CCR9 expression levels in psoriatic skin negatively correlates with clinical outcome to infliximab

Abstract Abstract 2609 Poster Board II-585 Defining specific subgroups within AML based on cytogenetic and molecular markers is crucial for diagnostic and prognostic purposes, as well as for adequate therapeutic decisions. Recently, we and others have reported mutations in a novel gene, TET2, that occur in a broad spectrum of myeloid neoplasms. Recent publications regarding the function of the TET protein family members implicate that these proteins play a role in epigenetic regulation of gene expression through DNA methylation, a process known to be disturbed in several hematological malignancies. Thus far, TET2 represents the most frequently mutated gene in myelodysplastic syndromes (26%), and mutations are also frequent in myeloproliferative disorders (12%), mastocytosis (30%), acute myeloid leukemia (10%) and chronic myelomonocytic leukemia (22%). The aim of this study was to define the incidence and clinical impact of TET2 mutations in acute myeloid leukemia patients who were treated uniformously within a defined clinical trial. In addition, we measured the mRNA levels of TET2 in patients with and without TET2 mutations, in order to establish whether the TET2 expression levels might correlate with clinical outcome. We performed direct DNA and/or RNA sequencing of the TET2 gene for mutation analysis and Q-PCR to measure mRNA expression levels. A cohort of up to 400 AML patients that was treated within the EORTC/GIMEMA AML-12/06991 trial was screened. In this trial newly diagnosed patients with AML between 15 and 60 years of age were included, with the exception of patients with acute promyelocytic leukemia. TET2 mutations were detected in 9% of the cases. Mutations were scattered along the whole coding region of the TET2 gene. In 12% of the cases, this led to a premature stop codon, in 24% to a frameshift and premature truncation of the reading frame, and in 60% to missense substitutions, clustering within the two conserved box 1 and box 2 regions of the TET2 gene. In one patient, a splice site mutation was found. TET2 mutations often co-occurred with other well-known mutations, including mutations in the nucleophosmin gene (NPM1), mutations of the fms-like tyrosine kinase 3 (FLT3), and the mixed lineage leukemia gene (MLL). Truncations in the TET2 gene co-occurred most frequently with mutations of NPM1 and FLT3. To determine the clinical significance of TET2 mutations, overall survival of TET2 mutated versus TET2 wild type patients was assessed. Analysis based on the first 224 AML patients showed a clear trend towards poor prognosis of patients carrying a TET2 mutation (p=0.065). So far, TET2 expression levels do not seem to correlate with clinical outcome. The multivariate analysis of the whole cohort will be presented. We conclude that TET2 represents a novel genetic marker that is mutated in approximately 10% of the cases of de novo AML and that in this patient category, mutation of TET2 correlates with poor clinical outcome. Disclosures: Muus: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Fcgammariib Expression As a Prognostic Marker in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v126.23.1727.1727 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1727-1727

Author(s):

