Gene Summary

Gene:EGFR; epidermal growth factor receptor
Aliases: ERBB, HER1, mENA, ERBB1, PIG61, NISBD2
Summary:The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Mutations in this gene are associated with lung cancer. Multiple alternatively spliced transcript variants that encode different protein isoforms have been found for this gene. [provided by RefSeq, Jul 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:epidermal growth factor receptor
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Overexpression of the EGFR protein occurs across a wide range of different cancers. This upregulation appears to be frequently associated with adverse prognosis. Mutations of the EGFR gene occur in a range of cancers, and these often cause the overexpression of the EGFR protein.

Epidermal growth factor receptor (EGFR) signaling pathway. Source Wikimedia Commons

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EGFR (cancer-related)

Nisimova L, Wen S, Cross-Knorr S, et al.
Role of Raf kinase inhibitor protein in Helicobacter pylori-mediated signaling in gastric cancer.
Crit Rev Oncog. 2014; 19(6):469-81 [PubMed] Related Publications
Helicobacter pylori is a helical bacterium that colonizes the stomach in over half of the world's population. Infection with this bacterium has been linked to peptic ulcer disease and gastric cancer. The bacterium has been shown to affect regulatory pathways in its host cells through specific virulence factors that control gene expression. Infection with H. pylori increases levels of phosphorylation of Raf kinase inhibitor protein (pRKIP) in gastric adenocarcinoma (AGS) cells in vitro and in vivo. We investigated the role of H. pylori in the phosphorylation of RKIP as a possible mechanism to downregulate pro-survival signals in gastric adenocarcinoma. pRKIP induces RKIP transcriptional activity, which serves to induce apoptosis of damaged cells to prevent further tumorigenesis. Infection of wild type and RKIP knockout mice with H. pylori for 2 months further confirmed roles of RKIP and pRKIP in the prevention of gastric cancer progression. Loss of RKIP in AGS cells results in increased expression of the Cag A virulence factor after H. pylori infection and RKIP overexpression inhibits H. pylori-mediated STAT3 phosphorylation and STAT3 and NF-κB transcriptional activity. We examined the role of mTOR (mammalian target of rapamycin) after H. pylori infection on the phosphorylation of RKIP. Cells treated with rapamycin, an inhibitor of mTOR, displayed less expression of pRKIP after H. pylori infection. Microarray antibody analysis was conducted on wild-type and RKIP-knockdown AGS cells and showed that in the absence of RKIP, there was increased expression of pro-tumorigenic proteins such as EGFR, Raf-1, and MAPKs. Although further work is needed to confirm the interaction of RKIP and mTOR in AGS cells as a result of H. pylori infection, we hypothesize that H. pylori-mediated induction of pro-survival signaling in gastric epithelial cells induces a feedback response through the activation of RKIP. The phosphorylated, or active, form of RKIP is important in protecting gastric epithelial cells from tumorigenesis after H. pylori infection.

Danilova NV, Davydova SY
Immunohistochemical characteristics of uveal melanoma assording to the age at diagnosis, histological type and extension of the tumor.
Arkh Patol. 2014 Sep-Oct; 76(5):55-60 [PubMed] Related Publications
The purpose of this study was to investigate the relationship between MMP9 expression and tumour invasion in different structures of the eye. We also examined whether there was any correlation between the growth factors (TGFb and EGF), onco-suppressor proteins (p16 and p53) and Ki-67, and the tumour histological subtypes, atypia level and age at diagnosis. Tumour specimens were obtained from 42 primary uveal melanomas immediately after enucleation at The Helmholtz Moscow Research Institute of Eye Diseases. The patients were not treated with radio- or thermotherapy. During our systematic study, we exclusively employed 10%-formalin fixed, paraffin-wax-embedded tissue sections of UM for histological diagnosis and immunohistochemistry. According to our data the hyperexpression of MMP9 and EGFR correlates with a high proportion of spindle cells in a tumour (Kruskal-Wallis test p=0,1 for each). Moreover, we have demonstrated the association between the level of EGFR, TGFb and MMP9 expression and the initial invasion stage (Spearman's test p=0,1). In addition, we have revealed the significant correlation between TGFb hyperexpression and atypia level (Spearman's test p=0,059). Our data reflect that the diagnoses at an advanced age correlate with hyperexpression of p16 (Kruskal-Wallis test p=0,068). An interesting result is that p16 level reduced in inverse proportion to that of TGFb. On the basis of our data and previous studies, we reached the conclusion that after the lapse of time the level of p16 rises significantly in order to inhibit proliferating activity of melanocytes in the normally functioning pigmented layer. However, although the probability of UM diagnoses in elderly is increasing, we have no reliable data for the relationship with high atypia levels.

