cMET expression in HER2+ MBC patients with first-line lapatinib (L) treatment

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1073-1073
Author(s):  
Y. Liu ◽  
L. Liu ◽  
H. Shi ◽  
J. G. Greger ◽  
K. D. Jackson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Los Angeles ◽  
Clinical Outcome ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Combination Study ◽  
Her 2

1073 Background: Overexpression of MET correlates with poor prognosis in breast cancer (Garcia et al., 2007) and is a factor associated with decreased sensitivity to L in HER2+ breast tumor cell lines in vitro (Liu et al., submitted). To test whether MET expression was associated with resistance to L in the clinic we evaluated baseline tumor MET expression levels and clinical outcome to L in 64 patients who participated in the EGF20009 trial of monotherapy L as first-line treatment in HER2+ advanced or MBC. Methods: RNA was extracted from FFPE tumors and MET and HER-2 gene expression was measured by qRT-PCR (Response Genetics, Inc., Los Angeles, CA). The correlation between expression levels of MET, HER2, and clinical outcome (overall response and progression free survival) was performed using JMP software. Results: A trend towards an association with increased MET expression and decreased response (p < 0.054) was observed.. Patients with high HER2 and low MET gene expression had the longest PFS (median difference = ∼9 weeks) compared to patients with low HER2 and high MET gene expression (p < 0.0038). Conclusions: These data support investigating a combination study of L and GSK1363089, a multi-kinase MET inhibitor, in HER2+ BC patients with high MET gene expression. [Table: see text]

Molecular determinants of capecitabine efficacy in colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3606-3606
Author(s):  
D. Vallbohmer ◽  
H. Kuramochi ◽  
D. Shimizu ◽  
K. D. Danenberg ◽  
J. N. Nielsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Single Agent ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Expression Levels ◽  
Cox 2 ◽  
Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

Molecular markers associated with response and clinical outcome to cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer (BOND2)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4113-4113 ◽  
Author(s):  
M. Azuma ◽  
D. Yang ◽  
M. Carpanu ◽  
E. Hollywood ◽  
M. Lue-Yat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Molecular Markers ◽  
Clinical Outcome ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Cart Analysis ◽  
Group I

4113 Background: Phase II (BOND2) trial of Cetuximab/Bevacizumab/Irinotecan (CBI) vs Cetuximab/Bevacizumab (CB) has shown that bevacizumab added to the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested whether expression levels of genes involved in angiogenesis (VEGF, IL-8), the EGFR pathway (EGFR, COX2) and DNA repair (ERCC1) are associated with clinical outcome. Patients and Methods: This randomized phase II trial enrolled 81 patients. Treatment plan as: Arm A received IRI at the same dose and schedule as last received prior to study, plus Cetuximab 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bevacizumab 5 mg/kg given every other week. Arm B received the same as arm A, but without IRI. FFPE samples for 35 out of 81 patients (M:W 24:11, median age 56 (29–80) enrolled in the BOND2 study were tested. Patients received either with CBI (n=18, Arm A) or with CB (n=17, Arm B). FFPE tissues were dissected using laser-captured microdissection and analyzed EGFR, ERCC1, VEGFA, VEGFR2, COX2, Cyclin D1, IL-8, and NRP1 mRNA expression using a quantitative real-time RT-PCR. Gene expression values are expressed as ratios between the target gene and internal reference gene. Results: All eight genes and treatment arm were considered in the CART analysis. The classification tree for response, progression-free survival, and overall survival are evaluated. The expression levels of VEGFR2 and NRP1 classified patients in 3 response groups with response rate range from 61% to 0%. Patients who were classified as responders (Group I; VEGFR2=0.65 and NRP1<2.285) were at a lower risk for progression, compared with patients who were classified as non- responders (Group II; VEGFR2=0.65 and NRP1=2.285 and Group III; VEGFR2<0.65). The expression levels of NRP1 and ERCC1, and EGFR and VEGFR2 were chosen to classify patients into 3 groups with distinct risk of progression-free survival and overall survival, respectively. Conclusion: These data suggest that gene expression levels may be molecular markers of response for patients with mCRC treated with CBI or CB. Prospective studies are needed to validate these preliminary findings. No significant financial relationships to disclose.

