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T. Mitsudomi

Moderator of

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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 8
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      O01.01 - Genetic polymorphisms of inflammatory and DNA repair pathways, radiation-related esophagitis and pneumonitis in definitive chemoradiation treated non-small cell lung cancer patients. (ID 2997)

      10:30 - 12:00  |  Author(s): K. Barrett, J. Xu, K.S. Woon, K. Boyd, D. Cheng, Z. Chen, A. Bezjak, A. Sun, A. Hope, J. Cho, E.P. Saibishkumar, N. Leighl, F. Shepherd, W. Xu, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      The benefits of concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) are tempered by treatment toxicity. Germline genetic variants have been associated with intrinsic radiosensitivity and radiotoxicity in various cancer settings. We investigated whether variants in genes involved in inflammation response and DNA repair pathways independently influence radiation-induced phenotypes of esophagitis and pneumonitis. From 19 candidate genes, 52 polymorphisms, directed by literature and by tagging procedures, were systematically selected for assessment. The candidate genes were involved in DNA repair (double-strand breaks, homology directed, nucleotide excision) and pro/anti-inflammatory signaling. The this investigation sought to evaluate the association of genetic sequence markers for two clinically significant radiation-induced toxicities - esophagitis and pneumonitis – seen in NSCLC patients treated with a curative intent.

      Methods
      From 312 patients treated at PMCC between 2005-12, a training cohort was defined consisting of 92 definitive concurrent chemoradiation/radiation-treated NSCLC patients with genotype information on the 52 polymorphisms. A second, validation cohort consisted of 209 patients. Multivariate logistic regression was performed for each polymorphism of interest, adjusting for known clinical and dosimetric prognostic factors on the dichotomized outcomes of radiation esophagitis (Grades 0-2 vs 3-5) and pneumonitis (Grades 0-1 vs 2-5). The CTCAEv4.03 grading criteria were used. Additive genetic models were used for genetic association analysis. In the training set, genetic variants, genotyped by IlluminaGoldenGate, with p<=0.05 were identified for validation; HWE was set at p>0.01, a criteria met by all polymorphisms with statistical significance.

      Results
      In the combined training and validation datasets, 63% were males, with median age of 65 years. Specifically in the training dataset, 65% were male, with median age of 62, median mean lung doses of 15.9, median max esophageal dose of 67.1 and median V20 of 27.6. For esophagitis, the final models were adjusted for concurrent chemotherapy, V20 and max esophageal dose. Five genetic variants linked to TNF and IL6 were significantly associated with outcome (each using wild-type genotype as reference) (Table 1). For pneumonitis, the final models adjusted for V20 and smoking status. Eight genetic variants found within four genes (ATM, BRCA2, IL1alpha, IL1RN) were associated with significant pneumonitis (Table 1).

      ESOPHAGITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      pro-inflammatory cytokine TNF rs3093662 3.54 1.9-10.6 0.02
      pro-inflammatory cytokine TNF rs3093664 3.42 1.2-10.2 0.03
      pro-inflammatory cytokine TNF rs3093665 4.95 1.2-21.1 0.03
      anti-inflammatory cytokine IL6 rs1800797 2.53 1.0-6.2 0.04
      anti-inflammatory cytokine IL6 rs1800795 2.45 1.0-5.9 0.046
      PNEUMONITIS
      Function / Pathway Gene refSNP OR 95% CI P value
      double-strand break repair ATM rs664143 2.67 1.3-5.6 0.01
      double-strand break repair ATM rs664677 2.37 1.2-4.7 0.01
      homology-directed repair BRCA2 rs1799955 2.59 1.3-5.3 0.01
      homology-directed repair BRCA2 rs1801406 2.42 1.2-4.8 0.01
      homology-directed repair BRCA2 rs1799943 2.09 1.0-4.2 0.04
      anti-inflammatory cytokine IL1alpha rs17561 2.63 1.2-5.7 0.01
      anti-inflammatory cytokine IL1alpha rs2856863 2.60 1.1-5.9 0.02
      anti-inflammatory cytokine IL1RN rs3087263 0.17 0.04-0.8 0.04

      Conclusion
      In our 92 patient training set, genetic variations in TNF and IL6 are associated with radiation esophagitis, while genetic variations in ATM, BRCA2, IL1alpha and IL1RN are associated with pneumonitis. Results from the 209 patients in the validation dataset will be presented at the meeting (A.H. and G. L are co-senior authors).

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      O01.02 - MicroRNA Signature Predicts Survival in Resectable Small-Cell Lung Cancer (ID 1641)

      10:30 - 12:00  |  Author(s): N. Bi, J. Cao, Y. Song, J. Fan, J. He, Y. Shi, X. Zhang, N. Lu, Q. Zhan, L. Wang

      • Abstract
      • Slides

      Background
      Small-cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the molecular mechanisms underlying its devastating clinic outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict clinical outcomes of SCLC patients.

      Methods
      A total of 82 patients with very limited SCLC, who received surgical resection followed by adjuvant chemotherapy according to the standard of care, were enrolled in this study. All the tumor samples used for miRNA profiling were required to contain at least 60% tumor cells and RNA was isolated from formalin-fixed paraffin-embedded specimens. First, we surveyed 924 miRNAs for their expressions from 42 SCLC patients to discover survival relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases. A risk score of miRNA signature for survival prediction was calculated according to a combination of expression level of the miRNA weighted by the regression coefficient derived by univariate Cox regression analysis. Kaplan-Meier overall survival curves were compared using the log-rank test and multivariate Cox regression model was used to test if the miRNA signature was an independent prognostic factor.

