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I. Wistuba



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-049 - Analysis of Tn antigen and its relationship with clinic, histologic and biomarkers profile in patients with non-small-cell lung cancer (NSCLC). (ID 2897)

      09:30 - 09:30  |  Author(s): I. Wistuba

      • Abstract

      Background
      The Tn antigen (GalNAc alpha-O-Ser/Thr), a product of incomplete O-glycosylation, is expressed in about 90% of human carcinomas, but not in normal human tissues, being associated with poor prognosis in breast cancer. There is no information about the relationship between Tn antigen expression and clinical outcome of patients with lung cancer. Aim: To study the frequency of expression of the Tn antigen in a large set of surgically resected NSCLC tumor tissues, and its association with clinical, pathological and molecular characteristics including patient’s recurrence-free survival (RFS) and overall survival (OS).

      Methods
      We used tumor tissue microarrays containing 426 NSCLCs, including 281 adenocarcinomas (ADC) and 145 squamous cell carcinomas (SCC). We performed immunohistochemistry using the murine monoclonal antibody 83D4. The expression of the Tn antigen was quantified using a four-value intensity score (0, 1+, 2+, and 3+) and the percentage (0-100%) of tumor stained cells. The final score obtained was in the range 0-300. The patients were divided into 2 groups: those who received neoadjuvant chemotherapy (WNA) (n=67), and those without this treatment (WONA) (n=359).

      Results
      We found frequent Tn antigen expression in NSCLC. ADCs expressed high levels of the Tn antigen in 72.7% of cases while in SCCs Tn antigen was found in 27.3% of cases (p<0,004). In relation to smoking, patients with positive smoking history (smokers and former smokers) presented statistically higher expression of Tn than nonsmokers, (p = 0.001). We observed a trend of the Tn antigen expression in favor of male, Caucasian, under 70 years, adjuvant treatment and stage higher than I, not statistically significant. In patients with ADC but without neoadyuvant treatment, we found a statistically significant correlation of Tn antigen expression with positive smoking history too (p = 0.001) and its expression is different according the histology pattern, showing higher value in solid histology pattern and lower in lepidic, papilar and acinar histology pattern. Using Spearman Correlation test, Tn antigen correlated significantly with EpCAM-N (n = 393, r = 0.20, p = 0.001), EpCAM-C (n = 391, r = 0.12, p = 0.01), TTF-1 (n = 250, r = -0.29 p = 0.001), mutated EGFR status (p = 0.001) and KRAS (p = 0.01) and not with EML4-ALK fusion gene (p = NS). Interestingly, in the ADC-WONA subset, the high level of Tn antigen, are significantly associated with poor prognosis in RFS (p <0.04, HR = 1.45) and strong tendency in OS (p = 0.06, HR = 1.47). In the group ADC-WNA, high level of Tn antigen was significantly associated with poor prognosis in OS (p <0.02, HR = 2.84) and no difference in RFS. Patients with SCC in both groups, with or without neoadjuvant, showed no difference in prognosis regarding Tn antigen expression.

      Conclusion
      Tn antigen is frequently expressed in NSCLC and associates with worse prognosis in patients with ADC. Our data showed a significant correlation between the Tn antigen expression and other useful molecular markers in lung cancer (EPCAM, TTF-1, EGFR and KRAS), opening a new possible candidate for targeted therapy.

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    P3.02 - Poster Session 3 - Novel Cancer Genes and Pathways (ID 149)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.02-006 - Downregulation of the candidate tumor suppressor gene SIRPA induces senescence mediated by Rb and p27 and is associated with mutation of EGFR (ID 1074)

      09:30 - 09:30  |  Author(s): I. Wistuba

      • Abstract

      Background
      The epidermal growth factor receptor (EGFR) signaling pathway is involved in numerous biological processes including proliferation and apoptosis, migration/invasion, and angiogenesis, and has emerged as one of the most important and frequently deregulated pathways in NSCLC. The discovery of oncogenic, activating mutations in the tyrosine kinase domain of EGFR and DNA amplification of EGFR have led to the development of multiple targeted therapeutics against this pathway. While effective at prolonging survival, these targeted therapies are only applicable to a subset of patients (~15-20%) that harbour these alterations and resistance to treatment ultimately develops. As multiple genomic and epigenomic mechanisms can disrupt genes, a comprehensive understanding of the genetic alterations affecting genes within this pathway is required. An integrative, multi-dimensional genomics approach can detect genes disrupted by multiple mechanisms which may otherwise be overlooked if only a single genomic dimension were assessed, improving the ability to identify causal genetic events and decipher downstream consequences.

      Methods
      A multi-dimensional integrative analysis of copy number, DNA methylation and gene expression profiles on 77 adenocarcinomas and matched non-malignant tissue, was performed to investigate the complement of genetic alterations affecting the EGFR pathway. Novel candidate genes were validated in external datasets and immunohistochemical analysis of a tissue microarray was used to verify disruption at the protein level and to correlate expression with clinical features. The tumor suppressive effects of SIRPA were assessed by stable knockdown and in vitro assays on a panel of lung cancer cell lines. The effect of SIRPA downregulation on TKI sensitivity was assessed by dose response assays.

