Mutant Epidermal Growth Factor Research Articles

Targeting MET and EGFR in NSCLC-what can we learn from the recently reported phase III trial of onartuzumab in combination with erlotinib in advanced non-small cell lung cancer?

The epidermal growth factor (EGFR) is overexpressed in non-small cell lung cancer (NSCLC), and treatment with erlotinib as monotherapy in patients previously treated with chemotherapy is associated with improved overall survival (OS) (1). However, resistance to tyrosine kinase inhibitors targeting the EGFR is observed in the majority of patients and may be associated with the overexpression and/or amplification of the tyrosine kinase receptor MET (2). Increased MET expression in NSCLC has also been associated with worse prognosis and is co-expressed in 70% of EGFR mutant tumours (2). This data generated a valid rationale for combining MET and EGFR targeted agents in the management of advanced NSCLC.

Phase Ib/Ii Trial of C-Met Inhibitor Msc2156119J and Gefitinib Vs Chemotherapy As 2Nd-Line Treatment in Asian Patients with Met-Positive (Met+), Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Nsclc) with Epidermal Growth Factor Mutation (Egfrm+) and Progression on Gefitinib

ABSTRACT Background: The main mechanisms for the development of resistance to EGFR tyrosine kinase inhibitors (eg, gefitinib) in EGFRm+ NSCLC patients (pts) are a secondary mutation in the EGFR (ie, T790M) and amplification of the c-Met proto-oncogene. The selective, small-molecule c-Met inhibitor MSC2156119J displayed promising antitumor activity in a Phase I trial in pts with advanced solid tumors (Falchook et al. J Clin Oncol 2013:31[Suppl]:2506). This Phase Ib/II, open-label, multicenter trial evaluates the antitumor activity of MSC2156119J + gefitinib in pts with Met+ advanced EGFRm+ NSCLC (NCT01982955). Trial design: Primary objectives include determination of the recommended Phase II dose (RP2D) for the combination (Phase Ib), and progression-free survival (PFS) per investigator read (Phase II). Secondary objectives are pharmacokinetics, safety, and antitumor activity of MSC2156119J (objective response, PFS per independent read, disease control, and overall survival). Adults from mainland China, South Korea, Taiwan, and other Asian countries, with advanced NSCLC with activating EGFR mutation, ECOG status 0–1, and resistance to first-line gefitinib (Phase II only) are recruited. Key eligibility criteria include confirmed Met+ status, defined either as Met gene amplification by in situ hybridization or strong to moderate protein overexpression by immunohistochemistry, life expectancy >3 mo, and no prior EGFR-targeting therapy other than gefitinib (Phase II only). For the Phase Ib part, 15–18 pts are planned to receive 300 or 500 mg MSC2156119J p.o. + 250 mg gefitinib p.o./d (3 + 3 design; 21-d cycle). Up to 200 pts are planned to be enrolled for the Phase II part into 2 predefined subgroups according to T790M mutation status, and subsequently randomized 1:1 to 250 mg gefitinib p.o./d + RP2D MSC2156119J p.o. or 75 mg/m2 cisplatin i.v. on day 1 + 500 mg/m2 pemetrexed i.v. (max. of six 21-d cycles). The enrollment began on Dec 23, 2013. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting. All rights reserved. Disclosure: Y. Wu: Board of Director of IASLC; President of Chinese Society of Clinical Oncology; J. Yang: Advisory board: Merck; L. Xu: Employee of Merck Serono Pharmaceutical RD U. Stammberger: Executive employee of Merck KGaA, Darmstadt, Germany; A. Johne: Employee of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

Activity of EGFR, mTOR and PI3K inhibitors in an isogenic breast cell line model

BackgroundThe epidermal growth factor receptor family is expressed in breast cancer, and agents targeting this pathway have single agent effects (e.g. traztuzumab). Development of resistance may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the epidermal growth factor (EGFR) inhibitors erlotinib and gefitinib in breast MCF10a isogenic cell lines with EGFR, BRAF, AKT, and PI3K mutations.ResultsPI3K mutation conferred increased activity of EGFR inhibitors against MCF10a cells in comparison with the parental cell line and other mutations studied. Combination of EGFR inhibitors with either the PI3K inhibitor ZSTK474 or the MTOR inhibitor sirolimus showed increased activity.ConclusionsThese results are encouraging for the use of combinations targeting the PI3K and EGFR pathway simultaneously.