MDR1 Gene Expression Predicts Response and Progression-Free Survival Of Ph+ CML Patients On Second-Line Nilotinib Therapy After Imatinib Failure - 4-Year Follow-Up

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1494-1494
Author(s):  
Mridul Agrawal ◽  
Benjamin Hanfstein ◽  
Philipp Erben ◽  
Dominik Wolf ◽  
Thomas Ernst ◽  
...  
Keyword(s):  
Gene Expression ◽  
Research Funding ◽  
Progression Free Survival ◽  
Mdr1 Gene ◽  
Imatinib Resistance ◽  
Free Survival ◽  
Mdr1 Gene Expression ◽  
Mdr1 Expression

Abstract Introduction The activity of the drug efflux transporter protein MDR1 reduces the intracellular concentration of nilotinib and thereby impairs its efficacy. Nilotinib has been shown to be efficacious in imatinib-resistant patients. In the face of competing second-generation tyrosine-kinase inhibitors (TKI), early identification of favorable responders is crucially important. We have reported the unexpected positive prognostic impact of high MDR1 gene expression at time of imatinib resistance for subsequent 2nd line nilotinib treatment. Here, we present (i) a 48-month follow-up of our clinical data and (ii) additional functional analyses studied in an established in vitro, transposon-based vector system with stable siRNA mediated knockdown of MDR1. Aim We sought to assess (i) whether high MDR1 expression remains associated with improved cumulative rates of major molecular remission (MMR), complete cytogenetic remission (CCyR) and patients’ outcome (progression-free survival, PFS) after 48 months and (ii) the impact of MDR1 expression on nilotinib in vitro sensitivity. Methods (i) We analyzed 83 patients resistant to imatinib frontline treatment in chronic phase CML treated with nilotinib 400 mg bid within the CAMN107A2101 trial. MDR1 and BCR-ABL mRNA expression levels were determined by qRT-PCR using LightCycler™ technology, normalized against beta-glucuronidase (GUS) and standardized according to the international scale (IS). Log-rank tests were performed to compare PFS and the cumulative incidences (CI) of MMR and CCyR at 48 months. (ii) MDR1high overexpressing (K562-DoxH1) and MDR1low knockdown (K562-DoxMM) cell lines were used for in vitro testing (Rumpold et al., Exp Hematol 2005). Results (i) (a) At 24 and 48 months, patients with MDR1/GUS ratios ≥2.0 attained MMR in 39% and 41%, CCyR in 58% (at both time points), and PFS rates of 75% and 67%, whereas patients with initial MDR1/GUS ratios <2.0 had significantly worse response and PFS rates, i.e. MMR in 13% and 16% (p=0.014), CCyR in 35% and 39% (p=0.044), and PFS of 50% and 46% (p=0.032). (b) BCR-ABL tumor burden prior to nilotinib revealed a significant impact on molecular response rates. BCR-ABLIS <28% separated best concerning cumulative incidences of MMR by 24 and 48 months (41% vs 21% and 48% vs 21%, p=0.009). (c) Nilotinib in vitro sensitivity of BCR-ABL kinase domain mutations at time of imatinib resistance was associated with improved PFS under nilotinib therapy: patients without any mutation showed PFS rates of 71% and 63% at 24 and 48 months, whereas those with either sensitive mutations, intermediately sensitive mutations or mutations with unknown IC50attained PFS rates of 67% and 61%; patients with mutations resistant to nilotinib achieved PFS rates of 23% at both time points (p=0.01). (ii) Even though MDR1high K562 cells are less sensitive than MDR1low expressing cells, nilotinib (applying doses from 0.01 µM up to 0.5 µM) was still able to significantly impede proliferation of both MDR1high and MDR1low, whereas imatinib-mediated growth inhibition was only seen in MDR1low, but not in MDR1highcells. Conclusion (i) At the time of imatinib-resistance, a high MDR1 gene expression predicts favorable MMR, CCyR, and PFS on consecutive 2nd line nilotinib treatment. As shown earlier, single nucleotide polymorphisms (SNPs) within MDR1 (1236CT/TT and 2677GT/TT) were significantly associated with higher MDR1 expression. (Agrawal et al., ASH 2010) (ii) Our functional data support our clinical observation that nilotinib remains efficacious in MDR1 overexpressing cells, whereas even dose-escalated imatinib does not reverse resistance. High MDR1 gene expression might select patients whose mode of resistance is essentially determined by increased efflux activity of MDR1 and not by other pathways of resistance that cannot be overcome by nilotinib. Altogether, our data might be used for the clinical risk stratification in case of imatinib resistance before switching to nilotinib and are undergoing prospective validation within the ENEST1st study. Disclosures: Saussele: Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Purkayasatha:Novartis: Employment. Woodman:Novartis: Employment. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