Chen CK, Lee MY, Lin WL, et al.
A qualitative study comparing the assay performance characteristics between the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists HER2 scoring methods in mucinous epithelial ovarian cancer.
Medicine (Baltimore). 2014; 93(27):e171 [PubMed] Related Publications
The remarkable success of trastuzumab and other newly developed anti-HER2 (human epidermal growth factor receptor 2) therapies in breast, gastric, or gastroesophageal junction cancer patients has supported us to investigate the HER2 status and its possible therapeutic implication in mucinous epithelial ovarian cancer (EOC). However, there is currently no standardization of HER2 scoring criteria in mucinous EOC. In this study, we aimed to compare both the assay performance characteristics of the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists scoring methods. Forty-nine tissue microarray samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using the 2007 and the 2013 criteria, respectively. The overall concordance between IHC and FISH by the 2007 criteria was 97.92 % (kappa = 0.921), and that by the 2013 criteria was 100% (kappa = 1.000). The percentage of Her2 FISH-amplified cases showed an increasing trend significantly through their corresponding HER2 IHC ordinals by the 2007 and the 2013 criteria, respectively (P < 0.001, P < 0.001). After excluding equivocal cases, the specificity (100%) and positive predictive value (100%) were unchanged under either the 2007 or the 2013 criteria. The sensitivity (100%), negative predictive value (NPV) (100%), and accuracy (100%) of HER2 IHC were higher under the 2013 criteria than those (sensitivity 87.5%, NPV 97.6%, and accuracy 97.9%) under the 2007 criteria. Of the total 49 cases, the number (n = 4) of HER2 IHC equivocal results under the 2013 criteria was 4-fold higher than that (n = 1) under the 2007 criteria (8.16% vs 2.04%). Conclusively, if first tested by IHC, the 2013 criteria caused more equivocal HER2 IHC cases to be referred to Her2 FISH testing than the 2007 criteria. That decreased the false-negative rate of HER2 status and increased the detection rates of HER2 positivity in mucinous EOC.

Paquet ER, Hallett MT
Absolute assignment of breast cancer intrinsic molecular subtype.
J Natl Cancer Inst. 2015; 107(1):357 [PubMed] Related Publications
BACKGROUND: Massively parallel gene expression profiling has provided a more objective, molecular-level characterization of breast cancer subtypes. Several bioinformatics tools are available to infer patient subtype from a gene expression profile including the well-studied PAM50. The specific algorithmic methods used in these tools require access to a broad patient dataset. The choice of subtype for an individual is determined relative to all other patients across the panel, making subtypes heavily dependent on the composition of the dataset. Our aim was to develop a bioinformatics approach assigning absolute breast cancer subtypes, independent of dataset composition.
METHODS: Using a dataset of 4924 breast cancer patients, we defined a new bioinformatics approach: Absolute Intrinsic Molecular Subtyping (AIMS) that assigns subtype from a gene expression profile for an individual sample without the need for a large, diverse, and normalized dataset. We evaluated the agreement of AIMS with PAM50 and compared subtype assignment and prognostic value of the subtypes. We assessed AIMS' robustness using a benchmark set of tests including subtype reproducibility between technologies, gene removal, and normal gene expression contamination, and compared it with PAM50. All statistical tests, except where noted, were two-sided.
RESULTS: AIMS vastly agreed with PAM50, with 76% and 77% agreement for cross validation and the test set, respectively, and the prognostic capacity of the intrinsic subtypes was preserved. AIMS is fully stable, and its absolute nature enables its use on a wide range of datasets and technologies, including RNA-seq.
CONCLUSIONS: The instability of a breast cancer subtyping scheme like PAM50 could have important consequences in clinical management of patients. AIMS is a fully stable and robust subtyping scheme that recapitulates PAM50.

Cohen AL, Colman H
Glioma biology and molecular markers.
Cancer Treat Res. 2015; 163:15-30 [PubMed] Related Publications
The tumors classified as gliomas include a wide variety of histologies including the more common (astrocytoma, glioblastoma), as well as the less common histologies (oligodendroglioma, mixed oligoastrocytoma, pilocytic astrocytoma). Recent efforts at comprehensive genetic characterization of various primary brain tumor types have identified a number of common alterations and pathways common to multiple tumor types. Common pathways in glioma biology include growth factor receptor tyrosine kinases and their downstream signaling via the MAP kinase cascade or PI3K signaling, loss of apoptosis through p53, cell cycle regulation, angiogenesis via VEGF signaling, and invasion. However, in addition to these common general pathway alterations, a number of specific alterations have been identified in particular tumor types, and a number of these have direct therapeutic implications. These include mutations or fusions in the BRAF gene seen in pilocytic astrocytomas (and gangliogliomas). In oligodendrogliomas, mutations in IDH1 and codeletion of chromosomes 1p and 19q are associated with improved survival with upfront use of combined chemotherapy and radiation, and these tumors also have unique mutations of CIC and FUBP1 genes. Low grade gliomas are increasingly seen to be divided into two groups based on IDH mutation status, with astrocytomas developing through IDH mutation followed by p53 mutation, while poor prognosis low grade gliomas and primary glioblastomas (GBMs) are characterized by EGFR amplification, loss of PTEN, and loss of cyclin-dependent kinase inhibitors. GBMs can be further characterized based on gene expression and gene methylation patterns into three or four distinct subgroups. Prognostic markers in diffuse gliomas include IDH mutation, 1p/19q codeletion, and MGMT methylation, and MGMT is also a predictive marker in elderly patients with glioblastoma treated with temozolomide monotherapy.