Phase I/II multicenter, randomized, open-label trial of the c-Met inhibitor MSC2156119J and gefitinib versus chemotherapy as second-line treatment in patients with MET-positive (MET+), locally advanced, or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor mutation (EGFRm+) and progression on gefitinib.

TPS8121 Background: Resistance to EGFR tyrosine kinase inhibitors (eg, gefitinib) in EGFRm+ NSCLC patients (pts) is mainly caused by a secondary mutation in the EGFR (ie, T790M) or by activation of...

Social factors, treatment, and survival in patients with advanced-stage non-small cell lung cancer

Background: Lung cancer is the leading cause of cancer death in North America with at least 40% of patients presenting with advanced, incurable non-small cell cancer (NSCLC) at the time of diagnosis. Chemotherapy has been shown to increase median survival in patients with a good performance status [Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2]. Objective: To determine factors associated with treatment in patients presenting with advanced NSCLC in two academic community-based hospital settings. Methods: Data were extracted from the 2009-2010 Scripps Cancer Registry. Advanced NSCLC patients were followed from initial diagnosis until death. The influence of socioeconomic status, performance status and access to care on the decision to pursue treatment and the correlating overall survival was assessed. Results: Chemotherapy was given to 64% of 111 patients from Scripps Mercy Hospital (SMH) and Scripps Green Hospital (SGH) diagnosed with advanced NSCLC. Chemotherapy was given to 58.8% of SMH patients and 78.3% of SGH patients (P=0.03). Patients with an ECOG status between 0-2 were more likely to receive chemotherapy compared with patients whose ECOG status was 3-4 (81% versus 0%, respectively, P<0.001). Those tested for the epidermal growth factor (EGFR) mutation were more likely to receive chemotherapy, compared to those not tested (96% versus 60%, P<0.001). Conclusions: Chemotherapy utilization for advanced NSCLC is increasing over time. Chemotherapy administration is associated with socioeconomic status, performance status, and access to care, relationships that likely reflect evolving clinical practice patterns.

Esophageal Cancer and the Importance of Epidermal Growth Factor (EGFR)

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignancies, worldwide. It is important to find out what prognostic factors can facilitate diagnosis, optimize therapeutic decisions, and improve the survival of these patients. Despite improvements in surgical techniques combined with chemotherapy and/or radiotherapy, the novel therapies such as small molecule inhibitors of tyrosine kinases (TKIs) and humanized monoclonal antibodies (mAbs) are very much needed. On the other hand, neoadjuvant chemotherapy which may improve the outcome is accompanied by toxicity by destruction of normal cells. Side effects may be avoided by developing therapies that specifically target molecular characteristics of tumors. Epidermal growth factor receptor (EGFR) is one of tyrosine kinases receptors widely distributed in human epithelial cell membrane. Genetic polymorphisms in EGFR genes influence cell cycle progression, angiogenesis, apoptosis and metastasis. EGFR mutations are mostly observed in lung tumors; curiously they are more prevalent in Asian women diagnosed with adenocarcinoma. Also, esophageal SCC shows a relatively high incidence of EGFR (33%) and/or HER2 (31%) overexpression. Patients who carry these mutations in EGFR have been founded tending to have a better response to gefitinib, an EGFR-TKI, whereas patients with the wild-type genotype show a better response to conventional chemotherapy. Therefore, finding clinical characteristics and environmental interactions with EGFR can affect on investigations about novel anti-cancer therapies like monoclonal antibodies and gene therapy and studies which identify patients who may benefit from EGFR targeted therapies. Hence, it may be effective on the improvement of prognosis in these patients.

Abstract IA10: Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer.