      Results
      Of the 35 genes examined, 11 were aberrantly expressed in over 50% of tumors, with 6 (RRAS, SIRPA, PIK3R1, TGFA, ERBB2 and EGFR) ranking in the 95th percentile of altered genes. Of these genes, all but SIRPA are known to be frequently disrupted in NSCLC and play a role in tumorigenesis. SIRPA is a transmembrane protein that negatively regulates receptor tyrosine kinsase activity and is frequently downregulated at both the mRNA and protein level in NSCLC tumors and cell lines. Underexpression of SIRPA is associated with EGFR mutations and is more prominent in adenocarcinoma than squamous cell carcinoma. Downregulation of SIRPA enhanced colony formation and wound healing but impaired viability and suppressed proliferation. Interestingly, SIRPA knockdown induced a senescent phenotype through the accumulation of p27 and Rb in its unphosphorylated state thereby blocking progression of the cell cycle. These results suggest senescence induced by SIRPA downregulation is a tumor suppressive mechanism that must be overcome to develop tumors.

      Conclusion
      Our integrative analysis of the EGFR pathway revealed SIRPA as one of the most frequently deregulated genes within the pathway. SIRPA functions as a tumor suppressor gene, controlling a number of biological functions through the inhibition of singaling pathways downstream of EGFR. To our knowledge, this is the first study to report a role for SIRPA in NSCLC tumorigenesis.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-015 - Integrated Prognosis in Early Stage Resectable Lung Adenocarcinoma (ID 1707)

      09:30 - 09:30  |  Author(s): I. Wistuba

      • Abstract

      Background
      Treatment decisions in stage I and II resectable lung adenocarcinoma (ADC) are heterogeneous due to low efficacy of treatment and a high frequency of co-morbidities in the patient population. Currently, pathological stage is the main determinant of adjuvant treatment recommendations. The cell cycle progression (CCP) score is a proliferation based expression profile that has been shown to add significant prognostic stratification within stage I and II patients. We have developed an integrated prognostic model of pathological stage and the CCP expression score in order to maximize the prognostic utility of both markers.

      Methods
      Cox proportional hazards models with pathological stage and the CCP expression score were created from two data sets: 256 patients (190 stage I, 66 stage II) from the Director’s Consortium microarray cohort and 381 adenocarcinomas (337 stage I, 44 stage II) from a clinical study set analyzed by qPCR. Expression microarray data were scaled to adjust for differences in experimental platforms. The primary outcome measure was cancer-specific death, defined as death from lung cancer or death with recurrence within five years of surgery. Coefficients for modeling were derived from the hazard ratio in the Cox PH model.

      Results
      Both pathological stage and CCP score were independent predictors of lung cancer death in both cohorts. The coefficients for pathological stage and CCP score were consistent across both data sets and did not differ significantly between the analysis of all patients and a subset of untreated patients. A combined score (CS) of stage and CCP score (0.33 * CCP score + 0.52 * stage) was created from the subset of untreated patients. When applied to untreated patients in the clinical ADC cohort, pathological stage alone provided estimates of five-year risk of cancer-specific death of 12.6% (stage IA), 22.6% (stage IB), 38.4% (stage IIA) and 60% (stage IIB). In the same cohort, the combined score could separate stage IA patients with five-year risk estimates ranging from 6% to 24%. Similarly increased discrimination of risk estimates were observed for stage IB (10% to 42%), stage IIA (21% to 63%) and stage IIB patients (32% to 75%).

      Conclusion
      A combination of pathological stage and the CCP expression score is a more effective predictor of post-surgical risk of cancer-specific death than either marker alone. A more precise risk assessment provides better guidance in balancing treatment related risks with disease-specific survival.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.07 - Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC) (ID 2444)

      09:21 - 09:33  |  Author(s): I. Wistuba

      • Abstract
      • Slides

      Background
      Detecting and targeting the oncogenic drivers EGFR and ALK have transformed the care of patients with lung adenocarcinomas. The LCMC was established to use multiplexed assays to test tumors for alterations in 10 genes and provide the results to clinicians to select treatments and clinical trials matched to the driver detected.

      Methods
      Fourteen LCMC sites enrolled patients with metastatic lung adenocarcinomas and tested their tumors in CLIA laboratories for activating mutations in 10 oncogenic driver genes.

      Results
      Tumors were tested from 1,007 patients for at least one gene and 733 for all 10 genes. An oncogenic driver was found in 466 (64%) of fully-genotyped cases. Among these 733 tumors, drivers found were: KRAS 182 (25%), sensitizing EGFR 122 (17%), ALK rearrangements 57 (8%), “other” EGFR 29 (4%), two genes 24 (3%), HER2 19 (3%), BRAF 16 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), AKT1 0. For cases with any genotyping, we used results to select a targeted therapy or trial in 275 (28%). Among 938 patients with follow-up, the median survivals were 3.5 years for the 264 with an oncogenic driver treated with genotype-directed therapy, 2.4 years for the 318 with an oncogenic driver with no genotype-directed therapy, and 2.1 years for the 360 with no driver identified (p<0.0001).

      Conclusion
      Individuals with lung cancers with oncogenic drivers receiving a corresponding targeted agent lived longer than similar patients who did not. An actionable driver was detected in 64% of tumors from patients with lung adenocarcinomas; more than one was present in 3%. Multiplexed testing aided physicians in choosing therapies and targeted trials in 28% of patients. This paradigm for care and research will expand as genotyping becomes more efficient with Next-Gen platforms, additional drivers are identified (i.e.ROS1 and RET), and more targeted drugs become available in the pharmacy and through clinical trials. Supported by HSS NIH NCI 1RC2CA148394-01. Trial Registered with Clinicaltrials.gov: NCT01014286.

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