Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer

Lang, I.; Inbar, Moshe; Kahán, Zsuzsanna; Greil, Richard; Beslija, S.; Stemmer, S. M.; Kaufman, B.; Zvirbule, Zanete; Steger, Guenther G.; Messinger, Diethelm; Brodowicz, Thomas; Zielinski, C.

doi:10.1016/j.ejca.2012.04.022

Cited by 18 publications

(10 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Angiogenesis is also necessary for the progression of metastasis making VEGF receptors potential therapeutic targets. Several clinical trials have investigated the efficacy of adding the monoclonal anti-VEGFR antibody bevacizumab to standard chemotherapy in hormone receptor negative patients (Cobleigh et al, 2003;Lang et al, 2012;K. D. Miller et al, 2005;Robert et al, 2011 Despite the initial promise of kinase inhibitors for the treatment of many cancers, these therapies often fail due the emergence of drug resistance after a pathological partial response.…”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

Goulet¹,

Foster²,

Zawistowski³

et al. 2020

Molecular Cancer Research

View full text Add to dashboard Cite

Daniel R. Goulet: Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple Negative Breast Cancer (Under the direction of Gary Johnson) Triple-negative breast cancer (TNBC) is characterized by genomic heterogeneity and high risk of relapse. Recent studies have demonstrated that breast cancers can contain a spectrum of epithelial and mesenchymal phenotypes. We identified epithelial (POS) and mesenchymal (NEG) subpopulations in a triple negative breast cancer cell line that have similar coding sequences, but unique enrichment of the epigenetic activators H3K27ac and BRD4. We show that localization of these epigenetic activators correlates with the expression of epithelial transcription factors TP63 and ELF3 in epithelial cells, and ZEB1 and TWIST1 in mesenchymal cells. Currently, there are no targeted therapies available for the treatment of triple negative breast cancer. However, overexpression of EGFR, KRAS, or BRAF occurs in approximately 30% of TNBC, suggesting that inhibiting the MAPK signaling pathway may be an effective therapy for TNBC. Acute treatment with the MEK inhibitor trametinib induced distinct transcriptional responses in epithelial and mesenchymal subpopulations. ChIP-Seq analysis of H3K27ac and BRD4 binding revealed epigenetic remodeling in response to trametinib treatment, especially at binding sites for AP-1 in NEG cells and epithelial-specific ETS transcription factors in POS cells. Chronic treatment with trametinib induced the emergence of trametinib resistant POS cells, but not NEG cells. In trametinib resistant POS cells, we observe increased expression of the Gi-coupled chemokine receptor CXCR7, and its cognate ligand adrenomedullin, as well as increased expression of KRAS. ChIP-Seq analysis revealed enrichment of H3K27ac and BRD4 at the CXCR promoter and enhancer, indicating epigenetic remodeling induces transcriptional activation. siRNA knockdown of CXCR7 and KRAS demonstrate these genes are essential for the proliferation of trametinib resistant cells, and reveals that epigenetic remodeling at the CXCR7 locus may be a mechanism for drug resistance. CCND1 Cyclin D1 CD49f Integrin alpha 6 CDH1 E-Cadherin CDK4 Cyclin-dependent kinase 4 CDK6 Cyclin-dependent kinase 6 CDKN2A Cyclin dependent kinase inhibitor 2A cDNA Complementary DNA CHD1 Chromodomain helicase binding protein 1 ChIP-Seq Chromatin Immunoprecipitation Sequencing xiv cm Centimeter CML Chronic Myelogenous Leukemia CpG Cytosine-Guanine dinucleotide CRISPR Clustered Regularly Interspaced Short Palindromic Repeats CTCF CCCTC-binding factor CTD C-terminal domain CXCR7 Chemokine receptor 7 DCLK1 Doublecortin-like kinase 1

show abstract

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

Goulet¹,

Foster²,

Zawistowski³

et al. 2020

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…22,26 Based on the results of this study, non-inferiority criteria was not met for the primary outcome of OS (HR 1.04, 97.5% CI -1 to 1.69, interim p ¼ 0.059). Median 1-year and 2-year survival was 81% and 60% in the paclitaxel arm versus 79% and 55% in the capecitabine arm, respectively.…”

Section: Bevacizumab In Metastatic Breast Cancermentioning

confidence: 99%

The life, death, and attempted rebirth of bevacizumab in breast cancer

Seddon

Cuéllar

Haaf

2013

J Oncol Pharm Pract

View full text Add to dashboard Cite

Breast cancer is the leading cause of cancer in women. In recent years, there has been immense drug discovery and development in the field of breast cancer. Most recently, the role of vascular endothelial growth factor has moved to the treatment forefront with bevacizumab immersed into the literature as well as the media. Bevacizumab, a vascular endothelial growth factor inhibitor FDA approved for the treatment of other cancers, was first studied in metastatic breast cancer. Its use in human epidermal growth factor receptor 2-negative metastatic breast cancer ultimately failed to show an improvement in overall survival in landmark trials (E2100, AVADO, RIBBON-1 and RIBBON-2) despite its positive impact on progression-free survival. The role is yet to be determined in triple negative breast cancer as well as in the adjuvant and neoadjuvant settings. Trends begin to emerge as bevacizumab is combined with other chemotherapeutic drugs in terms of toxicities. The addition of bevacizumab is associated with an increase in the dose-limiting toxicities of the drugs combined in the regimen. As previous literature suggest, hypertension and proteinuria were also seen with the addition of bevacizumab, both of which are known adverse events. Lastly, there is a trend towards increased incidence of heart failure when bevacizumab is combined with another cardiotoxic medication, doxorubicin. This toxicity has been shown to be reversible in the majority of the cases and has a low incidence in the currently published literature.

show abstract

“…During the last 13 mo, the results of no less than 60 clinical trials of this type have been published in peer-reviewed scientific journals (Table 3). The largest fraction of these studies involved the VEGF-targeting mAb bevacizumab, which has been tested, most often in combination with conventional chemotherapy and/or targeted anticancer agents, in cohorts of patients affected by acute myeloid leukemia, 121 multiple myeloma, 122 head and neck squamous cell carcinoma (HNSCC), 123 , 124 breast carcinoma, 48 , 125 - 130 melanoma, 131 hepatocellular carcinoma, 132 - 136 pancreatic cancer, 137 ovarian carcinoma, 138 - 143 prostate cancer, 144 and several other advanced or metastatic solid tumors 145 - 154 . Moreover, 89 Zr-conjugated bevacizumab has been investigated as a means to visualize neoplastic lesions by positron emission tomography (PET) in women with primary breast carcinomas, which often secrete high levels of VEGF 155 .…”

Section: Update On Clinical Reportsmentioning

confidence: 99%

Trial Watch

et al. 2014

View full text Add to dashboard Cite

In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.

show abstract

Safety results from a phase III study (TURANDOT trial by CECOG) of first-line bevacizumab in combination with capecitabine or paclitaxel for HER-2-negative locally recurrent or metastatic breast cancer

Cited by 18 publications

References 22 publications

Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer

The life, death, and attempted rebirth of bevacizumab in breast cancer

Trial Watch

Contact Info

Product

Resources

About