Rosa Bosch ◽

Gerardo Ferrer ◽

Eva Puy Vicente ◽

Alba Mora ◽

Rajendra N. Damle ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Outcome ◽

B Cell ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Disease Stage ◽

Advanced Stage ◽

Fcγ Receptor ◽

Expression Levels

Abstract BACKGROUND The Fcγ receptor IIb (FcγRIIb) is an inhibitory Fcγ receptor that suppresses B-cell activation when coligated with B-cell antigen receptor (BCR). Previous studies from our group indicate that the ability of the FcγRIIb to inhibit BCR signaling after coligation is attenuated in Chronic Lymphocytic Leukemia (CLL). Furthermore, in contrast to what has been described in normal murine B-cells, stimulation of the FcγRIIb alone induces proliferation of CLL cells. However, the correlation between FcγRIIb expression, immunophenotypic characteristics, and clinical variables in patients with CLL has not been studied. AIM The aim of this study was to correlate the expression of FcγRIIb on leukemic cells from previously untreated CLL patients and its immunophenotypic features and clinical parameters. METHODS The study population included 112 patients with untreated CLL for whom cryopreserved peripheral blood samples were available before treatment. The diagnosis was based on IWCLL 2008 criteria. The median patients' follow up was 57.92 months (range: 2.23-439.78 months). FcγRIIb expression levels were determined by flow cytometry on CD5+/CD19+ CLL cells using a specific Alexa488-conjugated murine mAb specific for human FcγRIIb. The following combinations were assessed: FcγRIIb/CD38/CD19/CD5, FcγRIIb/CD49d/CD19/CD5, and FcγRIIb/CD69/CD19/CD5. Results were expressed as the ratio between the MFI for FcγRIIb and the MFI for the corresponding isotype (MFIR). FcγRIIb expression levels were correlated with: i) expression of CD49d, CD38 and CD69, ii) clinico-biological characteristics, and iii) clinical outcome. Differences of FcγRIIb expression on dichotomized clinicopathological variables were assessed with Mann Whitney test. Kaplan-Meier survival and Cox regression analysis were performed to evaluate the correlation of FcγRIIb expression with clinical outcome. Best cut-offs for overall survival (OS) and treatment-free survival (TFS) were determined by ROC curves. RESULTS All CD5+CD19+ leukemic cells samples expressed FcγRIIb. However, FcγRIIb expression levels markedly varied between patients (median MFIR: 45.8; interquartile range: 14.9-76.6; 5th -95th percentile: 17.15-111.4). FcγRIIb expression was significantly higher in patients who had high (≥30%) CD49d expression than in those with low (<30%) CD49d expression (p =0.009). No correlation was observed between FcγRIIb expression and age, disease stage, IGHV mutational status or chromosomal abnormalities analyzed by fluorescence in situ hybridization, ZAP70 and CD38. Furthermore, within individual clones, FcγRIIb expression levels were higher on CD38+ or CD49d+ cells than on CD38- or CD49d- cells, respectively (median MFIR: 49.05 vs. 36.72, p =0.001 for CD38+ vs. CD38- cells; and 58.87 vs. 35.55, p <0.001 for CD49d+ vs. CD49d- cells). In univariate analysis, low FcγRIIb expression levels (MFIR< 26.67) were associated with shorter OS (HR 4.01, 95%CI 1.15-13.90, p=0.029), together with older age, advanced stage, and expression of CD38 and CD49d. Advanced stage, unmutated IGHV, and CD38, CD49d and ZAP-70 expression were also associated significantly with shorter TFS. Thus, patients with higher levels of FcγRIIb had better survival than those with lower levels (Log rank test, p = 0.018). A multivariate analysis adjusted for FcγRIIb expression, age, disease stage, CD38, and CD49d identified older age (≥65 yrs) (HR 150.76, 95%CI 5.39-4212.42, p =0.003), low FcγRIIb expression (HR 111.91, 95%CI 6.71-1866.97, p =0.001), advanced stage (B/C) (HR 17.44, 95%CI 1.45-210.24, p =0.024) and CD38 expression (HR 5.02, 95%CI 1.01-25.18, p =0.050) as independent predictors for shorter OS. CONCLUSIONS In this study, FcγRIIb expression on leukemic cells from untreated patients with CLL was found to be an independent prognostic marker for OS, overcoming the prognostic value of CD49d, which is consistent with the key role of the FcγRIIb in the pathogenesis of CLL. Further analysis aimed at validating this observation and to better understand the functional cooperation of FcγRIIb with other molecules, particularly CD49d, are warranted. These studies could open a new venue in CLL treatment. Disclosures Gorlatov: MacroGenics: Employment. Sierra:Novartis: Research Funding; Celgene: Research Funding; Amgen: Research Funding.

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1073 ◽

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]

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RRM1 and BRCA1 mRNA expression levels and clinical outcome of advanced NSCLC patients treated with cisplatin-based chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8097 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8097-8097

Author(s):

C. Zhou ◽

S. Zhou ◽

L. Zhang

Keyword(s):

