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D. Gwyn Bebb



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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-013 - ATM Mutation as a Predictor for Mutation Burden in NSCLC (ID 10468)

      09:30 - 09:30  |  Presenting Author(s): D. Gwyn Bebb

      • Abstract

      Background:
      Ataxia telangiectasia-mutated (ATM) is a critical first responder to DNA damage in the cell, but despite being one of the most mutated genes in lung cancer, no specific mutation hotspots have been linked with disease development. Our own quantitative analysis of ATM protein levels in patient samples suggests that ATM is lost in 20-25% of cases and that this loss correlates with poor overall survival and increased response to adjuvant chemotherapy treatments. We believe that this may be the result of increased genomic instability within the cancer cells caused by a lack of adequate DNA repair. Given that ATM-deficient cancers may have higher genetic instability, and that ATM is so highly mutated in lung cancer, we sought to quantify the relationship between ATM mutations and genomic instability, as measured by somatic mutation burden.

      Method:
      Using genomic and sequencing data available from publically available databases including the Broad Institute Cancer Cell Line Encyclopedia (CCLE) and the NIH Cancer Genome Atlas (TCGA), we correlated mutations in ATM and other genes involved with the DNA damage response with the total number of mutations annotated in ~900 cancer cell lines and ~200 lung adenocarcinomas.

      Result:
      We show that in cell lines across all cancer types, and particularly in lung, breast, and esophageal cancers, mutations in ATM correlate with a significantly higher number of total mutations. Only mutations in the direct damage response genes appeared to associate with total mutations, whereas p53 – while more commonly mutated – did not correlate with higher mutations in cell lines or patients. In lung cancer patients, however, neither ATM mutations nor ATM protein levels were similarly correlated with higher mutation burden.

      Conclusion:
      We have identified a potential relationship between ATM mutation and total somatic mutations in cancer cell lines which may be indicative of overall genetic instability. Analysis of the ATM mutations in both cell lines and patient samples clearly shows that there are no specific hotspots for mutation in ATM that correlate with increased total mutations. Thus screening for ATM mutations alone may not be sufficient to indicate loss of function or instability. However, this data may prove useful in developing panels of targets to screen as mutation hotspots of instability, and ultimately to help identify patients that may benefit from targeted or modified therapy options based on ATM-deficiency or higher genetic instability.

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    P1.06 - Epidemiology/Primary Prevention/Tobacco Control and Cessation (ID 692)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
    • Presentations: 1
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      P1.06-005 - Sex-Based Disparities in NSCLC: An Evidence-Based Study  (ID 8499)

      09:30 - 09:30  |  Author(s): D. Gwyn Bebb

      • Abstract

      Background:
      Previous studies report intrinsic sex differences among lung cancer patients; however, current epidemiological data remains inconclusive as to the existence and impact of inherent sex differences. This study aimed to perform a descriptive evidence-based study of the literature to identify and quantify sex-associated characteristics among non-small lung cancer (NSCLC) patients.

      Method:
      We retrieved all potentially relevant articles published in English by searching Medline between 1996 and 2016, worldwide. Using a systematic review protocol, all abstracts were reviewed for eligibility, and studies meeting inclusion criteria retained. We identified eligible studies on NSCLC and its subtypes, with the inclusion of both men and women of age over 45 in the study population. Pooled data was analyzed using a semi-parametric longitudinal regression model and an ANOVA Two-way test. A data-visualization tool was used to demonstrate global NSCLC incidence distribution and sex-based disparities.

      Result:
      Of 1405 articles identified on Medline, 46 studies met eligibility requirements; 36 were included in statistical analyses, and 10 underwent descriptive-systematic review. We found that disparities between the sexes are significant (p=0.01). Among men, we found a significant effect of race on age-standardized incidence rates (ASR) in this subset (p <0.001). Among women, the incidence of NSCLC was found to increase over time, irrespective of race. For adenocarcinoma (ADC), a significant interaction between sex and race was found (p=0.02), with women showing higher rates of ADC than men. Asians, however, had the highest rates of ADC among other races. For squamous cell histology (SCC), no interaction between sex and race was found (p=0.7); however, a significant difference in SCC incidence rates was found between the sexes (p= 0.01). Analyzing SCC data shows significant effect over time by gender (p=0.02), with ASR values in males decreasing by -0.31 units per year. Conversely, the data-visualizing tool showed an increase in incidence rates of SCC among Canadian women.

      Conclusion:
      Our findings demonstrate that NSCLC trends vary by sex, and both race and sex have a significant affect on incidence rates. However, the inclusion of women in clinical studies is increasing over time, and women often express ADC. This histology is also predominant among all Asians. Findings also illustrated that global trends do not always align with regional trends. Our study serve as a basis to begin to resolve the inherent controversies in the research, and highlight the importance of the inclusion of sex as a risk modifier in the development of screening initiatives and therapies in NSCLC.