Abstract The concept of “oncogene addiction” led to the realization that not all patients respond equally to each targeted therapy, and best therapeutic results are obtained when the therapy is given to patients whose tumor harbors the “driver mutation” that is sensitive to the drug. In lung cancer, two currently approved new therapies require patient selection based on the presence of sensitizing epidermal growth factor (EGFR) tyrosine kinase domain (TKD) mutation or the anaplastic lymphoma kinase (ALK) gene rearrangement. EGFR mutations occur almost always in lung cancer of adenocarcinoma histology, and uncommonly in other histologies except when they also contain adenocarcinoma component. They are more common in East Asian (~45%) compared to Caucasian (~15-25%) patients, in never/light smokers and in female patients. Ninety percent of EGFR sensitizing mutations involve the 3-5 amino acid deletions on exon 19 and the L858R mutation on exon 21. Although ALK rearrangement also occurs mainly in lung adenocarcinoma and never/light smokers, it is not associated with sex or ethnicity. A great majority of the ALK gene rearrangements that occur in lung cancer involve a fusion between the C-terminal of ALK containing the kinase domain and the N-terminal of echinoderm microtubule-associated protein-like 4 (EML4), which results from an inversion on the short arm of chromosome 2. While EGFR mutations are detected by mainly by sequencing or PCR-based techniques, ALK rearrangement is best detected by the fluorescent in situ hybridization (FISH). However, recent data suggest that the oncogenic ALK fusion proteins can be detected with close to 100% sensitivity and specificity in lung cancer by immunohistochemistry using commercially available ALK specific antibodies, while the native ALK protein is not expressed in normal lung cells. Based on a systematic review of the published literatures, experts representing the International Association for the Study of Lung Cancer (IASLC), in collaboration with the College of American Pathologists (CAP) and the Association of Molecular Pathologists (AMP) recently issued a guideline on Molecular Testing of EGFR and ALK in Lung Cancer. The testing algorithm reported in this guideline will be discussed. Citation Format: Ming Sound Tsao. Molecular testing to personalized EGFR and ALK inhibitor therapies in lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA10.

20 Testing for epidermal growth factor (EFGR) mutation in non-small cell lung cancer (NSCLC) patients; the Heart of England NHS Foundation Trust (HEFT) experience

20 Testing for epidermal growth factor (EFGR) mutation in non-small cell lung cancer (NSCLC) patients; the Heart of England NHS Foundation Trust (HEFT) experience

Frequency of Epidermal Growth Factor Mutation Status and Its Effect on Outcome of Patients with Adenocarcinoma of the Lung

he frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian population than in whites. The prevalence of these mutations among Arab patients is unknown. The objective of this study was to report the frequency and spectrum of EGFR mutations in our population with lung adenocarcinoma, and the effect of this mutation on treatment outcome. Tumor specimens from 81 patients histological diagnosed as NSCLC adenocarcinoma were reviewed by our local pathologist and then sent to Lab 21 London, UK. Samples were tested for 28 mutations in EGFR gene. Positive patients received TKI and negative patients received chemotherapy. Data were collected and retrospectively analyzed to determine frequency and spectrum of EGFR positivity. Patients were followed for time to progression (TTP) and overall survival (OS). Overall frequency of EGFR mutation was 37%; Del 19 (46.6%), L858R (40%), D719x and insertion 20 (6.7%) for each. Females and nonsmokers exhibited a statistically significant higher EGFR positivity (P = 0.003, 0.059) respectively. Overall response rate (ORR) was 76.6% and 43% in EGFR positive and negative cases respectively (P = 0.002). There was a statistically significant difference in TTP and OS between EGFR positive and negative patients (P = 0.035 and 0.039 respectively). Arab patients exhibit an EGFR mutation pattern that is closer to Asian population. EGFR gene mutation subtypes are the same as that reported worldwide. A statistically significant TTP and OS benefit was noticed in EGFR positive patients compared to EGFR negative cases.

Challenges to Implementation of an Epidermal Growth Factor Receptor Testing Strategy for Non–Small-Cell Lung Cancer in a Publicly Funded Health Care System

Data from seven recent randomized clinical trials have demonstrated that epidermal growth factor (EGFR) mutation status is predictive of improved progression-free survival and quality of life from first-line EGFR tyrosine kinase inhibitor therapy compared with platinum-based chemotherapy. We examined barriers to the initial implementation of a national EGFR testing policy in Canada. Five laboratories across Canada underwent a validation and quality-control exercise for EGFR mutation testing using reverse transcriptase-polymerase chain reaction with financial support from the pharmaceutical industry for the initial 12 months. Oncologists registered patients with nonquamous histology for EGFR mutation testing using a Web-based platform. Basic demographics were collected including age, histology, sex, smoking status, and ethnicity. The decision to prescribe gefitinib was subsequently registered on the system. Between March and December 2010, 2104 requests were received for EGFR mutation testing. Demographic details are as follows: adenocarcinoma (91.6%); Asian ethnicity (13.9%); female (58%); light/never smoker (41.3%); stage IV disease (87.1%). The number of tests requested each month ranged from 200 to 250. Mutation testing was conducted in 1771 of 2104 requests (84%). The median turnaround time for EGFR testing was 18 days (standard deviation 9.7). Gefitinib was prescribed in 302 patients (17.1%). The number of test requests dropped to 50 to 100 per month at the end of the initial 12 months. There was rapid uptake of EGFR mutation testing into routine clinical practice in Canada. Uptake of EGFR mutation testing dropped substantially once funding from pharmaceutical industry was discontinued. There is a need for a national strategy to ensure resources are in place to implement molecular testing for new molecularly targeted agents.