Kong LY, Wei J, Haider AS, et al.
Therapeutic targets in subependymoma.
J Neuroimmunol. 2014; 277(1-2):168-75 [PubMed] Related Publications
Subependymomas are usually treated with surgical resection; however, no standard, defined alternative medical therapy is recommended for patients who are not surgical candidates, owing to a paucity of molecular, immunological, and genetic characterization. To address this, an ex vivo functional analysis of the immune microenvironment in subependymoma was conducted, a subependymoma cytokine/chemokine microarray was constructed for the evaluation of operational immune and molecular pathways, and a subependymoma cell line was derived and used to test a variety of cytotoxic agents that target operational pathways identified in subependymoma. We found that immune effectors are detectable within the microenvironment of subependymoma; however, marked immune suppression is not observed. The subependymoma tissue microarrays demonstrated tumor expression of p53, MDM2, HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-α, PDGF-β, PDGFR-α, PDGFR-β, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50=0.83 μM) and a p-STAT3/HIF-1α inhibitor (WP1066, IC50=3.15 μM) demonstrated a growth inhibition of the subependymoma cell proliferation. Cumulatively, these data suggest that those agents that interfere with oncogenes operational in subependymoma may have clinical impact.

Ema A, Yamashita K, Ushiku H, et al.
Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer.
Cancer Sci. 2014; 105(12):1591-600 [PubMed] Related Publications
Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.

Iwamoto M, Kawada K, Nakamoto Y, et al.
Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS.
J Nucl Med. 2014; 55(12):2038-44 [PubMed] Related Publications
UNLABELLED: KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that (18)F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased (18)F-FDG accumulation.
METHODS: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured (18)F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in (18)F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples.
RESULTS: In the in vitro experiments, (18)F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and (18)F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and (18)F-FDG accumulation. In addition, HIF-1α knockdown decreased (18)F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo (18)F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value.
CONCLUSION: Mutated KRAS caused higher (18)F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased (18)F-FDG accumulation in hypoxic lesions. (18)F-FDG PET might be useful for predicting the KRAS status noninvasively.

Magnus N, Meehan B, Garnier D, et al.
The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis.
Biochem Biophys Res Commun. 2014; 454(2):262-8 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor-associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma.

Zhang L, Ge Y, Fuchs E
miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival.
Genes Dev. 2014; 28(22):2532-46 [PubMed] Article available free on PMC after 15/05/2015 Related Publications
Previously, we identified miR-125b as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans, miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. We further show that miR-125b can confer "oncomiR addiction" in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated miR125b targets that are specifically associated with tumors that are dependent on miR-125b. Through molecular and genetic analysis of these targets, we uncovered new insights underlying miR-125b's oncogenic function. Specifically, we show that, on the one hand, mir-125b directly represses stress-responsive MAP kinase genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing Vps4b (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate miR-125b as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.

Lee HJ, Seo AN, Kim EJ, et al.
HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer.
Am J Clin Pathol. 2014; 142(6):755-66 [PubMed] Related Publications
OBJECTIVES: Heterogeneity of HER2 gene amplification is found in a subset of breast cancers. We investigated the impact of HER2 heterogeneity on trastuzumab responses and clinical outcomes in 112 patients with HER2-positive metastatic breast cancer.
METHODS: Regional and genetic heterogeneity of HER2 gene amplification was determined in three different areas of each tumor by immunohistochemistry and silver in situ hybridization. We also assessed the overall levels of HER2 amplification and the proportion of tumor cells with a HER2/CEP17 ratio of more than 2.2 or strong and complete membranous (3+) expression of HER2 protein.
RESULTS: HER2 regional and genetic heterogeneity based on the HER2/CEP17 ratio was confirmed in 8.7% and 2.7% of cases, respectively. Poor response to trastuzumab was associated with overall low-level or equivocal amplification, HER2 regional heterogeneity by the HER2/CEP17 ratio, the HER2/CEP17 ratio of more than 2.2 in less than 80% of tumor cells, and HER2 immunohistochemical expression of 3+ in less than 75% of tumor cells. In survival analyses, low-level or equivocal HER2 amplification, HER2 regional heterogeneity based on the HER2/CEP17 ratio, and the HER2/CEP17 ratio of more than 2.2 in less than 80% of tumor cells were associated with shorter time to progression and lower overall survival in univariate and multivariate analyses.
CONCLUSIONS: These results suggest that accurate assessment of HER2 status, including HER2 heterogeneity, is important in predicting trastuzumab responses and outcomes in patients with HER2-positive metastatic breast cancer.