      Results
      For all the patients, the median follow up time was 57.2 months. Forty-four patients (53.7%) are still alive. Forty-two patients (51.2%) had recurrent disease and the median time to diagnosis of relapse was 12.3 months. In the training set, we identified that two miRNAs, miR-150 and miR-886-3p, were significantly associated with poor OS. The results compared between NL and SCLC tissues also verified that the miR-150 and miR-886-3p expression levels in SCLC were much lower than in normal lung samples (884±126 vs 2954±1652 for miR-150 and 1873±256 vs 3154±448 for miR-150 ). We then derived a miRNA signature 0.545×miR-150 + 0.617 ×miR-886-3p. Compared with patients with low-risk miRNA signature, patients with high-risk signature had significantly shorter median OS (12.6 months versus not reached, P=0.02). This signature was also demonstrated to be a significant predictor of survival in the validation set. Patients with high risk miRNA signatures had poor overall survival (P=0.005) and progression-free survival (P=0.017) compared to those with low-risk scores. It retained statistical significance in a model adjusting for age, gender and smoking status (HR 0.27, 95% CI 0.10-0.72, P=0.008), which suggesting that the miRNA signature may be an independent predictor of survival.

      Conclusion
      In this study, we developed a prognostic miR-150/miR-886-3p signature and validated in an independent dataset for resectable SCLC. Our results indicated that microRNAs may serve as promising molecular prognostic markers as well as new therapeutic targets for SCLC. Larger sample size studies are needed to further validate our findings.

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      O01.03 - BRM Promoter Variants and Survival Outcomes of Advanced Non-Small Cell Lung Cancer (NSCLC) Patients: A Validation Study in the NCIC Clinical Trials Group (NCIC-CTG) BR24 Clinical Trial (ID 1999)

      10:30 - 12:00  |  Author(s): S. Cuffe, L. Cheng, A.K. Azad, Y. Brhane, D. Cheng, Z. Chen, X. Qiu, K. Boyd, N. Leighl, W. Xu, B.E. Chen, P. Bradbury, F.A. Shepherd, L. Seymour, M.S. Tsao, D.N. Reisman, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Two BRM promoter insertion variants (BRM-741 and BRM-1321) result in epigenetic silencing of BRM through recruitment of histone deacetylases. The presence of double homozygous BRM variants is linked to loss of BRM expression and function in lung tumors, and double the risk of lung cancer. Pharmacological reversal of the epigenetic changes of BRM is feasible. In this study we evaluated the association between the BRM promoter variants and survival outcomes of advanced NSCLC patients.

      Methods
      The training cohort consisted of 564 stage III-IV NSCLC patients treated at the Princess Margaret Cancer Centre, Toronto 2006-2010. The validation cohort comprised 219 stage IIIb-IV NSCLC patients from the NCIC-CTG BR24 clinical trial, a phase II/III double-blind randomized trial of cediranib versus placebo in patients receiving carboplatin/paclitaxel for the treatment of advanced or metastatic NSCLC. Genotyping for the BRM promoter variants was performed using Taqman. Associations of BRM promoter variants and overall (OS) and progression free survival (PFS) were assessed using Cox proportional hazard models adjusted for clinically relevant variables, and in the case of the BR24 population, stratified by treatment arm.

      Results
      Among the training cohort, 73% were Caucasian, 52% male, median age 63 yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.5 [95% CI: 1.9-3.3; p=6x10E-10]) and PFS (aHR 2.0 [95% CI: 1.6-2.6; p=9x10E-8]) compared to the wild types. Similar findings were observed for the BRM-1321 homozygous variants (aHR for OS of 2.0 [95% CI: 1.5-2.6; p=2x10E-6]; aHR for PFS of 1.8 [95% CI: 1.4-2.4; p=3x10E-6]). The presence of double homozygous BRM-741 and BRM-1321 variants was strongly associated with worse OS (aHR 2.8 [95% CI: 1.9-4.0; p=7x10E-8]) and PFS (aHR 2.7 [95% CI: 1.9-3.8; p=1x10E-8]). Genotyping was possible for 219/296 BR24 participants. Of these, 59% were male, median age 59 yrs, 83% stage IV, 46% adenocarcinoma, with 50% receiving cediranib. Individuals carrying the homozygous variants of both BRM-741 and BRM-1321 (13% of cases) had a substantially worse OS (aHR 9.0 [95% CI: 4.3-18.5; p=1x10E-9]) and PFS (aHR 3.8 [95% CI: 1.9-7.3; p=3x10E-5]) compared to the wild types, irrespective of whether they were treated with cediranib (aHR for OS of 6.4; p=1x10E-4; aHR for PFS of 2.1; p=0.02) or placebo (aHR for OS of 16.8; p=2x10E-7; aHR for PFS of 8.3; p=1x10E-4).

      Conclusion
      The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this study of advanced NSCLC patients. We are completing additional studies focusing on the relationship between the BRM promoter variants and BRM protein expression; results will be presented at the meeting.