Analysis of the ETS Family Member Genes ERG, ETS2, ETS1 and FLI1 in Acute Myeloid Leukemia (AML) Patients with Normal Cytogenetics: Expression Levels and Impact On Clinical Outcome. A Study of the AMLSG.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1600-1600 ◽  
Author(s):  
Verena I. Gaidzik ◽  
Cailian Wang ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Peter Paschka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Clinical Outcome ◽  
Treatment Protocols ◽  
Ets Transcription Factors ◽  
Free Survival ◽  
Expression Levels ◽  
Ets Family ◽  
Multivariable Analyses ◽  
Normal Cytogenetics

Abstract Abstract 1600 Poster Board I-626 Background The V-ets erythroblastosis virus E26 (ETS) oncogene family is one of the largest families of transcription factors. ETS transcription factors are characterized by two major functional domains, a transcription domain and an evolutionarily highly conserved DNA-binding domain, also known as ETS domain that mediates binding to purine-rich DNA sequences. Most ETS family proteins are nuclear targets for activation of the Ras-MAP kinase signalling pathway. Therefore, they play a significant role in regulating cellular functions such as cell growth, apoptosis, development and differentiation. ETS transcription factors have been implicated in leukemia by chromosomal rearrangement, and more commonly by gene amplification and/or overexpression. Moreover, overexpression of ERG was shown to be an adverse predictor for clinical outcome in AML with normal cytogenetics (CN). In our recent study on complex karyotype AML, array-CGH (comparative genomic hybridization) analysis identified small genomic amplifications affecting ERG/ETS2 in 21q22 and ETS1/FLI1 in 11q23 in about 10% of the cases. Correlation with global gene expression profiling showed that ERG and ETS2 as well as ETS1 and FLI1 were overexpressed in these cases. Aims: To evaluate expression levels of ERG, ETS2, ETS1 and FLI1 in a large cohort of younger (16 to 60 years of age) adult CN-AML patients (pts) and their impact on clinical outcome. Methods The expression of ERG, ETS2, ETS1 and FLI1 was determined by quantitative real-time reverse transcriptase polymerase chain reaction (qPCR) assay in 343 CN-AML pts who were entered on 3 AMLSG treatment protocols (AMLHD93, AML HD98-A, AMLSG 07-04). ERG, ETS2, ETS1, and FLI1 were dichotomized into two major groups according to their expression levels. The upper quartile was chosen as the cut point and the set of patients with gene expression above were defined as Q4 group. Univariable as well as multivariable regression models were used to evaluate the influence of ERG, ETS2, ETS1 and FLI1 on induction success, event-free, relapse-free and overall survival. Multivariable analyses were stratified for AMLSG treatment protocols. Results Partial correlation analysis revealed positive correlations of expression levels between ETS2 and ERG (ρ=0.45) being the strongest, followed by ERG and FLI1 (ρ=0.4), as well as ETS1 and FLI1 (ρ=0.31). Correlation of ERG, ETS2, ETS1 and FLI1 with white blood count (WBC) revealed a significant association between high gene expression (Q4) and elevated WBC (ERG, p=0.004; ETS2, p=0.002, FLI1 p<0.001), whereas high expression of ETS1 was associated with a significantly lower WBC (p<0.001). Univariable as well as multivariable analyses on induction success revealed high ETS2 as an unfavourable marker (OR, 0.29, p=0.01). In univariable analysis, there was a significantly inferior relapse-free survival (RFS) and overall survival (OS) for high ERG (p=.01; p=.06, respectively) and high ETS2 (p=.002; p=.03, respectively) that was even more pronounced when both ERG Q4 and ETS2 Q4 (ERG Q4 ∩ ETS2 Q4) (p<0.001; p=.001, respectively) were included as one variable and compared with the rest. In multivariable analysis for the endpoints event-free survival (EFS), RFS and OS, a significant effect was found for RFS for ERG Q4 ∩ ETS2 Q4 (p=.002); the only significant variables that consistently appeared in the model were NPM1mut, FLT3-ITDpos and WBC. In subgroup analysis for the genotypes CEBPAmut, NPM1mut/FLT3-ITDneg, and all others (NPM1mut/FLT3-ITDpos, NPM1wt/FLT3-ITDpos, NPM1wt/FLT3-ITDneg) according to the hierarchical model, ERG Q4 was associated with an inferior EFS (p=.04) and OS (p=.03) in the favorable CEBPAmut genotype and became even more significant for the variable ERG Q4 ∩ ETS2 Q4 (EFS, p=.007, RFS, p=.002; OS, p=.06, respectively). For the NPM1mut/FLT3-ITDneg subgroup, again ERG Q4 ∩ ETS2 Q4 was associated with an adverse RFS (p=.04), but not with OS (p=0.07). Conclusions In our study on a large cohort of homogenously treated CN-AML patients, ERG and ETS2 expression were highly correlated. Overexpression of both genes had a significant impact on clinical outcome of CN-AML patients. Moreover, adverse effects of high ERG and high ETS2 expression on prognosis were also shown for the genetic AML subgroups CEBPAmut and NPM1mut/FLT3-ITDneg. Disclosures No relevant conflicts of interest to declare.