Carter CA, Nations JA, Lazarus A
Molecular targets in the treatment of non-small-cell lung cancer: is there hope on the horizon?
Postgrad Med. 2014; 126(7):139-48 [PubMed] Related Publications
Non-small-cell lung cancer (NSCLC) is a growing concern worldwide, and its incidence continues to increase in developing countries. It has a strong association with smoking. Lung cancer remains the leading cause of cancer-related deaths in most industrialized countries and in the United States. In the last 10 years, there have been significant advancements in the understanding of molecular oncogenes and how they play a role in driving lung cancer to both grow and metastasize. Understanding this rapidly expanding field has the potential to extend life, and it is an important field for all providers to conceptualize if they are treating patients with lung cancer. Currently, > 50% of all NSCLC is linked to 1 of several known genetic driver mutations. Using online databases, expert opinion, and practice-changing trials, we review the current standards of molecular testing of NSCLC and the expanding evidence of oncogenic drivers in nonsquamous NSCLC.

Malapelle U, Vigliar E, Sgariglia R, et al.
Ion Torrent next-generation sequencing for routine identification of clinically relevant mutations in colorectal cancer patients.
J Clin Pathol. 2015; 68(1):64-8 [PubMed] Related Publications
AIMS: To evaluate the accuracy, consumable cost and time around testing (TAT) of a next-generation sequencing (NGS) assay, the Ion Torrent AmpliSeq Colon and Lung Cancer Panel, as an alternative to Sanger sequencing to genotype KRAS, NRAS and BRAF in colorectal cancer patients.
METHODS: The Ion Torrent panel was first verified on cell lines and on control samples and then prospectively applied to routine specimens (n=114), with Sanger sequencing as reference.
RESULTS: The Ion Torrent panel detected mutant alleles at the 5% level on cell lines and correctly classified all control tissues. The Ion Torrent assay was successfully carried out on most (95.6%) routine diagnostic samples. Of these, 12 (11%) harboured mutations in the BRAF gene and 47 (43%) in either of the two RAS genes, in two cases with a low abundance of RAS mutant allele which was missed by Sanger sequencing. The mean TAT, from sample receipt to reporting, was 10.4 (Sanger) and 13.0 (Ion Torrent) working days. The consumable cost for genotyping KRAS, NRAS and BRAF was €196 (Sanger) and €187 (Ion Torrent).
CONCLUSIONS: Ion Torrent AmpliSeq Colon and Lung Cancer Panel sequencing is as robust as Sanger sequencing in routine diagnostics to select patients for anti-epidermal growth factor receptor (EGFR) therapy for metastatic colorectal cancer.

Vogt N, Gibaud A, Lemoine F, et al.
Amplicon rearrangements during the extrachromosomal and intrachromosomal amplification process in a glioma.
Nucleic Acids Res. 2014; 42(21):13194-205 [PubMed] Article available free on PMC after 15/05/2015 Related Publications
The mechanisms of gene amplification in tumour cells are poorly understood and the relationship between extrachromosomal DNA molecules, named double minutes (dmins), and intrachromosomal homogeneously staining regions (hsr) is not documented at nucleotide resolution. Using fluorescent in situ hybridization and whole genome sequencing, we studied a xenografted human oligodendroglioma where the co-amplification of the EGFR and MYC loci was present in the form of dmins at early passages and of an hsr at later passages. The amplified regions underwent multiple rearrangements and deletions during the formation of the dmins and their transformation into hsr. In both forms of amplification, non-homologous end-joining and microhomology-mediated end-joining rather than replication repair mechanisms prevailed in fusions. Small fragments, some of a few tens of base pairs, were associated in contigs. They came from clusters of breakpoints localized hundreds of kilobases apart in the amplified regions. The characteristics of some pairs of junctions suggest that at least some fragments were not fused randomly but could result from the concomitant repair of neighbouring breakpoints during the interaction of remote DNA sequences. This characterization at nucleotide resolution of the transition between extra- and intrachromosome amplifications highlights a hitherto uncharacterized organization of the amplified regions suggesting the involvement of new mechanisms in their formation.