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      O01.04 - DISCUSSANT (ID 3909)

      10:30 - 12:00  |  Author(s): G. Sozzi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      O01.05 - EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKI (ID 691)

      10:30 - 12:00  |  Author(s): J. Li, X. Li, S. Ren, X. Chen, C. Zhou

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR mutation is a strong positive predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with wild-type EGFR are responsive to TKIs, suggesting that other determinants of outcome besides mutant EGFR might exist. miR-200c is an important regulator of epithelial-to-mesenchymal transition and might be associated with drug-resistance. Our objective was to characterize miR-200c expression in NSCLC and its role in TKI sensitivity in EGFR wild-type NSCLC.

      Methods
      miR-200c levels in 7 NSCLC cell lines were measured by real-time quantitative reverse transcription-PCR (qRT-PCR). Direct target of miR-200c was identified through the TargetScan database and was validated through qRT-PCR and Western blot analysis. The precursor of miR-200c was up-expressed in H1975 and A549 cells using a lentivirus construct, and miRNA inhibitor was used to down-regulate the expression of miR-200c in PC9 cell line. Effects of miR-200c on cell proliferation and sensitivity to EGFR-TKIs were evaluated by MTT assay in vitro. The expression of proteins correlating with signaling pathway was determined by western blot analysis. 141 FFPE samples of advanced NSCLC patients were enrolled in this study, and miR-200c expression and EGFR mutations were detected by qRT-PCR and amplification refractory mutation system (ARMS), respectively.

      Results
      We identified a tight association between the expression of miR-200c, epithelial phenotype, and sensitivity to TKIs in NSCLC cell lines. Up-expression of miR-200c in A549 and H1975 cells up-regulated E-cadherin levels, down-regulated expression of ZEB1, vimentin, pERK and pAKT. Up-regulated miR-200c increased sensitivity to gefitinib in the primary resistant cell line A549. Analysis of 141 NSCLC specimens indicated that median PFS of EGFR wild-type (n=57) and EGFR mutant NSCLC patients (n=73) treated with second/third line targeted therapy was 1.8m vs. 12.0m respectively (P<0.0001). Patients with high expression level of miR-200c had a positive association towards a longer PFS in NSCLC harboring EGFR wild-type when considering 2[-ΔCt]=0.01128 (median level) as cut-off value (3.95m vs. 1.60m, P=0.015). The objective response rate (ORR) was 7% in the EGFR wild-type cohort, and patients with high miR-200c expression level had better ORR than those with low level (12.5% and 3.0%, P=0.3). In Cox regression analysis, miR-200c expression also present the same trend for benefit from EGFR-TKIs in EGFR-negative NSCLC (HR= 0.375, 95%CI: 0.198-0.712, P= 0.003).

      Conclusion
      miR-200c appears to act as a critical role in EGFR-TKIs sensitivity in NSCLC patients with wild-type EGFR. Up-expression of miR-200c can trigger MET and suppress PI3K/AKT, MEK/ERK pathway, which can also partially overcome EGFR-TKIs resistance. miR-200c might be a predictive biomarker of clinical response to EGFR-TKIs and assist in selecting the subpopulation in patients with wild-type EGFR to benefit from targeted therapy.

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      O01.06 - Dynamic change in plasma EGFR mutation DNA in response to first line therapy for advanced stage non-small cell lung cancer (NSCLC) (ID 2496)

      10:30 - 12:00  |  Author(s): T. Mok, Y. Wu, J.S. Lee, C. Yu, V. Sriuanpong, W. Wen, J. Tsai, M. Trueman, B. Klughammer, L. Wu

      • Abstract
      • Presentation
      • Slides

      Background
      Diagnostic utility study of EGFR mutation analysis of tumor and plasma from FASTACT 2 confirmed that the plasma EGFR mutation DNA (pEGFRmut) is a sensitive and specific biomarker. (Wu et al, Lancet Oncology 2013; T. Mok, ASCO 2013). Primary objective of this study is to investigate the dynamic change in pEGFRmut during course of treatment. Secondary objective is to study the diagnostic utility of pEGFRmut in patients with distant organ metastasis whom we assumed to have higher level of plasma DNA.

      Methods
      Retrospective EGFR mutation testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific assays, cobas® 4800 EGFR_FFPET test and cobas® EGFR_blood test (in Development). Both tests are designed to detect one or more of the 42 known EGFR mut. One FFPET section was used for tissue test and 2-ml plasma was used for blood test. We studied the plasma samples collected at baseline, post cycle 3 (C3) and at tumor progression according to RECIST criteria (PD).

      Results
      Complete analysis of plasma samples at baseline, C3 and PD was available in 305 of 451 pts(67.6%). Incidence of pEGFRmut positive at baseline, C3 and PD was 35% (106/305),15% (47/305)and 27% (81/305), respectively. 98 of 106 pEGFRmut patients harbor the Exon 19 deletion or L858R at baseline. (C arm 51; CE arm 47). At C3, 21 (41%) pts lose pEGFRmut positivity in C arm comparing to 39 (83%) in CE arm. At PD, 8 of the 21pts in C arm and 18 of the 39 in CE arm regained pEGFRmut positivity. Table 1 summarized the median pEGFRmut copies/PCR. There was a considerable decline at C3 in both C and CE arm. However, pEGFRmut copies/PCR rebounded to high level at PD in C arm only and remained low in CE arm. Correlation of dynamic change in pEGFRmut copies/PCR with clinical tumor response and PFS will be presented at the meeting. We have also identified 93 (out of 224 matched tissue and plasma samples) patients with known distant organ metastasis. Sensitivity of pEGFRmut in this patient subgroup is 91% (41/45), specificity at 98% (47/48) and overall concordance at 95% (88/93). Table 1