Stratification Of CLL By ZAP-70 Expression: Analysis Of Samples From The ECOG-Led Intergroup Trial E2997

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4116-4116
Author(s):  
David Kaplan ◽  
Zhuoxin Sun ◽  
Martin S. Tallman ◽  
Ian W. Flinn ◽  
Wenbin Xiao ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Prognostic Information ◽  
Apoptotic Pathway ◽  
Free Survival ◽  
Expression Levels ◽  
Flow Cytometric ◽  
Low Levels ◽  
Molecular Expression

Abstract Background ZAP-70 expression has been used as a negative prognostic indicator for patients with chronic lymphocytic leukemia (CLL) (N Engl J Med 2003;348:1764; N Engl J Med 2004;351:893); however, its usefulness as a clinical test has been undermined by technical difficulties relating to the subjective cut-off threshold for positivity. In fact, analyses of samples from CLL patients enrolled in the US Intergroup Phase III trial, E2997, by standard procedures did not result in ZAP-70 (or any other analyte) providing significant prognostic information. We have previously developed a powerful flow cytometric amplification system to assess many important intracytoplasmic molecules including signaling and apoptotic pathway components. We hypothesized that the technology could reveal previously hidden relationships between outcome and molecular expression. Methods We analyzed 79 blood and marrow samples from CLL patients enrolled in the E2997 trial for the expression of ZAP-70 and 28 other analytes. The 28 other analytes included mostly signaling pathway molecules and apoptotic pathway components. Molecular expression levels determined by flow cytometry were analyzed for their relationship to the clinical data. CD19+ B lymphocytes from 42 healthy volunteers were also assessed as a comparison group. Results We found that CLL samples could be clearly stratified by ZAP-70 expression with a distribution having a peak-trough-peak configuration (Figure). In this way, a definitive threshold was obtained by using the trough as the cut-off. Interestingly, ZAP-70 expression in B cells from healthy persons was unimodal and it peaked in the trough of the distribution of the CLL samples (Figure). Using the ZAP-70 expression trough as a cutoff, unlike the E2997 study, we could delineate patient populations with distinct progression-free survival (p < 0.001) and overall survival (p = 0.004). Moreover, by multivariate analysis ZAP-70 expression was found to be an independent variable (p = 0.01) relating to progression-free survival along with 17p deletion and Rai staging. By assessing the expression levels of the other 28 analytes stratified by ZAP-70 expression, we found statistically significant differences in 10 molecules which included phosphoantigens representing activation levels of various signaling pathways and apoptotic pathway constituents. These findings suggest that ZAP-70 stratification defines 2 distinct types of CLL cells. Besides expression, we found highly significant levels of bivariate correlations between expression levels of the molecules examined including over 30 with correlation coefficients of 0.85 or greater. Interestingly, the correlations varied according to ZAP-70 expression. In samples with high levels of ZAP-70 expression, ZAP-70 was correlated with 13 other analytes with r > 0.5 whereas phospho-ZAP-70 was only correlated with 1 other analyte with the 0.5 threshold. Conversely, in samples with low levels of ZAP-70, phospho-ZAP-70 was correlated with 12 other molecules with r > 0.5 whereas ZAP-70 was correlated with no other analytes. An example showing that ZAP-70 was strongly correlated with Mcl-1 in samples with high levels of ZAP-70 but not in samples with low levels is presented below in the figure. The differential intermolecular relationships seen by ZAP-70 stratification support the possibility that ZAP-70 expression defines 2 different types of CLL cells with clinical outcome implications. Conclusions Our study has uncovered highly significant differential expression levels, intermolecular associations, and organization in CLL samples stratified by ZAP-70 expression. Since stratification by ZAP-70 gave significant prognostic information, we propose that our flow cytometric amplification technology permits characterization of the distinct molecular constitution of the 2 types of CLL cells and provides us with a unique opportunity to understand how the composition of leukemic cells translates into clinical outcome. Additionally, these data provide clues for the development of novel therapies. Disclosures: Kaplan: Pathfinder Biotech: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding. Kaye:Pathfinder Biotech: Employment.

Large-Scale High Resolution Integration of Copy Number and Gene Expression in DLBCL Reveals Focal and Frequent Deletions in Chromatin Modifying Genes with Outcome Correlation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 295-295
Author(s):  
Fong Chun Chan ◽  
Susana Ben-Neriah ◽  
Raymond Lim ◽  
Sandy Hu ◽  
Sanja Rogic ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Clinical Outcome ◽  
Copy Number ◽  
Large Scale ◽  
Progression Free Survival ◽  
Rna Seq ◽  
Free Survival ◽  
Modifying Genes ◽  
Genomic Aberrations

