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D. Wigle



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    MTE 18 - Chemoprevention Trials: Past, Present, and Future (Ticketed Session) (ID 70)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Prevention and Tobacco Control
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2015, 07:00 - 08:00, 108+110+112
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      MTE18.01 - Chemoprevention Trials: Past, Present, and Future (ID 2003)

      07:00 - 08:00  |  Author(s): D. Wigle

      • Abstract
      • Presentation

      Abstract:
      Outcomes for the majority of cancer prevention trials overall have been disappointing at best. Lung cancer remains the leading cause of cancer-related mortality worldwide, causing an estimated 156,000 deaths in the United States for 2013. Most lung cancers (>60%) are diagnosed at an advanced stage, with associated 5-year survival of less than 15%. Efforts in early diagnosis and cancer prevention remain crucial to reverse the impact of this deadly disease. For this session, I will be joined by Dr. Eva Szabo and Dr. Avi Spira to review perspectives on the past, present, and future of lung cancer chemoprevention trials. We will review a number of current concepts and important themes in lung cancer chemoprevention, including: 1. Genomic alterations in pre-malignant lesions for both lung adenocarcinoma and squamous cell carcinoma. 2. Patient stratification for applying chemoprevention. 3. Novel agents. 4. Strategies for individualized or precision chemoprevention. 5. Trial designs for rapid and efficient testing of chemoprevention hypotheses. 6. Priorities for further study. To reduce the mortality rate of lung cancer, and to prevent cancer initiation, progression and development, new techniques and approaches to cancer prevention must be developed. We will present both data and opinion regarding promising leads, routes to evaluation, and a vision for research priorities to advance the science of lung cancer chemoprevention.

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    ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL34.05 - Survival Implications of Variation in the Lymph Node (LN) Count in ACOSOG Z0030 (Alliance) (ID 654)

      16:45 - 18:15  |  Author(s): D. Wigle

      • Abstract
      • Presentation

      Background:
      Variation in the thoroughness and accuracy of pathologic lymph node (LN) staging may contribute to within-stage variation in survival after curative-intent resection of non-small-cell lung cancer. Accurate staging mandates effective collaboration between surgeons and pathologists. ACOSOG Z0030 tightly controlled surgeon practice, but not pathology practice. We tested the impact of the thoroughness of pathologic examination (using the number of examined LNs as a surrogate) on detection of LN metastasis and survival.

      Methods:
      We reanalyzed the mediastinal LN dissection arm of ACOSOG Z0030, using linear regression to examine the clinical and demographic factors associated with LN count, Cox proportional hazards models to determine the association between the number of LNs examined and survival of patients with pN0 and pN1 disease, and logistic regression to determine association of number of LN examined and the discovery of unexpected N2 LN metastasis. Overall (OS) and recurrence-free survival (RFS), were analyzed without and with adjustment for T-category.

      Results:
      The 524 patients, had a mean age of 66.8 years, and were 52% male. Forty-four percent had adenocarcinoma, 27% squamous, 4% large cell, and 25% ‘other’ histology; 96% had T1/2 disease. Four hundred and thirty-nine (84%) were pN0, 63 (12%) pN1, and 21 (4%) pN2. In patients with pN0, pN1, and pN2 respectively, the mean number of mediastinal LNs examined was 13.5, 12.9, and 17.4; station 10 LNs were 2.4, 2.7, and 2.5; station 11-14 LNs were 4.6, 6.2, and 6.2; total LNs (from all stations) were 19.7, 21.3, 25. Tumor histology and pN-category were the only factors associated with the number of LNs examined: patients with squamous histology tended to have the most number of non-hilar N1 LNs examined (p<0.001); patients with pN1/N2 had more non-hilar N1 nodes than those with pN0 (p=0.005); those with pN2 had more N2 nodes examined than those with pN0 or pN1 (p=0.085). There was a consistent association between the number of LNs examined and survival. Patients with pN0 had better OS (HR 0.96; p=0.12) and RFS (HR 0.97; p=0.2) with examination of more non-hilar nodes; patients with pN1, had better OS and RFS with increased examination of LNs from N2 (OS HR=0.96, p=0.059; RFS HR=0.95, p=0.03) and all stations (OS HR=0.97, p=0.048; RFS HR=0.96, p==0.012). Adjustment for T-category strengthened these relationships between the number of LNs, pN-stage and survival. The likelihood of discovering N2 disease was associated with increased examination of LNs from mediastinal (odds ratio=1.04; p=0.035) and all stations (OR=1.03; p=0.035).

      Conclusion:
      Despite uniformly thorough surgical hilar/mediastinal LN harvesting, the number of LNs examined was associated with the likelihood of detecting nodal metastasis, and survival. Patients with more LNs examined were more likely to have LN metastasis, examination of more LNs was associated with better survival in patients within the same pN-category. This may indicate an effect of variable thoroughness in pathologic examination processes on the accuracy and prognostic value of the pathology nodal staging system. Heterogeneity in the cancer immune response may be an alternative hypothesis to explain these findings.