Clinical Outcome ◽

Mrna Expression ◽

Advanced Nsclc ◽

Response Rate ◽

Stage Iiib ◽

Expression Levels ◽

Platinum Based Chemotherapy ◽

Brca1 Mrna ◽

Nsclc Patients ◽

Mrna Expression Levels

8097 Background: Platinum-based chemotherapy is the standard treatment for advanced NSCLC patients. RRM1 and BRCA1 are important regulators of chemosensitivity of NSCLC. Methods: Stage IIIb/IV NSCLC patients were given cisplatin-based chemotherapy based upon expression levels of RRM1 and BRCA1 mRNA in the tumor. Expression levels of the two genes were determined by real-time PCR and cut-off points were reported in our previous study. The patients with low expression of RRM1 were treated with gemcitabine/cisplatin up to 4 cycles. The others were treated with vinorelbine or paclitaxel plus cisplatin up to 4 cycles. After the chemotherapy, the patients were followed every 6 weeks up to disease progression and then every 3 months up to death. Results: 90 chemonaive, stage IIIB/IV, PS 0–1 NSCLC patients were enrolled. Age 60 (40–78) yrs old, male/female: 73/27%; adenocarcinoma/squamous/adeno-squamous/undefined NSCLC: 49/33/11/7%;,stage IIIb/IV: 13/87%. Overall response rate was 41.1%, stable disease 42.2%, progressive disease 16.7%. Disease was not progressive in 33 patients. Median TTP was 5 months. Response rate and TTP were better in those with low RRM1 expression ( Table ). Toxicity of the chemotherapy was acceptable. Overall survival will be reported in the conference. Conclusions: RRM1 and BRCA1 mRNA expression levels in non-small cell lung cancer are associated with clinical outcome to cisplatin-based chemotherapy. Prospective studies are ongoing to evaluate the role of the two genes in tailoring chemotherapy in our center. [Table: see text] No significant financial relationships to disclose.

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Molecular determinants of capecitabine efficacy in colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3606 ◽

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]

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

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4113 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4113-4113 ◽

Cited By ~ 1

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.

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EGFR ligands and ERCC1 mRNA expression to predict clinical outcome in Japanese (JPN) patients (pts) with metastatic colorectal cancer (mCRC) harboring overexpressed EGFR and KRAS exon 2 wild-type (KRAS wt) treated with cetuximab (cet) plus oxaliplatin-based chemotherapy (JACCRO CC-05/06 AR).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.618 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 618-618

Author(s):

Yu Sunakawa ◽

Wataru Ichikawa ◽

Akihito Tsuji ◽

Miriana Moran ◽

Stephanie H. Astrow ◽

...

Keyword(s):

Clinical Outcome ◽

Mrna Expression ◽

Progression Free Survival ◽

Chi Square ◽

Exon 2 ◽

Predictive Values ◽

Expression Levels ◽

Egfr Ligands ◽

Modified Folfox6 ◽

Ercc1 Expression

618 Background: Previous studies have reported that EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), are potential predictive markers for cet and high ERCC1 expression is associated with resistance to platinum-containing chemotherapy. However, there are still few studies to assess predictive values of these expression levels in JPN mCRC pts. The aim of this study was to evaluate the values in JPN mCRC pts treated with cet. Methods: This study enrolled 77 pts with tissue available from 2 prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Total RNA isolated by macro-dissection from tissue was screened by RT-PCR for mRNA expression levels of AREG, EREG, and ERCC1, the cut-off values of which were based on the optimal cut-off value using the maximal chi-square approach on tumor response with adjusted p values. The same cut-off values were used to evaluate associations with progression-free survival (PFS) and overall survival (OS). Results: Median age and follow-up time were 63 (range: 39-79) years old and 24.7 (range: 5.5-39.3) months, respectively. In 73 evaluable pts, response rate (RR) was 77 % (95% CI, 67 to 86), but no significant association was seen in RR. Pts with high AREG expression (>1.59) had significantly longer PFS (11.6 vs. 6.6 months, HR: 0.53, logrank p=0.047) but not OS in 67 assessable pts. Pts with low ERCC1 expression (≤1.35) had significantly longer OS (42.8 vs. 22.0 months, HR: 2.46, logrank p=0.014) but a trend toward longer PFS (11.6 vs. 8.9 months, HR: 1.63, logrank p=0.092) in 68 assessable pts. On the other hand, high EREG expression (>3.21) was not associated with clinical outcome in 64 assessable pts. Conclusions: Our study identified predictive roles for AREG and ERCC1 mRNA expression in JPN mCRC pts treated with cet plus oxaliplatin. However, extended RAS mutations analysis is warranted (UMIN000010635).

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