Epidermal growth factor mutation in non-small cell lung cancer: Venezuelan experience.

e22060 Background: Lung cancer represents the most common cause of death related to cancer worldwide. The current treatment strategy includes the determinations of the EGFR somatic mutations. Currently in Venezuela the frequency and the type of EGFR mutation in NSCLC patients is unknown and due to its importance in the decision of treatment, it was decided to execute this study with the objective of knowing our population’s characteristics with respect to the stage and mutational type of EGFR. Methods: In the period between November of 2010 until March of 2012, the samples of 395 patients with NSCLC diagnostic all over the country were obtained, these samples were evaluated to determine the EGFR mutation, confidence intervals of 95% were calculated based on the binomial distribution. Results: From the total of 395 patients, 80 presented an inadequate sample, 19 had no registry, 296 patients remained for the analysis. It was obtained an EGFR mutation rate of 11.5%, that was more common seen in male gender (56%), younger than 65 years (66%), ex smokers (59%), with Adenocarcinoma histology (97%). About the mutation type of the EGFR, the specific mutation of the exon 21 was found in 59% of the positive cases, and deletion of exon 19 in 38%. Conclusions: The EGFR mutation is present within the Venezuelan population and shows a particular regional demographic behavior.

EGFR Tyrosine Kinase Inhibitors: Difference in Efficacy and Resistance

Lung cancer will be diagnosed in 230,000 patients in the U.S. in 2013. Adenocarcinoma will be the most common histology, and 10% of lung cancers will be diagnosed in never or former light smokers. These patients will be those most likely to harbor targetable mutations, in particular, mutations in epidermal growth factor (EGFR). Preclinical work beginning in the 1980s led to the development of EGFR-targeted therapy in lung cancer patients. Analysis of the responders to gefitinib and erlotinib led to the discovery of activating mutations underlying sensitivity to EGFR-directed treatment. Although EGFR-mutant patients have higher response rates, better quality of life, and longer progression free survival, all patients eventually develop resistance. Mutations in the tyrosine kinase domain that render tumors resistant to erlotinib and gefitinib are the most common mechanism of resistance. A second generation of EGFR inhibitors are now making their way to the clinic, with hopes of thwarting these resistance mechanisms or providing more durable responses via irreversible inhibition, as well as targeting of additional HER receptors. Here we review the evolution of EGFR as a target in lung cancer, and the second generation of EGFR inhibitors in development.

Reply to association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never‐smoker women with pulmonary adenocarcinoma

We thank Uramoto and Tanaka for their comments on our study.1 We think there are a few potential reasons for the discrepancy between their results and ours. First, the study population differed. Lung adenocarcinoma in nonsmoking Asian females has been found to be a unique entity in that it has a higher frequency of activating epidermal growth factor (EGFR) mutation and better prognosis.2 Our study further showed that 70% of subjects had activated EGFR mutation, and the remaining 30% had anaplastic lymphoma kinase (ALK) fusion.1, 3 Similarly, the different demographic characteristics in our study might also result in a different TS expression level. In addition, our selected population eliminated the impact of sex on TS expression, since TS expression differed between male and female subjects.4 Second, as Uramoto and Tanaka mention, disparities in sampling species (messenger RNA vs protein level) and experimental methods (real-time polymerase chain reaction vs immunohistochemistry) might have led to different results. Most importantly, the comparative population differed. We found that TS expression was significantly lower in patients with EGFR mutation than in those with both EGFR wild type and negative ALK fusion status.1 Uramoto and Tanaka compared TS expression in patients with EGFR mutation with patients who had EGFR wild-type. As we know, the EGFR wild-type group is heterogeneous, including the ALK fusion subgroup, which is not only associated with lower TS expression but also makes up a substantially large part of the wild-type group.3 As a result, Uramoto and Tanaka would be more likely to see a negative result. However, because Chinese and Japanese patients have a similar mutation spectrum and a similar therapeutic efficacy, ethnic difference would contribute little to the discrepancy. Hopefully, the worldwide multiplex mutation driver examination and pharmacogenomics detection efforts currently underway will shed light on the relationship between EGFR mutation and TS expression in the future. This study was supported by the Amory Company and was supported in part by the National Science Foundation of China (grants 81172108 and 81201707). The authors made no disclosures. Shengxiang Ren, MD and Caicun Zhou, MD, PhD Department of Medical Oncology, Shanghai Pulmonary Hospital Tongji University School of Medicine, Tongji University Medical School Cancer Institute, Shanghai, People's Republic of China