      Median pEGFRmut copies/PCR Baseline C3 PD
      C (Exon 19) 27.6 2.3 35.8
      CE (Exon 19) 43.2 0 2.7
      C(Exon 21) 40.9 2.6 63.9
      CE (Exon 21) 87.1 0 3.5

      Conclusion
      This is the first study demonstrating the quantitative dynamic change in pEGFRmut in pts who received C or CE for advanced NSCLC. At RECIST progression, pEGFRmut remained low in patients who received erlotinib but not in patients who received chemotherapy only. pEGFRmut is a potential biomarker for monitoring tumor response.

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      O01.07 - Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis (ID 3276)

      10:30 - 12:00  |  Author(s): V. Gregorc, C. Lazzari, S. Novello, S. Barni, M. Aieta, F. Grossi, T. De Pas, F. De Marinis, M. Mencoboni, A. Bearz, I. Floriani, V. Torri, F. Hirsch, H. Roder, J. Grigorieva, J. Roder, A. Bulotta, S. Foti, M. Viganò, M. Giaj Levra, A. Bachi

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR-TKis are more effective in NSCLC patients with EGFR activating mutations. However, about 90% of non-Asian patients are EGFR wild type, and a test for optimizing treatment in pts with wild-type or in patients with undetectable EGFR mutation status or squamous histology is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility in retrospective studies. PROSE is the first completed multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2[nd]- line NSCLC pts treated with E or CT. As reported at 2013 ASCO[1], VSG pts derived similar overall survival (OS) benefit from both agents (hazard ratio (HR) for E=1.06; p=0.71) whereas CT was the superior option for VSP pts (HR for E=1.72; p=0.02). PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p-value of 0.031. The present report discusses the results for the secondary endpoints, PFS.

      Methods
      285 pts, stratified by ECOG-PS, smoking, and blinded pre-treatment VS classification, were randomized 1:1 to receive E or CT at standard doses. Primary endpoint was overall survival (OS) and the primary hypothesis was a significant interaction between VS status and treatment. Sample size was calculated based on an estimated 65%/35% VSG:VSP ratio and hazard ratio (HR) for interaction of 2.35, with a 2-sided α=0.05 and 90% power.

      Results
      263 pts (129 CT, 134 E) were included in the per protocol primary analysis. 68% of pts in CT arm and 72% in E arm were classified as VSG, and analysis was performed at 226 survival events.VSP classification was significantly correlated with worse PFS as compared to VSG, in overall comparison (HR=1.75, 95%CI: 1.34-2.95, P <0.001) , in the CT (HR = 1.69, 95%CI: 1.15-2.48, P <0.007) and the E (HR = 1.91, 95%CI: 1.340-2.80, P<0.001) arms, demonstrating its prognostic value also in PFS. In VSG median PFS was 4.8 months (m) on CT, and 2.5 m on E (HR = 1.26, 95% CI: 0.94-1.69, P =0.129); in VSP median PFS was 2.8 m on CT and 1.7 m on E (HR=1.51, 95% CI: 0.96-2.38, P =0.078). No statistical significant interaction was detected (p=0.44)

      Conclusion
      The analysis of PFS and OS indicates that the differential treatment benefit in OS related to VS classification is determined by the combination of prognostic and predictive properties of the test.

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      O01.08 - DISCUSSANT (ID 3910)

      10:30 - 12:00  |  Author(s): D. Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    E10 - Targeting KRAS in Lung Cancer (ID 10)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Biology
    • Presentations: 1
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      E10.1 - Biology (ID 418)