Abstract Abstract 295 Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma (NHL), accounting for approximately 30–40% of all new lymphoma cases. While standard therapy using rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has significantly increased the survival of DLBCL patients, approximately one third of DLBCL patients still remain unresponsive to or relapse after standard treatment. Further investigation into the genomic architecture of DLBCL will contribute to elucidating the causes of the poor outcomes in this subgroup of patients. While the copy number and the gene expression profiles of DLBCL specimens have been well described as separate analyses, a large-scale high resolution integration of both orthologous measurements has yet to be reported. The integration of these two data types in a clinically well-annotated cohort of DLBCL is crucial as it can potentially distinguish driver from passenger genomic aberrations and reveal associations with clinical outcome. Methods and Patients: Affymetrix SNP 6.0 microarrays were used to ascertain the copy number profiles in 151 pretreatment biopsies of DLBCL that were representative of the population of DLBCL patients treated at the British Columbia Cancer Agency. Clinical outcome data were available for all 151 patients with 142 patients receiving R-CHOP or R-CHOP-like treatment. Matching RNA-seq libraries were used to quantitate the gene expression levels in 91 samples. The SNP 6.0 pre-processing method cRMAv2 was used to generate raw probe intensities that were then normalized to 1258 HapMap3 SNP 6.0 arrays. Copy number state calls were predicted using HMM-Dosage. RNA-seq data were aligned using the split-read aware aligner GSNAP and gene expression values were generated using the metric reads per kilobase of transcript per million mapped reads. DriverNet analyses were utilized to predict functionally relevant driver genes and outcome correlations in R-CHOP treated patients were performed using Cox regression and the log-rank test. Results: The copy number landscape derived from the SNP 6.0 microarrays revealed previously reported large scale chromosomal deletions in chromosome 6p and amplifications in chromosomes 3, 7 and 18. By integrating the gene expression with copy number data, we found that gene copy number was correlated with its own gene expression (classified as being cis-correlated) in 23.5% of genes. In addition, we investigated copy number aberrations which were highly correlated with gene expression across the genome (classified as trans-correlated). This analysis revealed aberration hotspots in genomic locations 3q26-q28 (TBL1XR1, BCL6, TP63), 17p12 (NCOR1, MAP2K4), 18q11.1-q11.2 (RBBP8) and 22q11.21 (BID, IL17RA) suggesting that these hotspots regulate important pathways that may contribute to the pathogenesis of DLBCL. We identified previously reported focal amplifications (e.g. REL) and deletions (e.g. B2M, CDKN2A). Moreover, we identified novel focal deletions, including homozygous deletions, in chromatin modifying genes: LCOR (7.9%), RCOR1 (9.9%), and NCOR1 (17.9%), all of which were cis-correlated and were validated using fluorescence in situ hybridization. DriverNet analyses identified RCOR1 deletions as one of the main driver alterations. RCOR1 deletions were also found to be associated with progression-free