Efficacy of tyrosine kinase inhibitors in routine clinical practice: Epidermal growth factor mutations and their implications

Activating mutations in the epidermal growth factor (EGFR) gene confer sensitivity to the tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). TKI treatment efficacy and EGFR mutation implications were evaluated in clinically selected advanced NSCLC patients treated with TKIs in routine clinical practice. A retrospective chart review for clinicopathological characteristics and mutation status (EGFR, KRAS) analysis of 40 consecutive patients treated with TKIs between 2005 and 2010 was performed. PFS and OS were estimated by the Kaplan-Meier method, the log-rank test was used to test for differences. The strength of the associations between the EGFR mutation status and clinicopathological characteristics were tested with the Mann-Whitney U-test or the Kruskal-Wallis H-test. The prevalence of EGFR mutations was 45% with a predominance of deletion mutations in exon 19 (55.5%). Significant correlations between gender, histology, and EGFR mutations were observed. Median progression-free survival (mPFS) for the entire group of patients was 8.7 months and median overall survival (mOS) was not yet reached. Patients with EGFR mutant tumors derived significantly higher benefit from TKI therapy compared to patients with mutation-negative disease; with mPFS of 22.0 vs. 3.2 months (HR: 3.9, 95% CI 1.56-9.89) and with a trend towards better OS (probability of survival at 12 months 82.0 vs. 63.0%, P = 0.080). We demonstrated that screening for EGFR mutations is reliable in a routine clinical setting and might allow for a better selection of NSCLC patients for anti-EGFR TKI therapy.

17 Assessment of epidermal growth factor (EGFR) mutations in patients with NSCLC – a single institution experience

17 Assessment of epidermal growth factor (EGFR) mutations in patients with NSCLC – a single institution experience

Effects of entinostat onresistance to cetuximab and EGFR TKIs in non-small cell lung cancer.

e18077 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor (EGFR) is active in patients with NSCLC. Gate keeper mutations in EGFR, such as T790M and activation of alternative driven pathways such as Met amplification are known mechanisms of acquired resistance to EGFR TKI. Here we evaluated the effects of the class I histone deacetylase inhibitors (HDACi), entinostat with cetuximab or EGFR TKIs in NSCLC cell lines with 3 potential mechanisms of intrinsic and acquired EGFR inhibitor resistance: RAS mutation according to E-cadherin expression, T790M EGFR mutation, and amplified MET. Methods: In vivo efficacy of entinostat alone or in combination with cetuximab or gefitinib was tested in athymic nude mice bearing RAS mutant, E-cadherin positive (A549) and E-cadherin negative (NCI-H460) NSCLC xenograft tumors. NSCLC cell lines were treated with various dilutions of cetuximab, entinostat or erlotinib. The NCI-H1975 and NCI-H1993 cell lines harboring the EGFR-L858R/T790M mutation and MET amplification, respectively, were treated with the combination of entinostat and erlotinib. Cell growth was analyzed by the MTT assay. Expression of e-cadherin was evaluated using affymetix microarrays. Results: When entinostat (E; 5mg/kg) was combined with cetuximab (C; 25mg/kg) in nude mice bearing the E-cadherin positive A549 xenograft, tumor growth inhibition was higher than each drug alone in (C: 65%; E: 70%; E+C: 88%; p=0.001) or what is detected in the E-cadherin negative H460 xenografts (C: 3%, E: 64%, E+C: 75%). Synergistic effects were detected when entinostat was combined with erlotinib in the NCI-H1975 or NCI-H1993 cell lines (combination index, CI&lt;1). Conclusions: Entinostat enhances the effect of Cetuximab in vivo in Ras mutant, E-cadherin positive NSCLC cell lines, or erlotinib in cell lines harboring the EGFR mutation T790M or amplified MET. The combination of entinostat and EGFR inhibitors could provide the rational for developing clinical trials in patients with NSCLC with tumors resistant to EGFR inhibitors.

