP1 is about 8 μg/mL. These data show that MNRP1685A inhibits the VEGF pathway in humans as assessed by an increase in plasma PlGF. MNRP1685A seems to enhance bevacizumab-mediated VEGF pathway blockade, as showed by an increase in the magnitude of PlGF elevation when combined with bevacizumab. PK/PD analysis of biomarkers in the phase I population allowed identification of doses at which apparent maximal pathway modulation was observed.