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R.E. Merritt



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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O18.06 - Vietnamese non-small cell lung cancer patients in California: molecular profiles and clinical characteristics (ID 1079)

      11:25 - 11:35  |  Author(s): R.E. Merritt

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of cancer-related deaths worldwide with 1.3 million deaths per year. Discoveries of oncogenic mutations in non-small cell lung cancer (NSCLC) over the past decade have led to targeted therapies against epidermal growth factor receptor (EGFR) activating mutations, anaplastic lymphoma kinase (ALK) gene rearrangement, and repressor of silencing 1 (ROS1) gene rearrangement. The frequencies of these mutations and gene rearrangements have been elucidated in the Western and East Asian populations. However, the frequencies of these oncogenic alterations remain unknown in Vietnam, where lung cancer is one of the leading causes of cancer mortalities but molecular testing is not routinely performed due to limited resources. In this project, we aimed to analyze the Vietnamese patients treated at Stanford, California, with a future plan to compare with another cohort inside Vietnam.

      Methods
      We collected molecular and clinical variables of NSCLC patients of Vietnamese origin, based on patients' self-reported ethnicity, language, or country of origin, treated at Stanford from 2009 to 2012. Comparison of the molecular and clinical characteristics of never smokers versus smokers was performed with Pearson's chi-squared test for nominal variables and Student's t test for continuous variables. Survival analyses were done using the Kaplan-Meier method and Cox proportional hazards modeling.

      Results
      Forty-six patients of Vietnamese origin were seen at the Stanford thoracic oncology clinic from 2009 to 2012, including 22 men and 24 women with a mean age of 58 years. Twenty-seven (58.7%) were never-smokers. Forty-two (91.3%) of the tumors were adenocarcinoma. Ten patients (21.7%) presented at stage I, none at stage II, 8 patients (17.4%) at stage III, 28 patients (60.9%) at stage IV. Fifteen patients out of 28 tested for EGFR (53.6%) had an activating mutation; 14 of these 15 patients were never-smokers. Five patients out of 16 tested for ALK (31.3%) had ALK gene rearrangement. No ROS1 gene rearrangement out of 3 patients tested was found. Only one patient, a former smoker, out of 23 tested (4.4%) was found to have a KRAS mutation. Eighteen out of 27 never-smokers (66.7%) and 3 out of 19 smokers (15.8%) had a targetable driver mutation (EGFR, ALK, or ROS1). For all stages, the median overall survival (OS) for never-smokers was 22.3 months (95% confidence interval (CI); 11.9 months, 24.3 months) compared to 12.9 months (95% CI; 5.8 months, 20.0 months) for smokers. For only stage IV, the median OS for never-smokers was 21.2 months (95% CI; 13.0 months, 24.3 months) compared to 11.6 months (95% CI; 1.4 months, 30.9 months) for smokers.

      Conclusion
      Approximately two-thirds of never-smoker patients of Vietnamese origin had NSCLC with a targetable driver mutation. OS differ markedly by smoking status. The high percentage of Vietnamese patients in California with driver mutations warrants further studies to evaluate the frequencies of NSCLC driver mutations inside Vietnam, strongly suggesting that nationwide implementation of routine molecular testing will have a positive impact on clinical management of Vietnamese patients with NSCLC.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-007 - Energy metabolism in lung adenocarcinoma (ID 2557)

      09:30 - 09:30  |  Author(s): R.E. Merritt

      • Abstract

      Background
      Cancer cells have defects in regulatory circuits governing proliferation and homeostasis. Consequently, cell metabolism is altered to meet the demand for accelerated, deregulated growth. Metabolic perturbations arising from malignant transformation have not been well characterized in human lung cancers in situ. The most well known metabolic derangement(s) in tumors is that of enhanced glycolysis and a decrease in mitochondrial oxidative phosphorylation. We wanted to characterize this phenomenon more accurately in human lung adenocarcinomas by metabolomic profiling.

      Methods
      We performed metabolomic analysis of matched pairs of solid, non-small cell lung adenocarcinomas and normal lung tissue from 25 surgically resected patients. Metabolites were extracted by a methanol-chloroform-water technique. The resulting extracts were divided into multiple fractions. Ultrahigh performance liquid chromatography/ mass spectrometry coupled with tandem mass spectrometry and gas chromatography/ mass spectrometry experiments were conducted. Agilent MassHunter Qualitative software was utilized. The Molecular Feature Extractor was utilized to find features in raw data files. Extracted peaks were retention time aligned using Mass Profiler Professional and unique features detected by least squares analysis. The Agilent version of the Metlin database was utilized to identify metabolites. Matched pairs t-test identified biochemicals significantly altered between tumor and normal specimens. The false discovery rate method assessed for significance; p-value ≤ 0.05 and q-value < 0.10.

      Results
      Based on known library standards to identify biochemicals, our global metabolomic profiling found 204 overexpressed and 42 underexpressed metabolites in tumors relative to normal lung (p< 0.05). We observed altered metabolite levels in lung tumors that mapped to not one, but two glucose utilization pathways. Glucose-6-P (2.7-fold), fructose-6-P (2.6-fold), fructose-1,6-bisP (6.9-fold), lactate (2.7-fold), and NAD[+] (1.4-fold) were significantly upregulated in tumors consistent with an aerobic glycolysis (i.e. Warburg) biosignature, the major source of ATP. Concurrently, pentose phosphate pathway (PPP) metabolites were upregulated in tumors: ribulose-5-P (2.6-fold), ribulose (3.6-fold), ribitol (4.6-fold), ribose (4-fold), and sedoheptulose-7-P (3-fold). Our data reveals evidence of multiple active pathways to explain glucose utilization in lung adenocarcinomas. The PPP is important to protect against oxidative stress as it serves to generate NADPH, and is a key anabolic pathway of nucleotide synthesis by generating the ribose-5-P backbone for proliferating cells. Observing both pathways simultaneously in lung adenocarcinomas suggests they are coupled to give tumors a growth advantage over normal tissue. Consistent with this, we observed an overall increasing nucleotide biosynthesis signature in tumors: multiple metabolites (range 2 to 17-fold) in purine and pyrimidine pathways were significantly elevated.

      Conclusion
      Metabolomic analysis identified a unique glucose energetic biosignature in lung tumors that is more complex that just a single process/ pathway. Our results suggest a specific strategy to target lung adenocarcinomas by exploiting their high glucose uptake.