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M. Ferguson



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    MINI 19 - Surgical Topics in Localized NSCLC (ID 138)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI19.01 - Benefits of Surgical Treatment and Complementary Utility of Metabolic Tumor Volume in Selecting Therapy for Stage III NSCLC (ID 3143)

      16:45 - 18:15  |  Author(s): M. Ferguson

      • Abstract
      • Presentation
      • Slides

      Background:
      Stage III NSCLC has large variations in primary and nodal metastatic tumor burden and its treatment is controversial.We determined the benefit to overall survival (OS) of these patients from surgery, and potentially complementary role of FDG-PET/CT-based metabolic tumor volume of primary tumor (MTV~T~), nodal metastasis (MTV~N~), and whole-body (MTV~WB~) in selecting patients for surgery.

      Methods:
      With IRB approval, we retrospectively reviewed 239 stage III NSCLC cases with pre-therapy FDG-PET/CT scans treated 2004 – 2013 (141 IIIA and 98 IIIB, 115 men and 124 women, median age 67.2 years), and measured MTV~T~,MTV~N~, and MTV~WB~. Kaplan-Meier curves and log-rank test were used for determining survival differences between surgically and non-surgically treated patients. Multivariate Cox regression analyses were conducted. Logistic regression analysis was used to evaluate whether each covariate was associated with receiving surgery(including surgery alone and surgery in combination with chemo or radiation). Wilcoxon rank-sum tests were performed for determining differences of primary, nodal, and whole-body MTV between the groups.

      Results:
      30% (42/141) of IIIA patients and 10% (10/98) of IIIB patients had surgical treatment (p<0.001, Chi-square test). OS was different between surgically and non-surgically treated patients (p<0.001) at 1 year(86% vs. 54%), 2 years(64% vs. 32%), 3 years(52% vs. 21%), and 5 years(39% vs. 14%), with median survival of 37.3 months vs.13.6 months, respectively. Covariates associated with OS were: surgery (0.43 ≤ HR ≤ 0.46, p≤0.001), log~10~MTV~T~ (HR=1.54, p<0.001), log~10~MTV~N~ (HR=1.63, p<0.001), and log~10~MTV~WB~ (HR=2.06, p<0.001) (Figure 1). Log~10~MTV~T~, Log~10~MTV~N~, and Log~10~MTV~WB ~were inversely associated with receiving surgery, with odds ratio of 0.53(p=0.01), 0.55(p=0.036), and 0.38 (p=0.002), respectively. MTV~T~, MTV~N~, and MTV~WB~ were smaller in surgically treated patients, with median of surgically vs. non-surgically treated patients of 17.8 vs. 55.0, 5.3 vs. 15.1, and 27.8 vs. 92.0 cc, respectively (p≤0.004). Additionally, those with stage IIIB disease were significantly less likely to receive surgery after controlling for age, gender, and MTV. No statistically significant interactions were found between surgery and stage or between surgery and log~10~MTV~T~, log~10~ MTV~N~, or log~10~MTV~WB~.Figure 1



      Conclusion:
      Surgery and smaller MTV are associated with better OS of stage-III NSCLC patients. Smaller MTV and stage IIIA (vs. IIIB) are associated with receiving surgery. FDG PET/CT-based metabolic tumor volume can potentially inform surgical treatment decisions to further improve survival outcome.

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-001 - MET/RON Inhibition in KRAS Mutated Non Small Cell Lung Cancer (ID 2174)

      09:30 - 17:00  |  Author(s): M. Ferguson

      • Abstract
      • Slides

      Background:
      Molecular genetics have allowed us to categorize non-small cell lung cancer (NSCLC) based on their genetic profile. KRAS mutations occur in 25-30% of NSCLCs. KRAS regulates cellular function in response to growth factors and their receptors. When mutated, KRAS is constitutively active and is responsible for driving tumor oncogenesis. Direct inhibition of KRAS has not been a successful clinical strategy. The strategy of synthetic lethality (targeting a non-lethal defect in cancer cells combined with a second defect, that together make the cancer cell more susceptible to treatment) has gained traction in recent years. Several synthetic lethal targets have been identified with KRAS. We have previously shown that MET plays an important role in the oncogenic addiction observed in KRAS mutated NSCLC and contributes to both tumor growth and metastasis. However, the development of resistance in MET targeting due to upregulation of RON, a related receptor tyrosine kinase, is also evident. Our hypothesis is that dual targeting of MET and RON may be synthetic lethal to KRAS mutated NSCLC and studies to investigate this as a potential therapeutic strategy are warranted.

      Methods:
      MET- and RON-specific siRNAs (small molecule inhibitors), crizotinib, and the ligand for MET (hepatocyte growth factor), were used in in vitro assays. Immunoblotting, cell viability, and cell migration assays were carried out in a panel of KRAS mutated as well as KRAS wild type NSCLC cells. In addition, human bronchial epithelial cells (HBECs) that were rendered tumorigenic with sequential mutations in CDk4, hTERT, p53, and KRAS genes were also used.

      Results:
      Our analysis of a panel of NSCLC cells showed that most KRAS mutant cell lines express both MET and RON, and stimulation with HGF activated KRAS effector pathways such as MAPK, AKT and S6RP. When we silenced MET expression with siRNA, it led to upregulation of RON, indicating the interaction between MET and RON. Cell viability assays using crizotinib showed that KRAS mutant cell lines (A549 and H460) are three-fold more sensitive than KRAS wild type cells (H1975 and H1437), and cells with MET amplification (H1993) showed the highest response. Preliminary data with the KRAS-transformed HBECs also showed that they are more sensitive to crizotinib inhibition than the non-transformed control HBECs. Wound healing assays with these same cells showed a similar trend in MET specific inhibition of cell migration in KRAS-mutated cells compared to wild type cells.

      Conclusion:
      These data highlight the potential therapeutic benefit of targeting MET and RON simultaneously in a subpopulation of KRAS mutated NSCLC patients who may have MET overexpression or amplification. Based on KRAS oncogenic addiction to MET, we propose that NSCLC cells that are MET amplified and KRAS mutated are potentially synthetic lethal and will benefit from dual MET/RON treatment

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