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Publications (5)16.06 Total impact

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    ABSTRACT: Background Preclinical and early clinical data support the use of Vascular Epithelial Growth Factor (VEGF)-targeted therapy with trastuzumab in Human Epidermal Receptor 2 (HER2) positive breast cancer. Adding bevacizumab to a taxane (docetaxel or paclitaxel) improves progression free survival (PFS) of metastatic breast cancer (MBC) patients. Objectives We evaluated the efficacy and feasibility of combining bevacizumab with trastuzumab and docetaxel in patients with HER2- positive MBC who received 0-1 prior chemotherapy regimens for metastatic disease. The primary end point was PFS. Materials and Methods Eligible patients received bevacizumab (15 mg/kg), trastuzumab (8 mg/kg loading dose followed by 6 mg/kg), and docetaxel (100 mg/m2 initially, later amended to 75 mg/m2) every three weeks for six cycles and then were allowed to receive bevacizumab and trastuzumab alone. Results Thirteen (50 %) of 26 patients enrolled completed all 6 cycles of bevacizumab, trastuzumab and docetaxel and went on to receive bevacizumab and trastuzumab alone (median: 11 cycles). The most common grade 3 or 4 toxicities include: neutropenia (8 %), septic death (4 %), infection not associated with neutropenia (15 %), fatigue (27 %), mylagia and/or arthraligia (20 %), and hand-foot syndrome (8 %). One patient (4 %) and six patients (23 %) developed grade 3 and grade 2 hypertension, respectively. Two (8 %) patients had transient grade 2 drop in Left Ventricular Ejection Fraction (LVEF) with full recovery later. The median progression free survival (PFS) was 14.3 months (95 % CI: 9.3-35 months), the objective response rate (ORR), defined as the best response of complete response (CR) or partial response (PR) was (12/26) 46 %. The clinical benefit rate (CBR), defined as the best response of CR or PR or stable disease (SD) for at least 24 weeks, was (18/26) 69 % (95 % CI: 48-86 %). Conclusion The combination of bevacizumab, trastuzumab and docetaxel is well tolerated and is clinically active in patients with HER2-positive MBC, with response rate and PFS comparable to previous reports utilizing higher dose of docetaxel (100 mg/m2). Recent randomized trials did not demonstrate additional overall survival (OS) benefit of adding bevacizumab to trastuzumab and docetaxel despite an improvement in PFS. Identification of predictive biomarkers and careful patient selection should be incorporated in further investigation of anti-VEGF in breast cancer.
    Investigational New Drugs 06/2014; · 2.93 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTCs) are commonly isolated from the blood by targeting the epithelial cell adhesion molecule (EpCAM) through positive selection. However, EpCAM can be downregulated during metastatic progression, or initially not present. A prospective trial was designed to characterize CTCs as well as other circulating cell populations in blood samples from women with metastatic breast cancer without EpCAM dependent enrichment/isolation technology. A total of 32 patients with metastatic breast cancer were enrolled and blood samples were processed using previously described immunomagnetic negative depletion methodology. Samples from healthy volunteers were run as controls (n = 5). Multistep, sequential labeling was performed to label and fix cell surface markers followed by permeablization for cytokeratin (CK) 8, 18, 19. Multiparameter flow cytometry analysis (FCM) was next conducted on a BD LSR, Aria II or Aria III. Immunocytochemical (ICC) staining on post-enrichment specimens for DAPI, EpCAM, CD45, CK, epidermal growth factor receptor (EGFR) and vimentin was performed. Expression of these markers was visualized using confocal microscopy (CM). CD45 negative (-) CK positive (+) populations with EpCAM+ and EpCAM - expression were identified with both FCM and CM from the negatively enriched patient samples. In addition, EpCAM+ and EpCAM- populations that were CK+ and co-expressing the pan- hematopoietic marker CD45 were also noted. There were statistically significantly more CK+EpCAM- events/mL than CK+EpCAM+ events/mL in both the CD45- or CD45+ fractions (both p <= 0.0005). The number of CK+CD45- and CK+CD45+ events per mL of blood sample, (regardless of EpCAM status) were higher in patient samples than in normal control samples (p <= 0.0005, and 0.026, respectively). Further, a significant fraction of the CK+CD45+ events also expressed CD68, a marker associated with tumor associated macrophages (TAMs). Higher levels of CD45-CK+EpCAM- was associated with worse overall survival (p = 0.0292). Metastatic breast cancer patients have atypical cells that are CK+EpCAM- circulating in their blood. Since a substantial number of these patients will not have EpCAM+CTCs, additional studies are needed to evaluate the role of EpCAM- circulating cells as a prognostic and predictive marker.
    Breast cancer research: BCR 03/2014; 16(2):R23. · 5.88 Impact Factor
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    ABSTRACT: PURPOSE: Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy. PATIENTS AND METHODS: We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5-21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1. RESULTS: Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59-0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11-0.69) of patients. CONCLUSIONS: Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
    Cancer Chemotherapy and Pharmacology 02/2013; · 2.80 Impact Factor
  • CNS Neuroscience & Therapeutics 06/2012; 18(9):791-3. · 4.46 Impact Factor
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    ABSTRACT: Increased expression of the vascular endothelial growth factor (VEGF) is a poor prognostic factor in breast cancer, indicating that antiangiogenic therapies may improve outcomes. Novel antiangiogenic agents targeting the proangiogenic VEGF ligand and receptor tyrosine kinase inhibitors have been developed. Of these, bevacizumab, a humanized monoclonal antibody directed against VEGF, is very promising in breast cancer. A large phase 3 clinical trial demonstrated a statistically significant improvement in progression-free survival with the addition of bevacizumab to paclitaxel as first-line treatment of advanced breast cancer, establishing the benefit of antiangiogenic therapy in breast cancer. Additional studies of bevacizumab in the metastatic, adjuvant, and neoadjuvant settings are underway. Ongoing trials are also evaluating the efficacy of multitargeted tyrosine kinase inhibitors in advanced breast cancer. This article reviews the results of the key trials evaluating antiangiogenic agents in breast cancer with particular emphasis on bevacizumab and future directions of antiangiogenic therapy. KeywordsAngiogenesis-Bevacizumab-Breast cancer
    Current Breast Cancer Reports 03/2010; 2(1):4-15.