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    P2.01 - Advanced NSCLC (ID 618)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.01-026 - Distribution of Metastatic Disease in Survival Outliers with Stage IV Non-Small Cell Lung Cancer (ID 8823)

      09:00 - 09:00  |  Presenting Author(s): D. Gwyn Bebb

      • Abstract

      Background:
      Lung cancer is the leading cause of cancer deaths among men and women in Canada. Many non-small cell lung cancer (NSCLC) patients have metastatic disease at the time of diagnosis, which is associated with poor survival outcomes. However, there appears to be a small subset of patients with advanced disease that live substantially longer than anticipated. Studies have examined the association of various clinical parameters, such as metastatic disease, with survival in cancer patients. Our study aims to determine the impact of metastatic disease burden and distribution on survival in survival outliers with stage IV NSCLC.

      Method:
      Data on stage IV NSCLC patients diagnosed between 1999-2011 was obtained from the Glans Look Lung Cancer database. Survival outliers were defined as patients who lived > 5 years, or greater than 2 standard deviations from mean survival (adenocarcinoma, 47.5 months; squamous cell carcinoma, 57.4 months); patients not meeting survival outlier criteria were defined as average survivors. Clinical characteristics such as age, gender, smoking history, and treatments were compared between survival outliers and patients with average survival. Metastatic disease was evaluated by comparing differences in organ sites, number of metastatic sites, and local versus distant metastases. Fisher's exact test was used to analyze categorical factors, and Wilcoxon rank-sum test was performed to study continuous factors. Statistical analyses were implemented by R v3.3.0.

      Result:
      1803 stage IV NSCLC patients (1291 adenocarcinoma and 512 squamous cell carcinoma) were identified. In the adenocarcinoma group, there were 29 patients who lived >5 years, and 49 who lived >47.5 months. There were 13 squamous cell carcinoma patients who lived greater than 5 years and >57.4 months. Survival outliers tended to be younger, and had a smaller smoking history. Metastatic disease distribution differed significantly between adenocarcinoma and SCC survival outliers. Among adenocarcinoma patients, longer survival was associated with local metastatic disease (stage M1a), ≤1 site of metastasis at diagnosis, the presence of solitary bone metastasis, and the absence of liver metastasis (all p-values <0.05). In comparison, M1a disease, and the presence of solitary bone metastasis and solitary brain metastasis was associated with longer survival in SCC patients (all p-values <0.05).

      Conclusion:
      Survival outliers with local metastatic disease lived longer than patients with distant metastases. There were marked differences in the sites of distant metastases between adenocarcinoma and squamous cell carcinoma patients, and this was associated with differences in survival outcomes. The present study helps us better understand the role of metastatic disease distribution on survival, in hopes of determining important prognostic factors for lung cancer patients in the future.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-077 - Platin Sensitivity and ATM-Deficiency in Non-Small Cell Lung Cancer (ID 10415)

      09:30 - 09:30  |  Presenting Author(s): D. Gwyn Bebb

      • Abstract

      Background:
      Platinum based antineoplastic therapies (platins) are a first line treatment for non-small cell lung cancer (NSCLC) that generate DNA breaks and stimulate DNA damage response pathways. An inability to repair damage generated by these agents leads to cytotoxicity and cell death. A key mediator of the DNA damage response is ataxia telangiectasia mutated (ATM), an activator of downstream targets involved in DNA repair, cell cycle arrest, and apoptosis. Our lab has demonstrated that cell lines lacking ATM show increased sensitivity to platins. We hypothesize that platin exposure will activate ATM and that cells deficient in ATM will be innately sensitive to platins. Here we assess the molecular action of ATM in response to platins to determine if ATM-deficiency is predictive of platin sensitivity.

      Method:
      ATM status was determined in five NSCLC cell lines using western blotting and RT-qPCR. Cell lines were treated with varying concentrations cisplatin, carboplatin and oxaliplatin for 18-hours and assessed for ATM phosphorylation by western blot. Additionally, downstream targets of ATM (KAP-1, p53, and gamma-H2AX) were investigated to determine ATM pathway activation. Knockdown cell lines were generated using shRNA to ATM before testing for IR and cisplatin sensitivity using clonogenic assay. ATR and ATM inhibitors were tested on knockdown cell lines to investigate pathway response differences after cisplatin and IR.

      Result:
      NSCLC cell lines NCI-H226, NCI-H460, and NCI-H522 were found to be ATM-proficient whereas cell lines NCI-H23 and NCI-H1373 were found to be ATM-deficient. ATM-proficient cell lines demonstrated an increased level of phosphorylated-ATM in response to treatments with cisplatin, carboplatin, and oxaliplatin. ATM knockdown cell lines were found to have increased sensitivity to IR, however analysis of cisplatin sensitivity was inconclusive with only 1 out of 4 showing increased sensitivity. ATR inhibition in combination with cisplatin caused a large increase in DNA damage response from ATM and DNA-PKcs suggesting an avenue for synthetic lethality.

      Conclusion:
      It is clear that platin exposure induced an ATM mediated signalling response and that cells lacking ATM showed deficiencies in the phosphorylation of key downstream targets. Cells deficient in ATM may therefore be more susceptible to platin therapy due to an impaired DNA repair response. However, the predictive capabilities of ATM loss for platin sensitivity is still unclear. This data suggests that individuals with low or non-functioning ATM may be candidates for precision low dose therapies that exploit this deficiency.