Cortez V, Samayoa C, Zamora A, et al.
PELP1 overexpression in the mouse mammary gland results in the development of hyperplasia and carcinoma.
Cancer Res. 2014; 74(24):7395-405 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Estrogen receptor (ER) coregulator overexpression promotes carcinogenesis and/or progression of endocrine related-cancers in which steroid hormones are powerful mitogenic agents. Recent studies in our laboratory, as well as others, demonstrated that the estrogen receptor coregulator PELP1 is a proto-oncogene. PELP1 interactions with histone demethylase KDM1 play a critical role in its oncogenic functions and PELP1 is a prognostic indicator of decreased survival in patients with breast cancer. However, the in vivo significance of PELP1 deregulation during initiation and progression of breast cancer remains unknown. We generated an inducible, mammary gland-specific PELP1-expressing transgenic (Tg) mouse (MMTVrtTA-TetOPELP1). We found more proliferation, extensive side branching, and precocious differentiation in PELP1-overexpressing mammary glands than in control glands. Aged MMTVrtTA-TetOPELP1 Tg mice had hyperplasia and preneoplastic changes as early as 12 weeks, and ER-positive mammary tumors occurred at a latency of 14 to 16 months. Mechanistic studies revealed that PELP1 deregulation altered expression of a number of known ER target genes involved in cellular proliferation (cyclin D1, CDKs) and morphogenesis (EGFR, MMPs) and such changes facilitated altered mammary gland morphogenesis and tumor progression. Furthermore, PELP1 was hyper-phosphorylated at its CDK phosphorylation site, suggesting an autocrine loop involving the CDK-cyclin D1-PELP1 axis in promoting mammary tumorigenesis. Treatment of PELP1 Tg mice with a KDM1 inhibitor significantly reduced PELP1-driven hyperbranching, reversed alterations in cyclin D1 expression levels, and reduced CDK-driven PELP1 phosphorylation. These results further support the hypothesis that PELP1 deregulation has the potential to promote breast tumorigenesis in vivo and represent a novel model for future investigation into molecular mechanisms of PELP1-mediated tumorigenesis.

Candas D, Lu CL, Fan M, et al.
Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells.
Cancer Res. 2014; 74(24):7498-509 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF-MEK-ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2(+)/CD44(+)/CD24(-/low)) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization.

Sheffield BS, Garratt J, Kalloger SE, et al.
HER2/neu testing in gastric cancer by immunohistochemistry: assessment of interlaboratory variation.
Arch Pathol Lab Med. 2014; 138(11):1495-502 [PubMed] Related Publications
CONTEXT: Immunohistochemical (IHC) testing for HER2/neu is becoming the standard of care for guiding adjuvant treatment of gastric carcinoma with trastuzumab.
OBJECTIVE: To assess interlaboratory variation in IHC staining and interpretation across multiple laboratories.
DESIGN: A tissue microarray consisting of 45 cores from 28 gastric cancers was distributed to 37 laboratories for HER2/neu assessment. The IHC results were compared against expert scores at an academic institution and correlated with in situ hybridization results from the originating specimen. Interlaboratory agreement was calculated using Cohen κ statistic.
RESULTS: The survey demonstrated several variations in IHC methods, including the primary antibodies in use. There was excellent agreement among laboratories in HER2/neu(+) (IHC 3(+)) cases (κ = 0.80 ± 0.01) and very good agreement among laboratories in HER2/neu(-) (IHC 0 or 1(+)) cases (κ = 0.58 ± 0.01). Less agreement was observed among laboratories when scoring equivocal (IHC 2(+)) cases (κ = 0.22 ± 0.01). Sensitivity and specificity of HER2/neu IHC were 99% and 100%, respectively, when measured against expert review and consensus score as a reference standard.
CONCLUSIONS: There is substantial interlaboratory agreement in the interpretation of HER2/neu IHC despite variability in protocols. Although HER2/neu IHC is a highly sensitive and specific test, primary antibody selection may significantly affect IHC results. Furthermore, gastric tumors require a unique scoring system and expertise in interpretation. Intratumoral heterogeneity has a significant effect on HER2/neu scoring by IHC. Ongoing quality assurance exercises among laboratories will help ensure optimized HER2/neu testing.

Hu J, Ahuja LG, Meharena HS, et al.
Kinase regulation by hydrophobic spine assembly in cancer.
Mol Cell Biol. 2015; 35(1):264-76 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
A new model of kinase regulation based on the assembly of hydrophobic spines has been proposed. Changes in their positions can explain the mechanism of kinase activation. Here, we examined mutations in human cancer for clues about the regulation of the hydrophobic spines by focusing initially on mutations to Phe. We identified a selected number of Phe mutations in a small group of kinases that included BRAF, ABL1, and the epidermal growth factor receptor. Testing some of these mutations in BRAF, we found that one of the mutations impaired ATP binding and catalytic activity but promoted noncatalytic allosteric functions. Other Phe mutations functioned to promote constitutive catalytic activity. One of these mutations revealed a previously underappreciated hydrophobic surface that functions to position the dynamic regulatory αC-helix. This supports the key role of the C-helix as a signal integration motif for coordinating multiple elements of the kinase to create an active conformation. The importance of the hydrophobic space around the αC-helix was further tested by studying a V600F mutant, which was constitutively active in the absence of the negative charge that is associated with the common V600E mutation. Many hydrophobic mutations strategically localized along the C-helix can thus drive kinase activation.