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    P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P2.03-025 - Predictors of Relapse and Evaluation of Post-Operative Radiotherapy in Patients with Resected Stage III (N2) Non-Small Cell Lung Cancer (ID 1291)

      09:30 - 17:00  |  Author(s): D. Wigle

      • Abstract
      • Slides

      Background:
      For patients with stage III (N2) NSCLC treated with surgical resection, chemotherapy improves survival, whereas the role of PORT is controversial. The purpose of this study was to evaluate risk factors for recurrence and the role of PORT in a modern series of patients with surgically resected stage III (N2) NSCLC.

      Methods:
      A retrospective review was performed of patients with Stage III (N2) NSCLC who underwent curative intent surgical resection at our institution between February 1999 and January 2012. Patients who received neoadjuvant RT were excluded. Chi-Square or Fisher’s exact tests assessed associations between patient/disease characteristics and receipt of PORT. Local control was defined as lack of disease recurrence within the radiation field for PORT patients, or in the mediastinum or resection area for chemotherapy patients. Overall survival (OS), local control (LC), and metastasis-free survival (MFS) were estimated from the date of surgery using the Kaplan Meier method, with between-group comparisons (PORT vs. no PORT) made with the Log-rank test. Univariate Cox proportional hazards models were used to assess association of patient/disease characteristics and outcomes.

      Results:
      A total of 76 patients were included. Median age was 62.5 years. Histology was adenocarcinoma in 66%. Clinical N stage was N0 (51%), N1 (4%), or N2 (45%). Baseline positron emission tomography staging was performed in 91%. Pre-operative chemotherapy was administered to 21%. Surgery was pneumonectomy in 16%. Median (range) number of positive pN2 nodes was 1 (0-15). Seven patients with biopsy-proven cN2 had negative pN2 nodes after induction chemotherapy. Extranodal extension occurred in 9%. Surgical margins were positive in 4%. Chemotherapy (preoperative and/or postoperative) was administered to 83%. PORT was administered to 41 patients (54%) with a median (range) dose of 50 (41.4 – 60) Gy. Factors associated with increased likelihood of receiving PORT were increasing age (p=0.006) and no receipt of chemotherapy (p=0.0001). Median follow-up time for living patients was 4.5 (range 0.2 – 15.4) years. For all patients, OS at 5 years was 65%. OS at 5 years for patients receiving PORT vs. no PORT was 71% vs. 58% (p=0.19). For all patients, LC at 5 years was 84%. LC at 5 years for patients receiving PORT vs. no PORT was 89% vs. 77% (p=0.16). Factors associated with decreased LC were male gender (p=0.004), pT3/4 (vs. pT1/2, p=0.008). For all patients, MFS at 5 years was 61%. MFS at 5 years for patients receiving PORT vs. no PORT was 62% vs. 61% (p=0.89).

      Conclusion:
      In this modern series of patients with surgically resected stage III (N2) NSCLC, patients who received PORT (vs. no PORT) had numerically higher rates of OS and LC, although these differences were not statistically significant, potentially related to limited statistical power.

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    P3.05 - Poster Session/ Prevention and Tobacco Control (ID 217)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Prevention and Tobacco Control
    • Presentations: 1
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      P3.05-002 - Heterogeneity of Metformin Response for Lung Cancer Chemoprevention (ID 2942)

      09:30 - 17:00  |  Author(s): D. Wigle

      • Abstract

      Background:
      Squamous cell carcinoma accounts for about 25-30% of all non-small cell lung cancers. Metformin is a drug commonly prescribed as first-line treatment for type-2 diabetes, with some evidence showing that the drug can also act directly on cancer cells. Recent observational studies and meta-analysis show that diabetic patients who are long term users of metformin have lower risk for breast cancer and that metformin use lowered cancer development in the liver and lung. The goal of this study was to determine metformin response in different cell lines and different cellular contexts, and to use that information to work towards the generation of a metformin “sensitivity index” that could be used guide individualized chemoprevention.

      Methods:
      We performed cell survival analysis to assess differences in the sensitivity of patient-derived fibroblast cells and squamous cancer cell lines exposed to metformin. We also evaluated metformin response of Nkx2.1 positive lung progenitor cells that were differentiated from induced pluripotent stem (iPS) cells to identify differences for cells in different cellular contexts. Gene expression profiling and DNA sequencing analyses were performed to identify genes, pathways and genomic alterations that mediate metformin response in order to generate a “sensitivity index” for predicting metformin response.

      Results:
      Cell survival analysis showed that different cell lines respond differently to metformin, and cells of identical genotypes in a variety of differentiated states or cellular contexts also show differential response to metformin. Gene expression profiling of metformin treated cells identified eight differentially expressed gene including ADH1B, TMEM161B, CPED1, SNAI2, FOXF1 and DLGAP1 that may mediate metformin response. Exome sequencing and analysis identified unique single nucleotide variants (SNV) in TRAF3IP3, DMBT1, RIT2, SERPINB2, PIK3R2 that were present in all non-responders but absent in all responders. SNVs and indels present in all responders but absent in all non-responders included those in GRK7, SMARCA5, CTSB, CHD4, PLCB2, ZADH2, RPLP2, CLASP2, NEDD4, DNAH17, CPXCR1, LDHD and CLTC.

      Conclusion:
      Differences in response to metformin treatment across a variety of cell lines and cellular contexts suggest heterogeneity that may be patient-specific. A list of differentially expressed genes and genetic mutations can be used as a metformin “sensitivity index” to stratify patients into metformin responders and non-responders and guide individualized chemoprevention.