      14:00 - 15:30  |  Author(s): T. Mitsudomi

      • Abstract
      • Presentation
      • Slides

      Abstract
      Biological function of RAS An activity that transforms mouse NH 3T3 cells in DNA from human cancers turned out to be present in human homologues of retroviral oncogenes found earlier. These genes were named as HRAS or KRAS according to the names of corresponding viruses; Harvey- or Kirsten- ratsarcoma viruses. The difference between RAS gene present in normal tissue and that in cancer tissue was a single missense point mutation either at codon 12 , and less frequently at codons 13 or 61. The third member of the RAS family gene, NRAS was identified one year later from a human neuroblastoma cell line, although its viral homologue was not identified. There is a tendency that a certain type of cancer uses a particular type of RAS gene; e.g. most RAS mutations in lung or pancreas cancer occur in KRAS gene, whereas most RAS mutations in bladder cancer occur in HRAS gene . RAS gene encodes for a 21kDa protein that toggles guanosine diphosphate (GDP)-bound inactive form to and from guanosine triphosphate (GTP)-bound active form because RAS has a GTPase activity. Guanine nucleotide-exchange factors (GNEFs) and RAS GTPase activating proteins (RAS-GAPs) positively and negatively regulate the amount of GTP bound RAS, respectively. Oncogenic point mutations either at codon 12,or less frequently at codons 13 or 61 make RAS impair its intrinsic GTPase activity and confer resistance to GAPs, thereby causing RAS to accumulate in its active GTP-bound state and sustained activation of RAS signaling. It is known that GTP-bound, active RAS interacts with more than 20 effector proteins and stimulates downstream signaling cascades. These effectors and corresponding functional outcomes include RAF (proliferation), RIN1 (endocytosis), PI3K (survival), PLCe (second messenger signaling), RalGEF (endocytosis). Rather paradoxically, oncogenic RAS has been shown to cause senescence in primary cell culture through the activation of the WAFp21-p53 or p16-Rb pathways. It is also known that, to acquire its biological and transforming activities, RAS proteins should be bound to inner surface of the plasma membranes by appropriate post-translational modification. This process includes farnesyltation, proteolytic cleavage of AAX motif, carboxymethylation of the terminal Cys and palmitoylation. This process was initially thought to be a target of therapeutic intervention. However, inhibition of farnesyl transferase results in alternative geranylgeranylation of RAS which supports membrane binding. RAS gene activation in lung cancer Frequent somatic mutation of the RAS gene in lung cancer was first identified in 1987. RAS mutation in lung cancer usually occurs in KRAS, although rare instances of HRAS or NRAS mutations are reported. Mutation of the KRAS gene usually occurs in adenocarcinoma, rarely in squamous cell carcinoma and almost never occurs in small cell lung cancer. KRAS mutations predominantly occur in Caucasian patients (~30%) rather than East Asians (~10%). Association between KRAS mutation and smoking exposure has been reported back in 1991. KRAS mutation at codon 12 in lung cancer is characterized by the frequent a G to a T transversion in contrast to the frequent a G to a A transitions found in colorectal cancer. Even within lung cancer, more than half of KRAS mutations in smokers are either G12C (GGT-TGT) or G12V (GGT-GTT), while those in never smokers are G12D (GGT-GAT). It is thought that not all the KRAS mutations are created equal. There is a report that G12V has a weaker GTPase activity than G12D, suggesting stronger oncogenic activity of G12D. It is also generally believed that KRAS codon 13 mutation is weaker oncogene than codon 12 mutation. In terms of effect of cetuximab in colon cancer, tumors with G13D behaves like those with WT KRAS. Prognostic impact of KRAS mutations in lung cancer are variably reported, but in general it is thought to be a weak negative prognostic factor. Whether there is a difference in prognostic impact among different KRAS mutations remains to be elucidated. In terms of histologic types, KRAS mutations are associated with lung adenocarcinoma with mucus production / goblet cell morphology. Lung cancer with KRAS mutations often accompanies with CK20 and CDX2. These phenotypes are commonly observed in colorectal, pancreato-biliary, and ovarian mucinous carcinomas. How to cope with KRAS mutated lung cancer Although KRAS mutations occur in mutually exclusionary fashion with activation of other driver oncogenes such as EGFR, ALK, ROS1, RET, etc, it appears that not all cancers with KRAS mutations are dependent on mutant KRAS. Upon treatment of shRNAs to deplete KRAS in lung cancer cell lines harboring KRAS mutations, half of the cell lines maintained viability without expressing KRAS. This makes it difficult to develop treatment strategy against KRAS mutated tumors.. Although MEK-ERK signaling is an essential downstream of mutant KRAS, single treatment of MEK inhibitor exhibits variable responses and PI3K pathway activation strongly influences its sensitivity. Therefore, simultaneous downregulation of MEK-ERK and PI3K-AKT may have potential therapeutic value. Recent approach is to identify synthetic lethal interactions in cancer cells harboring KRAS mutation. In other words, it is to find which genes, when silenced, kill cells harboring mutant RAS gene but not cells without this mutation. However, the list of genes with synthetic lethal activity against RAS mutated tumors are expandingand includes THOC1, eNOS, Myc, Survivin, STK33, PLK1, SYK, RON, integrin b6, TBK1, NFkB, WT1, PKC delta, CDK4, JNK, ATR, GATA2. However, a subsequent and comprehensive study could not reproduce the synthetic lethal activity of STK33, throwing out the caveat that one should be cautious to interpret the RNAi data because individual shRNA can downregulate tens or hundreds of off-target genes . Above-mentioned experimental evidence suggests that RAS collaborate with many different molecules depending on cellular contexts to have oncogenic activity. This is why the development of RAS-targeted therapy is difficult and suggests that it would be necessary to develop combination therapy depending on different cellular context.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-003 - Exon 19 deletions, smoking history and gender as additional predictive factors for treatment benefit with EGFR Tyrosine Kinase Inhibitors in patients harbouring activating EGFR mutations: A Meta-analysis of 1432 patients in six randomised trials. (ID 1789)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now recognised as the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Many studies consistently demonstrated superior tumour response and progression-free survival (PFS) over chemotherapy. However, there are still ongoing questions whether there are any significant differences in treatment outcomes between patients of different ethnicity, gender, age, performance status, smoking history, tumour histology and different subtypes of EGFR mutation. We performed a meta-analysis to assess the impact of these factors on the PFS benefit of EGFR-TKIs in advanced NSCLC patients harbouring activating EGFR mutations.

      Methods
      An electronic search of all randomised controlled trials comparing efficacy of first-line therapy of EGFR-TKI vs chemotherapy in advanced NSCLC patients harbouring EGFR mutation was performed. We extracted the published hazard ratio (HR) and the 95% confidence interval (CI) for PFS, if available, or obtained unpublished data, for subgroups defined by each factor. For each subgroup, pooled estimates of treatment efficacy of EGFR-TKI vs chemotherapy were calculated with the fixed-effects inverse variance weighted method. The predictive effect of each factor was analysed by a test for interaction between the factor and treatment effect; P<0.05 was considered statistically significant. All statistical tests were two-sided.