survival (5-year progression-free survival: deleted 40% vs. non-deleted 75%, p=0.0188). Discussion: Our systematic integration of SNP 6.0 and RNA-seq data confirmed findings of previous studies and also revealed novel genomic aberration hotspots and highly focal and frequent deletions in chromatin modifying genes. Results derived from our large-scale high resolution data set indicate the feasibility and efficacy of integrative genomic analyses in revealing novel and pathogenetically relevant genomic aberrations in lymphoid cancers. The discovery of the association of RCOR1 deletions with progression-free survival suggests that RCOR1 deletions could be used as a prognostic marker and might indicate a molecular phenotype that can be targeted by novel therapeutic agents in DLBCL. Disclosures: No relevant conflicts of interest to declare.

High prognostic potential of glioblastoma stem cell analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10580-10580
Author(s):  
G. L. Banna ◽  
R. Pallini ◽  
L. Ricci-Vitiani ◽  
M. Signore ◽  
D. Lombardi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Clinical Outcome ◽  
Prognostic Value ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Free Survival ◽  
Long Term Culture ◽  
Cd133 Expression

10580 Background: Cancer stem cells (CSCs) are a rare cell population responsible for tumor development and maintenance. Recent studies have shown that glioblastoma stem cells express the CD133 marker and are resistant to radiotherapy and chemotherapy. However, clinical data based on the study of CSCs in patients with glioblastoma are not available yet. Methods: Glioblastoma samples from 44 patients treated with complete or partial tumorectomy, followed by radiotherapy and temozolomide were prospectively analyzed. Immunohistochemistry was performed to evaluate the prognostic value of the number of CD133+ cells present in tumors. Moreover, the relationship between the ability to generate long-term culture of tumorigenic cells in vitro and the clinical outcome of glioblastoma patients was tested. Results: CD133 expression did not show an overall prognostic value. CSC cultures were obtained from 14 of the 44 tumors (32%). The generation of CSCs emerged as significant independent prognostic factor by the Cox multivariate analyses, with an adjusted hazard ratio of 2.50 (95% CI, 1.04 to 6.06; P=0.004). The median overall survival among patients with tumors generating CSCs was 8.0 months (95% CI, 4.0 to 11.5), as compared with 15 months (95% CI, 11.0 to 19.0) among those without generation of CSCs (P=0.0002). The median progression-free survival was 3.5 months (95% CI, 2.0 to 6.0) for glioblastoma generating CSCs and 9.0 months (95% CI, 7.0 to 12.0) for glioblastoma not generating CSCs (P=0.0001). A higher CD133 expression significantly associated with tumors generating CSCs (P=0.006), and correlated with a higher risk of death in patients with tumors generating CSCs in vitro (hazard ratio of 1.65, 95% CI, 1.05 to 2.60; P=0.0285). Conclusions: Generation of long-term culture of tumorigenic CSCs in vitro from glioblastoma predicts a poor clinical outcome for patients, in terms of both overall and progression-free survival. In tumors generating CSCs, CD133 expression may have a prognostic value. No significant financial relationships to disclose.

