Author of

• 31237

  +

  P1.10 - Prevention and Tobacco Control (ID 175)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Prevention and Tobacco Control
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 31250

    +

    P1.10-11 - Examination of Lifestyle Factors and Associations with Genetic Mutations in Lung Cancer Cases (ID 2545)

    09:45 - 18:00  |  Author(s): Rajeswara Rao Arasada
    • Abstract

    Background
    

    With the advent of targeted therapy it is extremely useful to know what factors may be associated with specific mutations in order to better target treatment therapies. Few reports have assessed factors related to targeted therapies for lung cancer, especially in the United States. Common driver mutations relevant to lung cancer include EGFR, ROS1, ALK, KRAS and RET. In this report, we examined demographic, clinical and selected lifestyle factors, including age, sex, smoking, body mass index (BMI) and NSAID use and their association with lung cancer specific mutations.

    Method
    

    Electronic medical records were reviewed for lung cancer cases (ICD-9: 162.2-9; ICD-10: C34.X) from the Ohio State University James Cancer Hospital from 2013-2018; demographic, clinical and lifestyle data were extracted, including age, sex, smoking, body mass index (BMI), NSAID use, as well as any driver mutations (EGFR, ROS1, ALK, KRAS and RET). Due to the small sample sizes for some of the mutations, they were combined into one overall mutation variable. Logistic regression analysis was performed to assess whether any associations exists between the risk factors and the presence of a mutation. Odds Ratios (ORs) were used to estimate the associations with alpha=0.05.

    Result
    

    We identified 892 lung cancer cases in which tumor specimens were examined for mutations. Four types of mutations were identified: EGFR (n=89), ALK (n=19), ROS1 (n=8) and RET (n=12), for a total of 127 cases with mutations compared to 765 without mutations. The mean age for both groups was 65 years, with over 61% of the mutation group being female versus 54% of the non-mutation group). Overall, 84% of cases were white race, with slightly more non-whites in the mutation group (86% versus 83%). Logistic regression analyses revealed that age <50 years (OR=1.9; 95%CI=1.1, 3.6), female gender (OR=2.1, 95%CI=1.4, 3.1), and never smoking (OR=7.5, 95%CI=4.08, 3.5) were significantly associated with increased odds of having a mutation after controlling for other factors. Having a BMI>30 approached significance (OR=1.01, 95%CI=0.99,1.02) but NSAID use (aspirin, ibuprofen and/or acetaminophen) did not show significant associations with the presence of lung cancer mutations in this analysis.

    Conclusion
    

    This study revealed significant associations between younger age (<50 years), female gender and never smoking with the presence of driver mutations in lung cancer cases. Previous reports have not assessed the relationship between BMI, NSAID use and lung cancer driver mutations to our knowledge. We also understand the significant limitations in obtaining quality data on NSAID use from the medical charts, and a more in-depth review is being planned. Nevertheless, this report confirms several known predictive factors related to driver mutations, and for the first time shows a lack of correlation with NSAIDs and potentially BMI. Future reports should also aim to assess more diverse populations.

• 31515

  +

  P2.14 - Targeted Therapy (ID 183)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 31537

    +

    P2.14-19 - Notch3 and β-Catenin Are Frequently Co-Expressed in EGFR Mutant NSCLC (ID 2976)

    10:15 - 18:15  |  Presenting Author(s): Rajeswara Rao Arasada
    • Abstract

    Background
    

    In the USA approximately 15% of the patients with lung adenocarcinoma have tumors associated with “driver” mutations in the EGFR gene that demonstrate major clinical responses to EGFR Tyrosine Kinase Inhibitors (EGFR TKIs). However, despite the fact that these mutations are always “truncal” (present in every tumor cell), and dramatic tumor shrinkage is seen initially in almost all patients, EGFR TKIs are never curative and tumors always recur. Some tumors that develop resistance appear to have pre-existing resistant sub clones, but the majority appear to acquire resistance by mutational target reactivation or bypass mechanisms. In order to develop acquired resistance, a subset of cells must survive at initial stage of therapy (“drug persister cells”, or DPCs) which are known to serve as a reservoir for accumulation mutation rendering drug resistance. We have demonstrated that Notch3 mediated β-catenin activation enables drug persistence, an essential step for the development of drug resistance.

    Method
    

    We have conducted tumor protein expression analysis on a tissue micro array (TMA) containing 86 NSCLC tumors obtained before therapy. These TMAs were subjected to IHC analysis to detect the expression of Notch3 and β-catenin signaling which is known to regulate drug persistence. We have also performed cell viability and biochemical assays under various perturbations to study drug persistence mechanisms in EGFR mutant NSCLC cells.

    Result
    

    Previously, we have demonstrated that EGFR TKI treatment leads to drug persistence through Notch3 mediated β-catenin activation. Using pre-treatment NSCLC patient tissue micro array (TMA) we identified that there is frequent co-expression of Notch3 and β-catenin (total) proteins in 90% of EGFR mutant NSCLC. We also observed that there are a relatively low proportion (10%) of patients with active β-catenin in these pretreatment samples. This suggests that the EGFR mutant tumors upregulate Notch3 protein expression, but that β-catenin is predominantly transcriptionally inactive before EGFR TKI treatment. We have also identified that Notch3 is a novel transcriptional target of β-catenin which in turn promotes both β-catenin and EGFR stability. These findings suggest that the Notch3 and inactive β-catenin co-expression is characteristic of EGFR mutant tumors, and β-catenin activation at baseline is infrequent. EGFR TKI therapy activates β-catenin signaling in a Notch3 dependent manner, and here we show that both proteins are frequently highly expressed in these tumors.

    Conclusion
    

    The concept of DPCs serving as a reservoir for accumulation of mutations that could cause drug resistance is novel. However, signaling pathways that are associated with the activation of drug persistence are not well characterized. For the first-time, our studies demonstrate that Notch3, β-catenin andEGFR regulate each other and EGFR TKI therapy mediated Notch3 activation leads to β-catenin activation which is essential for the maintenance of drug persister cells in a positive feedback loop. By understanding and targeting the Notch3 - β-catenin axis that control DPCs, these studies can develop therapeutics to prevent resistance to EGFR TKI therapy.