      Results
      We included 6 eligible studies, with two trials for each of these different EGFR-TKIs - Gefitinib, Erlotinib, and Afatinib – with a total of 1432 patients. As expected, overall the use of EGFR-TKIs in this mutated population significantly prolonged PFS as compared with chemotherapy (HR 0.37, 95% CI 0.32 to 0.43, P<0.001). While mutations at both Exon 19 (deletions) and at Exon 21 (L858R point mutations) were associated with significantly prolonged PFS, the benefit with Exon 19 mutations was greater: HR 0.26, 95% CI 0.21 to 0.31, P<0.001; as contrasted to Exon 21: HR 0.42, 95% CI 0.34 to 0.52, P<0.001 (treatment-EGFR mutation interaction P=0.001). Smoking status also showed differential benefit in this mutated population: never smokers: HR 0.30, 95% CI 0.26 to 0.36, P<0.001; contrasted to current or ex-smokers: HR 0.48, 95% CI 0.37 to 0.61, P<0.001; treatment-smoking history interaction P=0.003). There was also a trend for greater benefit for females with EGFR-TKI therapy as contrasted to males (HR [females] 0.32, 95% CI 0.27 to 0.38, P<0.001; HR [males] 0.42, 95% CI 0.33 to 0.53, P<0.001; treatment-gender interaction P=0.06). Interestingly, several parameters were not significant predictors of PFS benefit with EGFR-TKI treatment in this mutated population: performance status (ECOG 0 and 1 vs 2; interaction P=0.86); age (<65 vs ≥65 years; interaction P=0.58); ethnicity (Asian vs others; interaction P=0.18); and tumour histology (adenocarcinoma vs others; interaction P=0.52).

      Conclusion
      While EGFR-TKIs significantly prolong PFS in all advanced NSCLC patients harbouring classic activating EGFR mutations when compared with chemotherapy, other molecular and demographic factors have a further influence on benefit. Exon 19 deletions, never-smoking history, and possibly female gender were all associated with longer PFS in these patients when treated with EGFR-TKIs as compared with chemotherapy. These findings should enhance better trial design in future clinical trials.

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-013 - Prophylaxis against pulmonary thromboembolism with unfractionated heparin for the patients undergoing pulmonary resection for lung cancer (ID 1061)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after lung cancer surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. In our institution, deep vein thrombosis (DVT) is intensively screened by measuring preoperative D-dimer. Unfractionated heparin (UFH) is routinely administered to the patients having lung cancer surgery in addition to mechanical prophylaxis using elastic stockings(ES) or intermittent pneumatic compression devices(IPC). Here, we retrospectively evaluated efficacy and safety of these strategies to prevent PTE.

      Methods
      We retrospectively reviewed charts of 531 patients who underwent lung cancer surgery from January 2009 through April 2013. The patients who were deemed high-risk for DVT (those with past history of thrombosis, or those with elevated preoperative D-dimer (>1.0μg/ml), or those with varicose veins in their lower extremities), in principle, underwent venous ultrasonography of lower extremities. Among high-risk patients, those with or without DVT were classified as a group A and B, respectively. Those who failed to undergo venous ultrasonography were referred to as a group C. Those who did not meet above-mentioned criteria for high-risk group were classified as a group D. As perioperative prophylactic measures against PTE, all the patients in the group A wore ES from two days before surgery to one month after surgery. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to postoperative day (POD) 1, and then received subcutaneous UFH (5000 units twice daily) from POD 2 until the patients became ambulatory. The patients in groups B, C and D wore ES during and after surgery. In addition, IPC was applied intraoperatively. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to POD 1.

      Results
      Number of patients in each group were 14, 41, 87, and 389 in the group A, B, C, and D, respectively. In the group A, none was diagnosed as having PTE preoperatively. Eleven patients received postoperative UFH. However, two patients with intrathoracic adhesions did not receive UFH to avoid excessive postoperative bleeding. One patient with coronary artery complications underwent perioperative anticoagulation therapy. In this group, one patient without postoperative UFH administration due to adhesion developed symptomatic PTE. One patient was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery despite UFH administration. In the groups B, C and D, 473 patients received postoperative UFH. Twenty-one patients with intraoperative bleeding or intrathoracic adhesions did not receive UFH. Twenty-three patients with coronary artery complications underwent perioperative anticoagulation therapy. In these groups, none developed symptomatic PTE. In 4 patients of 473 who received UFH, UFH was discontinued before POD 1 due to increase in sanguineous drainage without further complication.

      Conclusion
      Only one patient of 531(0.19%) developed symptomatic PTE after surgery. This patient had had preoperative DVT. Therefore, we regard that our strategies were effective to prevent PTE at least for patients without preoperative DVT. However, it may be necessary to apply even more intensive prophylactic measures for patients with evidence of preoperative DVT or PTE.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-010 - Several receptor tyrosine kinase is activated but orchestrated by EGFR in EGFR-TKI acquired resistant lung adenocarcinoma cells with EGFR mutation (ID 1387)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      Lung adenocarcinomas with EGFR mutation initially show good responses to EGFR- tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is almost inevitable. To analyze molecular mechanisms underlying acquired resistance, we established a cell line from a patient who acquired resistance to gefitinib/erlotinib.