Kwak TK, Sohn EJ, Kim S, et al.
Inhibitory effect of ethanol extract of Ocimum sanctum on osteopontin mediated metastasis of NCI-H460 non-small cell lung cancer cells.
BMC Complement Altern Med. 2014; 14:419 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Osteopontin (OPN) is one of important molecular targets in cancer progression, metastasis as a calcium-binding, extracellular-matrix-associated protein of the small integrin-binding ligand and, N-linked glycoprotein. In the present study, anti-metastatic mechanism of ethanol extracts of Ocimum sanctum (EEOS) was elucidated on OPN enhanced metastasis in NCI-H460 non- small cell lung cancer cells.
METHODS: Cell viability was measured by MTT assay. Adhesion and invasion assays were carried out to see that EEOS inhibited cell adhesion and invasion in OPN treated and non-treated NCI-H 460 cells. RT-PCR was used to determine the mRNA levels of uPA, uPAR, and EGFR.
RESULTS: EEOS significantly inhibited cell adhesion and invasion in OPN treated and non treated NCI-H460 cells, though EEOS did not show any toxicity up to 200 μg/ml. EEOS effectively attenuated the expression of OPN and CD44 and also OPN activated the expression of CD44 in NCI-H460 cells. In addition, EEOS effectively suppressed the expression of phosphatidylinositide 3-kinases (PI3K) and cyclooxygenase 2 (COX-2) and the phosphorylation of Akt at protein level in OPN treated NCI-H460 cells. Also, EEOS significantly attenuated the expression of urokinase plasminogen activator (uPA), its receptor (uPAR) and epidermal growth factor receptor (EGFR) at mRNA level and reduced vascular endothelial growth factor (VEGF) production and MMP-9 activity in OPN treated NCI-H460 cells. Furthermore, PI3K/Akt inhibitor LY294002 enhanced anti-metastatic potential of EEOS to attenuate the expression of uPA and MMP-9 in OPN treated NCI-H 460 cells.
CONCLUSION: Overall, our findings suggest that anti-metastatic mechanism of EEOS is mediated by inhibition of PI3K/Akt in OPN treated NCI-H460 non-small cell lung cancer cells.

Samkoe KS, Tichauer KM, Gunn JR, et al.
Quantitative in vivo immunohistochemistry of epidermal growth factor receptor using a receptor concentration imaging approach.
Cancer Res. 2014; 74(24):7465-74 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
As receptor-targeted therapeutics become increasingly used in clinical oncology, the ability to quantify protein expression and pharmacokinetics in vivo is imperative to ensure successful individualized treatment plans. Current standards for receptor analysis are performed on extracted tissues. These measurements are static and often physiologically irrelevant; therefore, only a partial picture of available receptors for drug targeting in vivo is provided. Until recently, in vivo measurements were limited by the inability to separate delivery, binding, and retention effects, but this can be circumvented by a dual-tracer approach for referencing the detected signal. We hypothesized that in vivo receptor concentration imaging (RCI) would be superior to ex vivo immunohistochemistry (IHC). Using multiple xenograft tumor models with varying EGFR expression, we determined the EGFR concentration in each model using a novel targeted agent (anti-EGFR affibody-IRDye800CW conjugate) along with a simultaneously delivered reference agent (control affibody-IRDye680RD conjugate). The RCI-calculated in vivo receptor concentration was strongly correlated with ex vivo pathologist-scored IHC and computer-quantified ex vivo immunofluorescence. In contrast, no correlation was observed with ex vivo Western blot analysis or in vitro flow-cytometry assays. Overall, our results argue that in vivo RCI provides a robust measure of receptor expression equivalent to ex vivo immunostaining, with implications for use in noninvasive monitoring of therapy or therapeutic guidance during surgery.

Labussière M, Di Stefano AL, Gleize V, et al.
TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.
Br J Cancer. 2014; 111(10):2024-32 [PubMed] Article available free on PMC after 11/11/2015 Related Publications
BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.
METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.
RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.
CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

Yang HS, Horten B
Gain of copy number and amplification of the RET gene in lung cancer.
Exp Mol Pathol. 2014; 97(3):465-9 [PubMed] Related Publications
RET rearrangement represents a unique molecular subset of lung cancer. The identification of specific clinicopathologic characteristics and RET gene status would provide critical information on targeted therapeutics. In this study, we investigated the patterns of RET gene in a series of lung carcinomas. Of one hundred and sixteen tumors, a low frequency (1.7%) of RET translocation was identified. Only two specimens of lung adenocarcinomas displayed the rearrangement of RET in 54% and 78% of tumor cells respectively. A high incidence of gain of copy number (3-4 copies) and amplification (≥ 5 copies) of the RET gene was observed in 52% and 12% of all 116 samples. An association between increased copy number of RET and EGFR mutation was statistically significant (p < 0.05) in these lung carcinomas. This study sheds light on the unique molecular characteristics of the RET gene in lung carcinomas.