Wt Kras and gene expression levels of VEGFR2, EGFR, and ERCC-1 associated with progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4056-4056
Author(s):  
A. B. El-Khoueiry ◽  
A. Pohl ◽  
K. Danenberg ◽  
J. Cooc ◽  
W. Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kras Mutation ◽  
Chemokine Receptors ◽  
Progression Free Survival ◽  
Vegf Receptor ◽  
First Line ◽  
Tissue Samples ◽  
Expression Levels ◽  
Kras Status ◽  
Gene Expression Levels

4056 Background: While wild type (wt) Kras is associated with improved outcome to anti-EGFR therapy in pts with mCRC, there are no identified predictors of outcome for FOLFOX/BV. We evaluated Kras status and expression of genes involved in angiogenesis, DNA repair and 5-FU metabolism in 68 patients treated with FOLFOX/BV or XELOX/BV. These genes included VEGF, VEGF-receptor 2 (KDR), Cox-2, IL 6 and 8, chemokine-receptors 1 & 2, EGFR and ERCC-1. Methods: Tissue samples from 68 patients with mCRC were analyzed. mRNA was extracted from laser-capture-microdissected tumor tissue. cDNA was prepared by reverse transcription and quantitation of the candidate genes was performed using a fluorescence- based real-time detection method (TaqMan). Allele specific RT-PCR was performed to determine Kras mutation status in codons 12 and 13. Results: There were 68 pts (38 males, 30 females), median age: 56 years (range 29–81). All received first line 5FU, oxaliplatin and BV (28 FOLFOX/BV, 40 XELOX/BV). Radiologic response: 1 CR, 39/68 (57%) PR, 27/68 (40%) SD, and 1 PD. Median OS is not reached. At a median follow-up of 32.0 months (mo) (range: 2.3–47.8 mo), the median PFS was 12.4 mo (95% CI: 9.8–15.2). Kras mutation was identified in 39 pts (57%). RR was 64% in pts with wt Kras and 52% in pts with mutant Kras (p=0.33). PFS was significantly longer for pts with wt kras compared to pts with mutant kras (13.7 mo [95% CI: 6.9–13.2] versus 8.3 mo [95%CI: 6.9–13.2], P=0.039). High EGFR (median PFS: 15.2 mo; 95% CI 11.7–16.5 mo), high VEGFR2 (median PFS: 13.9 mo; 95% CI 11.0–16.5 mo), and low ERCC1 (median PFS: 12.4 mo; 95% CI 10.9–16.4 mo) were associated with longer PFS compared to low EGFR (median PFS: 7.9 mo; 95% CI 6.9–11.0 mo, P=0.040), low VEGFR2 (median PFS: 7.2 mo; 95% CI 6.5–8.1 mo, P=0.032), and high ERCC1 (median PFS: 9.6 mo; 95% CI 5.8–15.2 mo, P=0.045). Conclusions: To our knowledge, this is the first report of a potential association between Kras status as well as gene expression levels of VEGFR2, ERCC-1 and EGFR and clinical outcome to FOLFOX/BV therapy in pts with mCRC. Prospective clinical trials are needed to validate these results. [Table: see text]

scholarly journals The Plasticity of CD4+CD25+FOXP3+CD127low T Cells in Patients with Metastatic Renal Cell Carcinoma in the Course of Interferon-Alpha Immunotherapy