      Methods
      A 64-year-old woman underwent a pulmonary resection for lung adenocarcinoma in February 2009 (pT2aN0M0, EGFR L858R mutation). In April 2010, pulmonary metastases, mediastinal lymph node metastases, and right pleural effusion were identified. Gefitinib was started and this led to a complete response. However, despite continuous treatment with gefitinib, pleural effusion and serum carcinoembryonic antigen (CEA) levels gradually increased. In December 2010, gefitinib was switched to erlotinib but the serum CEA level continued to increase, and erlotinib was stopped on March, 2011. Even though she received no treatment after erlotinib withdrawal, interestingly, the serum CEA level was decreased significantly (from 89.5ng/ml on March 2011 to 19.2ng/ml on April 2011), and erlotinib was re-started on April 2011. The serum CEA level increased after re-administration of erlotinib (55.7ng/ml on May 2011). Therefore the regimen was switched to cisplatin/pemetrexed and she responded to this combination chemotherapy (CEA 9.1ng/ml on July 2011). This clinical experience may be an actual case of “drug addiction phenomenon” that we and others have observed in preclinical acquired resistance models (Suda K, et al. Lung Cancer 2012; Das Thakur M, et al. Nature 2013). We established a cell line from her pleural effusion obtained on March 2011 in drug-free condition (designated as ACC-GR1 cells). We analyzed this cell line to evaluate the efficacy of erlotinib and dacomitinib, an irreversible EGFR-TKI. In addition, we examined phosphorylation status of 42 receptor tyrosine kinase (RTK) of ACC-GR1 cells using Human Phospho-RTK Array Kit (R&D Systems) with/without erlotinib or dacomitinib. We also examined PC9 lung adenocarcinoma cell line for phosphorylation status of RTKs with/without erlotinib.

      Results
      ACC-GR1 cells harbored the T790M mutation, in addition to the original L858R mutation in the EGFR gene. ACC-GR1 cells do not have amplification of MET proto-oncogene. IC~50~ values for erlotinib and dacomitinib were 2.9 uM and 0.05 uM, respectively. Phospho-RTK array analysis revealed marked activation of EGFR and MET, in addition, activation of ERBB2, ERBB3, RET, and AXL in a culture condition without EGFR-TKI. Treatment with 1 uM of erlotinib led to mild inhibition of EGFR and MET phosphorylation (71% and 58%, respectively, compared with control), and phosphorylation of other RTKs fell below detectable limits. Treatment with 1 uM of dacomitinib led to further inhibition of EGFR phosphorylation (35% compared with control). In PC9 cells, phosphorylation of EGFR and MET were also observed in drug-free condition, and remarkably inhibited by 1 uM erlotinib treatment (10% and 64%, respectively, compared with control).

      Conclusion
      A cell line model established from pleural effusion of a patient who acquired resistance to gefitinib/erlotinib harbored T790M mutation and responded to dacomitinib in vitro. The acquired resistant cells showed activation of several RTKs in drug free condition, and these are remarkably inhibited by EGFR-TKI treatment.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-033 - Identification f IGF-1R activation as a candidate molecular target in KRAS-mutated lung cancer (ID 2519)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      KRAS mutations are common driver mutations in 30% of non-small cell lung cancer. However, treatment for lung cancer patients with KRAS mutations remains unestablished. Therefore, to screen other targetable receptor tyrosine kinases (RTKs) in lung cancers with KRAS mutations, we performed phospho-RTK array analyses using 6 KRAS mutated lung cancer cell lines.

      Methods
      Sixteen NSCLC cell lines were analyzed using Human-Phospho-RTK Array Kit (R&D Systems, MN) and relative phosphorylation levels of 42 RTKs were examined. Phosphorylation levels of RTKs were quantified relative to the average of positive controls using image analysis software JustTLC (Sweday, Lund, Sweden). We also examined growth inhibitory effect of small interfering RNA (siRNA) and erlotinib in KRAS mutant lung cancer cell lines. In addition, we developed erlotinib-resistant cell lines from erlotinib-sensitive H358 cells by chronic drug exposure for 3 months.

      Results
      In the phospho-RTK array analysis, phosphorylation levels of EGFR were lowest in the cell lines with KRAS mutation (Table1). Three of six cell lines with KRAS mutation showed IGF-1R phosphorylation and the difference was statistically significant compared with 0 of ten cell lines without KRAS mutation (P=0.03, Fisher's Exact test). KRAS siRNA did not induce apoptosis in 5 cell lines with KRAS mutation but mild apoptosis in H358 cells. Moreover, only H358 showed mild sensitivity to erlotinib (IC~50~ 120nmol/L). Analysis for erlotinib-resistant H358 cells identified increased phosphorylation of IGF-1R compared with H358 parent cells (18.0 times).Figure 1

      Conclusion
      These results suggest IGF-1R may be a candidate molecular target in lung cancers with KRAS mutation.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-008 - Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib and received subsequent chemotherapies (ID 1723)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      Non-small-cell lung cancers (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement are highly sensitive to the ALK kinase inhibitor crizotinib, but drug resistance invariably emerges. Morphological transformation from adenocarcinoma to SCLC represents one acquired resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors. We present the case of transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib.