Chikarmane SA, Tirumani SH, Howard SA, et al.
Metastatic patterns of breast cancer subtypes: what radiologists should know in the era of personalized cancer medicine.
Clin Radiol. 2015; 70(1):1-10 [PubMed] Related Publications
There is accumulating evidence that molecular phenotyping of breast cancer determines the timing, pattern, and outcome of metastatic disease. The most clinically relevant subtypes are hormonal-positive [oestrogen and progesterone receptor (ER/PR) positive], HER2 expressing, and triple-negative breast cancers (TNBCs). ER/PR-positive breast cancers demonstrate the best prognosis; however, metastases, in particular osseous disease, may develop much later. HER2-expressing breast cancers, although aggressive, have improved outcomes due to the advent of HER2-targeted therapies, with increased risk of central nervous system (CNS) relapses later. Finally, TNBCs present in younger women, BRCA1 mutations carriers, and carry the worst overall prognosis, with high incidence of CNS metastases, especially during the first 5 years of diagnosis. It is important for radiologists to understand the nuances of these breast cancer subtypes to predict metastatic behaviours and guide possible imaging surveillance.

Li Y, Zhang R, Pan D, et al.
KRAS mutation in adenocarcinoma of the gastrointestinal type arising from a mature cystic teratoma of the ovary.
J Ovarian Res. 2014; 7:85 [PubMed] Article available free on PMC after 11/11/2015 Related Publications
Mature cystic teratomas (MCT) in the ovary rarely undergo malignant transformation. Moreover, adenocarcinoma of the gastrointestinal type is much rarer. We present two cases of perimenopausal female pateints with mature cystic teratoma of single ovary, while local adenocarcinoma arising in the MCT. The malignancies showed immunohistochemical features of intestinal differentiation, such as strong positivity for CDX-2, villin and CK-20, and negativity for CK-7. Furthermore, the mutation analysis of molecular alteration revealed a KRAS gene mutation in the intestinal adenocarcinoma part, extending into benign intestinal-type epithelium linings. Yet the mutation was not present in the epidermal component of the teratoma. We present these as two unique cases of mucinous adenocarcinoma of the intestinal type arising from mature cystic teratoma. Moreover, we also submit that this KRAS mutation might contribute to identify malignant transformation of a MCT and suggest possible effect on targeted treatment decisions for anti-epidermal growth factor receptor (EGFR) therapy in metastasized patients.

Kanazawa K, Yokouchi H, Wang X, et al.
Phase II trial of carboplatin and pemetrexed as first-line chemotherapy for non-squamous non-small cell lung cancer, and correlation between the efficacy/toxicity and genetic polymorphisms associated with pemetrexed metabolism: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0902.
Cancer Chemother Pharmacol. 2014; 74(6):1149-57 [PubMed] Related Publications
PURPOSE: This phase II study evaluated the response rate (RR) and safety of combination therapy with carboplatin (CBDCA) and pemetrexed (PEM) in Japanese patients with non-squamous non-small cell lung cancer (non-sq NSCLC). Further, the relationship between therapy efficacy/toxicity and genetic polymorphisms associated with PEM metabolism was analyzed.
METHODS: Forty-one patients received CBDCA at a dose targeting an area under the concentration-time curve of 5 mg/mL × min and PEM of 500 mg/m(2) on day 1 every 3 weeks. Single-nucleotide polymorphisms of the thymidylate synthase (TYMS) coding gene, the variable number of tandem repeat (VNTR) in the TYMS, and the methylenetetrahydrofolate reductase (MTHFR) coding gene were analyzed.
RESULTS: The overall RR was 36.6 %. Median progression-free survival and median survival time were 4.7 months [95 % confidence interval (CI) 3.9-5.6 months] and 16.2 months (95 % CI 6.1-26.2 months), respectively. Epidermal growth factor receptor gene mutations were detected in 6 patients (14.6 %). The VNTR in the TYMS significantly correlated with anemia (p = 0.047) and thrombocytopenia (p = 0.038).
CONCLUSIONS: This combination therapy was effective and tolerable in patients with advanced non-sq NSCLC. The VNTR in the TYMS appears to be a predictive factor for anemia and thrombocytopenia in patients treated with this regimen.