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Maria S. Sayapina ◽  
Svetlana N. Bykovskaia
Keyword(s):  
Progression Free Survival ◽  
Serum Levels ◽  
Treg Cells ◽  
First Line ◽  
Initial Value ◽  
Free Survival ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Start

Aims. To examine changes in subpopulation of CD4+CD25+Foxp3+CD127low T lymphocytes (Treg) and their association with the efficiency of the IFN-α therapy. Materials and Methods. Pts with mRCC who had undergone nephrectomy were treated with IFN-α at a dose of 6×106 U/day three times a week (n = 18). An immunophenotypic analysis of lymphocytes in peripheral blood expressing CD4, CD25, CD127, and Foxp3 antigens could be performed in 18 pts before, 2 weeks, and 2 mo after IFN-α therapy and 22 normal volunteers. Blood samples were collected at baseline and 2 mo after treatment start. Serum levels of TGF-β1, IL-17A, and Epo were measured by ELISA. Results. PR was achieved in 3 (16.6%) pts who received first-line therapy. Long-lasting SD (≥6 months) was noted in 6 (33.3%) pts. The median progression free survival (PFS) was 4 mo (95% CI: 2-NE). The study of the population of Treg indicated that there were no significant differences in the groups depending on the effect (p = 0.71). In one patient, the reduction of Treg cells was associated with increased TGF-β and IL-17 levels, whereas in other two pts the increase in Treg cells was associated with decreased TGF-β and IL-17 levels. The endogenous levels of Epo did not show significant correlation with response to IFN-α immunotherapy. In the patient subgroup with an initial value of MCH > 31 pg, the median PFS was not achieved, but in the subgroup with an initial value of MCH < 31 pg, the median PFS was 2 months (p = 0.032). Conclusions. In our study, we have described functional plasticity of Treg cells, which prevents them from being used as a prognostic marker. The conversion of Treg cells into Th17 can serve as a basis for the development of a new specific immunotherapeutic method in oncology after confirmation in the experiment in vitro. Given the small dataset, the results will need further validation.

Immediate and long-term results of the first line chemotherapy in patients with metastatic triple negative breast cancer. Final analysis of randomized study

2020 ◽  
pp. 75-80
Author(s):  
S.A. Lyalkin ◽  
◽  
L.A. Syvak ◽  
N.O. Verevkina ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Randomized Study ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Group 2 ◽  
Line Chemotherapy ◽  
Group 1

The objective: was to evaluate the efficacy of the first line chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Materials and methods. Open randomized study was performed including 122 patients with metastatic TNBC. The efficacy and safety of the first line chemotherapy of regimens АТ (n=59) – group 1, patients received doxorubicine 60 мг/м2 and paclitaxel 175 мг/м2 and ТР (n=63) – group 2, patients received paclitaxel 175 мг/м2 and carboplatin AUC 5 were evaluated. Results. The median duration of response was 9.5 months (4.5–13.25 months) in patients received AT regimen and 8.5 months (4.7–12.25 months), in TP regimen; no statistically significant differences were observed, р=0.836. The median progression free survival was 7 months (95% CI 5–26 months) in group 1 and 7.5 months (95% CI 6–35 months) in group 2, p=0.85. Both chemotherapy regimens (AT and TP) had mild or moderate toxicity profiles (grade 1 or 2 in most patients). No significant difference in gastrointestinal toxicity was observed. The incidence of grade 3–4 neutropenia was higher in patients of group 2 (TP regimen): 42.8% versus 27% (р<0.05). Conclusions. Both regimens of chemotherapy (AT and TP) are appropriate to use in the first line setting in patients with metastatic TNBC. Key words: metastatic triple negative breast cancer, chemotherapy, progression free survival, chemotherapy toxicity.

Sign in / Sign up

Export Citation Format

Share Document