      Methods
      not applicable

      Results
      A 32-year-old man presented with cough and bloody sputum. Computed tomography (CT) showed a mass in the S6 segment and diffuse consolidation throughout the lower lobe of the left lung. Transbronchial lung biopsy revealed adenocarcinoma with lymphangiosis. Immunohistochemistry (IHC) showed ALK protein expression and break-apart fluorescent in-situ hybridization (FISH) showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started. After tumor progression, the patient was enrolled in the clinical trial and was allocated to the pemetrexed arm. Subsequently, he was enrolled in other trial to receive crizotinib in July 2011. After partial response was observed, a nodule in the S9 segment developed to 2cm in February 2012, and crizotinib was discontinued. CT scans performed after 4 cycles of carboplatin and gemcitabine showed a mixed response, with improvements in lymphadenopathy and lymphangiosis but progression of the mass in S9. CT-guided core-needle biopsy revealed ALK-positive atypical cells but it was impossible to distinguish histological types because of degeneration and necrosis. Thereafter, carboplatin, paclitaxel, and bevacizumab were administered, but the same mixed response was observed. The mass in S9 increased rapidly and reached 7 cm.  Left lower lobectomy was performed. The primary tumor in S6 was diagnosed as adenocarcinoma positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1-negative sarcomatoid carcinoma. ALK was positive with IHC in both tumors, and FISH revealed high-level gene amplification of the ALK fusion gene only in the sarcomatoid carcinoma. Reverse transcriptase polymerase chain reaction revealed the same variant of echinoderm microtubule-associated protein like 4-ALK (E13; A20) and it indicated that these tumors have the same origin. Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23. Brain metastases occurred 2 months after pulmonary resection and he underwent brain surgery. The tumor was diagnosed as sarcomatoid carcinoma. Ten days later, he died due to exacerbation of lymphangiosis To discuss potential epithelial-to-mesenchymal transition (EMT), we performed E-cadherin and keratin staining as epithelial markers, and vimentin staining as a mesenchymal marker in 4 specimens. The specimens were pre-crizotinib specimen in S6, surgical specimen in S6, rebiopsied specimen in S9 after carboplatin and gemcitabine, and surgical specimen in S9. Rebiopsied specimen in S9 was unevaluable for IHC staining because of degeneration and necrosis. All of the 3 evaluable specimens showed positive expression of vimentin and only surgical specimen in S9 showed negative of epithelial markers.

      Conclusion
      The transformation from adenocarcinoma to sarcomatoid carcinoma could be interpreted as kind of EMT. This transformation might represent a novel acquired resistance mechanism to crizotinib, although there is another possibility that subsequent chemotherapies induced this transformation.

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    P2.19 - Poster Session 2 - Imaging (ID 180)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.19-010 - The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity (ID 1729)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      Pulmonary nodules with ground-glass opacity (GGO) are frequently encountered. We previously reported that, based on natural history of 108 pulmonary nodules that were 3 cm or less and had 50 % or more GGO component, these nodules should be followed for at least 3 years to accurately evaluate lesion growth. However, it remains unclear whether all GGOs should be followed for as long as 3 years. To establish reasonable follow-up plan, it would be useful to if we could predict which of GGO lesions tend to grow by any of clinical-radiographic characteristics. The purpose of this study was to clarify which baseline clinical and radiological characteristics were associated with growth of these nodules.

      Methods
      We retrospectively studied patients between 1999 and 2013 with pulmonary nodules that met the following criteria: (1) lesion diameter of ≤ 3 cm, (2) GGO proportion of ≥ 50%, and (3) observation without treatment in the prior 6 months. We evaluated the changes in lesion size on serial computed tomography. Two endpoints, “Time to 2-mm growth” and “2-mm growth incidence”, were analyzed using Cox proportional hazards and logistic regression models, respectively.Variables for univariate analysis were as follows: age; gender; smoking history; past history of lung cancer; lesion multiplicity; lesion diameter; and solid proportion. Factors for which p-value was < 0.05 in univariate analysis, as well as past history of lung cancer which was reported as a predictor in previous reports, were included in multivariate analysis. To strictly define “no growth”, we excluded lesions which had been observed for less than 3 years in logistic regression analyses.

      Results
      120 pulmonary lesions in 67 patients fulfilled inclusion criteria. At the median observation period of 4.2 years, 34 lesions had become larger by 2mm or more, whereas the remaining 86 had persisted without changing in size. Smoking history and initial lesion diameter were statistically significant in both regression and time-to-event analyses. In terms of time to 2mm growth, hazard ratio (HR) for smoking history was 3.67 (P < 0.01). Compared to those ≤ 1 cm, HRs for 1.1–2 cm and 21-3 cm lesions were 2.23 (P = 0.08) and 5.08 (P = 0.04), respectively. In contrast, odds ratio (OR) for the likelihood of 2mm growth for smoking history was 6.51 (P < 0.01), and OR for lesion diameter of 1.1–3 cm in comparison to ≤ 1 cm was 4.06 (P = 0.02).

      Conclusion
      Smoking history and initial lesion diameter are significantly associated with the growth of these nodules. These results suggested that closer follow up of larger size GGO in smoking patients be recommended.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 16:30  |  Author(s): T. Mitsudomi

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years ([email protected]) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
       cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.