Sun H, Gan ZC, Gao JJ, Zheng F
Non-invasive detection of EGFR deletion at exon 19 in non-small cell lung cancer by real time diagnostic.
Clin Lab. 2014; 60(9):1517-26 [PubMed] Related Publications
BACKGROUND: The non-invasive identification of epidermal growth factor receptor (EGFR) mutations is important for the institution of individualized therapy of non-small cell lung cancer (NSCLC). In this study, the feasibility of screening for EGFR exon 19 E746_A750del mutations in circulating DNA from plasma was assessed.
METHODS: Mutant-specific primers with a Taqman probe (MST-PCR) were designed. The ability of this method to accurately detect decreasing concentrations of E746_A750del mutant within a wild type DNA background that mimics the situation of a plasma sample from patients with acquired mutations is verified. To verify the clinical applicability of this method, 55 plasma samples from NSCLC patients were tested, and the sensitivity of MST-PCR was compared to that of direct sequencing.
RESULTS: The results showed that MST-PCR could detect 10 to 50 copies/microL of E746_A750del, representing 0.1% of the wild type EGFR allelic population. Among the 55 cases of NSCLC, 10 cases of E746_A750del were detected by MST-PCR, while only 1 case was revealed by direct sequencing.
CONCLUSIONS: These findings demonstrate that MST-PCR provides superior sensitivity for the detection of the E746_A750del mutation, suggesting its potential application in the noninvasive detection of E746_A750del mutations in plasma samples from NSCLC patients.

VandenBussche CJ, Illei PB, Lin MT, et al.
Molecular alterations in non-small cell lung carcinomas of the young.
Hum Pathol. 2014; 45(12):2379-87 [PubMed] Related Publications
Lung cancer is the leading cause of cancer death in the United States. Gene alterations are significant in lung tumorigenesis, with certain genes (Kristen rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], and B-Raf proto-oncogene, serine/threonine kinase (BRAF)) possessing alterations important in the prognosis and treatment of lung adenocarcinoma. Mutation frequencies are affected by different patient factors, such as smoking history, age, and race. Because most lung cancers occur in patients older than age of 50 years, few studies have examined molecular alterations present in these younger patients. The pathology database was searched for patients age of 50 years or younger with non-small cell lung carcinomas (NSCLCs) tested for EGFR, ALK, KRAS, and/or BRAF alterations. A total of 53 cases were identified. The mean patient age was 44.4 years old, and there were 19 men and 34 women. Of the tumors, 11.6% had ALK rearrangements, 25.5% had KRAS mutations, and 20.0% had EGFR mutations. No BRAF mutations were identified in the 28 cases tested. All but 1 (92% [12/13]) tumor with KRAS mutation were from women patients. A smoking history of greater than 5 pack-years was associated with KRAS mutations and negatively associated with EGFR mutations and ALK translocation. The frequencies of EGFR mutation and ALK translocation in the study cohort are greater than the reported frequencies among NSCLC from adults of all ages in the United States but less than the reported frequencies among NSCLC from East Asian young adults. The frequency of KRAS mutation is significantly greater than what was previously found in young Japanese patients.

Ikeda K, Osumi H, Matsuishi K, et al.
Multiple lung adenocarcinomas associated with von hippel-lindau disease.
Ann Thorac Surg. 2014; 98(4):1467-70 [PubMed] Related Publications
Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas.

Waisberg J, De Souza Viana L, Affonso Junior RJ, et al.
Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer.
Anticancer Res. 2014; 34(10):5599-607 [PubMed] Related Publications
BACKGROUND/AIM: The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. We evaluated the relationship between the expression of SPARC, ITGAV, THBS1 and VCAM-1 genes of extracellular matrix in the progression and dissemination of colorectal cancer (CRC).
PATIENTS AND METHODS: Adult patients (N=114) underwent resection of CRC. Gene expression in CRC was determined by quantitative real-time polymerase chain reaction (PCR). Protein expression was analyzed by immunohistochemistry (IHC). Correlation with pathway-related molecules (p53, Bcl-2, Ki-67, EGFR and VEGF) was assessed.
RESULTS: Tumors with perineural invasion showed overexpression (p=0.028) of the ITGAV gene with regard to cancers without perineural invasion and validation of the result through IHC expression of the corresponding proteins, was significant for the expression of ITGAV protein (p=0.001).
CONCLUSION: The overexpression of ITGAV gene was associated with higher progression and spread of CRC via perineural invasion.

von Minckwitz G, Puglisi F, Cortes J, et al.
Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial.
Lancet Oncol. 2014; 15(11):1269-78 [PubMed] Related Publications
BACKGROUND: Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy.
METHODS: In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with, number NCT01250379.
FINDINGS: Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1-21·7) in the chemotherapy-alone group and 16·1 months (10·6-22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4-7·2] vs 4·2 months [3·9-4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61-0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (<1%) of 238 patients receiving chemotherapy alone. Serious adverse events were reported in 61 (25%) of 245 patients receiving bevacizumab plus chemotherapy versus 44 (18%) of 238 patients receiving chemotherapy alone.
INTERPRETATION: These results suggest that continued VEGF inhibition with further bevacizumab is a valid treatment option for patients with locally recurrent or metastatic HER2-negative breast cancer whose disease was stabilised or responded to first-line bevacizumab with chemotherapy.
FUNDING: F Hoffmann-La Roche.

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