Control of Germline Stem Cell Division Frequency – A Novel, Developmentally Regulated Role for Epidermal Growth Factor Signaling

Exploring adult stem cell dynamics in normal and disease states is crucial to both better understanding their in vivo role and better realizing their therapeutic potential. Here we address the division frequency of Germline Stem Cells (GSCs) in testes of Drosophila melanogaster. We show that GSC division frequency is under genetic control of the highly conserved Epidermal Growth Factor (EGF) signaling pathway. When EGF signaling was attenuated, we detected a two-fold increase in the percentage of GSCs in mitotic division compared to GSCs in control animals. Ex vivo and in vivo experiments using a marker for cells in S-phase of the cell cycle showed that the GSCs in EGF mutant testes divide faster than GSCs in control testes. The increased mitotic activity of GSCs in EGF mutants was rescued by restoring EGF signaling in the GSCs, and reproduced in testes from animals with soma-depleted EGF-Receptor (EGFR). Interestingly, EGF attenuation specifically increased the GSC division frequency in adult testes, but not in larval testes. Furthermore, GSCs in testes with tumors resulting from the perturbation of other conserved signaling pathways divided at normal frequencies. We conclude that EGF signaling from the GSCs to the CySCs normally regulates GSC division frequency. The EGF signaling pathway is bifurcated and acts differently in adult compared to larval testes. In addition, regulation of GSC division frequency is a specific role for EGF signaling as it is not affected in all tumor models. These data advance our understanding concerning stem cell dynamics in normal tissues and in a tumor model.

Abstract 4157: DACH1 Inhibited proliferation and tumor growth of lung adenocarcinoma cells

Abstract Lung cancer is the leading cause of cancer death worldwide. A key driver to the proliferation of lung cancer includes increased activity of the gene encoding the epidermal growth factor receptor (EGFR) and mutation of K-ras oncogene. Target therapies through small molecules to inhibit the tyrosine kinase domain of EGFR (Gefitinib) or monoclonal antibody to EGFR (Cetuximab) have demonstrated clinical benefit. Unfortunately, development of resistance to those treatments occurs in most patients within one year. Studies of the hyperactive EGFR in drosophila identified a genetic inhibitor of EGFR signaling, known as dachshund (dac). Activate ras inhibits DACH1 expression in malignant peripheral nerve sheath tumor. Dachshund can activate or represses transcription, and regulates cell proliferation and differentiation in multiple context-dependent manners. Our studies have proved that DACH1, human homolog of dac, functions as a potential tumor suppressor of breast and prostate cancer. Expression of DACH1 is lost during cancer progression and re-expression of DACH1 gene inhibited cellular proliferation, migration and tumor formation. The expression levels and the role of DACH1 in lung cancer are largely unknown. As both EGFR and Ras signaling interact with DACH1, we hypotheses that loss of endogenous DACH1 may contribute to the lung tumorigenesis. The mRNA expression of DACH1 was decreased in lung adenocarcinoma compared with normal lung tissues. Ectopic expression of DACH1 by stably transduction inhibited cellular proliferation of lung cancer cell lines A549 and SKLU, cell cycle progression and clone formation rate in contact-dependent and -independent growth. ELISA using conditional medium from A549 cells expressing vector control or DACH1 demonstrated remarkable inhibition of secreting factors, such as CXCL1, CXCL2, CXCL5 and CXCL8. Those chemokines have already been proved to positively regulating angiogenesis and proliferation. To test in vivo tumorigenesis, 2x106 A549 cells expressing DACH1 or vector control were injected subcutaneously into nude mouse and tumor size was monitored weekly. Tumor growth was dramatically blocked by DACH1. Tumor weight was 297.8 ± 38.6mg for vector control and 31 ± 6.1mg for cells expressing DACH1(p value &amp;lt;0.001). Importantly, over-expression of CXCL5 can partly rescue tumor growth inhibition by DACH1 in A549 cells. Together, our study demonstrated that DACH1 is a potentially tumor suppressor of lung cancer though repression of chemokines secretion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4157. doi:1538-7445.AM2012-4157

Highlights of This Issue

Improving risk classification of children with neuroblastoma is an important challenge in pediatric oncology. Through one of the largest microRNA (miRNA) expression studies on cancer biopsies, De Preter and colleagues developed a 25-miRNA signature that identifies neuroblastoma patients with increased risk for adverse outcome. This classifier is independent of currently used risk factors and enables further patient stratification within the current highrisk subgroup. Importantly, the 25-miRNA signature performs equally well in archived formalin-fixed, paraffin-embedded material as it does in fresh frozen samples. Results were confirmed in 2 independent patient cohorts and indicate that use of the miRNA signature can substantially improve risk stratification of patients with neuroblastoma.The insulin-like growth factor 1 receptor (IGF-1R) is a potential new therapeutic target. Unfortunately, a suitable biomarker predictive for anti-IGF-1R therapy response is not available. Fleuren and colleagues investigated whether indium-111-labeled R1507 (111In-R1507) immuno-SPECT, a novel noninvasive, in vivo screening method to visualize membranous IGF-1R expression and accessibility, can be used to predict IGF-1R treatment response in Ewing sarcoma and osteosarcoma. This novel imaging technique could clearly distinguish among high, modest, and nonresponsive xenografts, whereas conventional techniques could not. This new technique may therefore enable the selection of patients susceptible to IGF-1R targeted therapy and monitor treatment response.Ever since its approval in 1976, dacarbazine has represented the standard of care for the treatment of patients with metastatic melanoma; however, only a minority of melanoma patients responds to dacarbazine treatment. This article presents clinical evidence that the combination of dacarbazine with the tumor-targeting immunocytokine L19-IL2 (a biopharmaceutical agent consisting of the human recombinant antibody L19, specific to the alternatively-spliced EDB domain of fibronectin, fused to human interleukin-2) is well tolerated in patients with metastatic melanoma and can induce long-lasting objective responses in a subset of patients.Examination of epidermal growth factor (EGFR) mutations is a diagnostic routine for treatment of lung cancer that involves the use of EGFR tyrosine kinase inhibitors. Because it is difficult to obtain primary lesions, especially in patients with progressive disease, a noninvasive procedure is desirable. Taniguchi and colleagues used BEAMing (beads, emulsion, amplification, and magnetics) to detect EGFR mutations in circulating tumor DNA. In addition to its high sensitivity, BEAMing can estimate the extent to which the activating mutation alleles have been converted into resistant alleles. Because BEAMing and next-generation sequencers are based on the same technologic principle, we can predict how next-generation sequencers will detect mutations in circulating tumor DNA based on the findings from this study.

Epidermal growth factor receptor gene mutations, amplification and clinicopathologic correlation in patients with lung cancer

To investigate the clinicopathological features of patients with lung cancers associated with epidermal growth factor receptor (EGFR) gene amplification and/or mutations. Mutations and amplification status of EGFR gene were detected by PCR-DNA sequencing and FISH, respectively, followed by subsequent clinicopathological correlative studies. Among 454 patients, the overall mutation rate of EGFR was 48.2% (219/454). The EGFR mutation rate in females was significantly higher than that of males, 59.6% (118/198) vs. 39.5% (101/256), P<0.001. The mutation rate of EGFR gene of non-smokers was higher than that of smokers, 52.7% (147/279) vs. 41.4% (72/175), P=0.017. The mutation rate in patients with adenocarcinoma was higher than that in patients with other cancer types, 56.8% (193/340) vs. 22.8% (26/114), P<0.05. Moreover, a significant difference of mutation rates among different subtypes of adenocarcinomas was found (P=0.001). Among 134 patients with available FISH analysis, no statistical significance of EGFR gene amplification was found in age, gender, histopathological types and subtypes of adenocarcinomas (P>0.05). There was a significant correlation between EGFR mutation and its gene amplification (P=0.0005), although with poor consistency (P=0.275). EGFR gene mutations occur more frequently in females, non-smokers and patients with adenocarcinoma subtype. A significant variation of the mutation types exits among the subtypes of adenocarcinoma. The presence of EGFR amplification appears not related to age, gender, histopathological types of lung cancer and subtypes of adenocarcinoma. There is a significant correlation between EGFR mutations and its gene amplification (P=0.0005), although with poor consistency.