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M. Das



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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): M. Das

      • 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): M. Das

      • 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.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-006 - Erlotinib (E) and Dovitinib (TKI258) (D) in Patients (pts) with Metastatic Non-Small Cell Lung Cancer (NSCLC): A Significant Pharmacokinetic (PK) Interaction (ID 878)

      09:30 - 09:30  |  Author(s): M. Das

      • Abstract

      Background
      Dovitinib (TKI 258) is an oral antiangiogenic agent that targets PDGFR, KIT, FLT3, VEGF, RET, and FGFR. Dovitinib induces CYP1A1/A2, CYP2C19, CYP2C9, and it inhibits CYP3A4. Dovitinib is metabolized mainly by FMO, CYP3A4, and CYP1A1/A2. Erlotinib is metabolized mostly by CYP3A4 (70%) but also by CYP3A5, CYP1A1, and CYP1A2.

      Methods
      This is a phase I 3+3 trial of E+D in patients with EGFR wild-type or mutated metastatic NSCLC who could have previously received E. Four cohorts were planned with E given daily and D given 5 days on/2 days off, starting after a 2-week lead-in of E alone. Only two cohorts enrolled due to dose limiting toxicity (DLT): cohort 1 [150 mg E +300 mg D] and cohort -1 [150 mg E+200 mg D]. Plasma concentrations of E and its metabolite OSI-420 were measured on day 14+/-4 (E alone; pre-dose, 2, 4, 6, 8, and 24 hours) and day 29 +/- 4 (D+E, at same time points). Pharmacokinetic (PK) samples were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters for E and OSI-420 were estimated from the plasma concentration data via noncompartmental analysis. Paired-t tests on log transformed PK parameters were used to detect a statistical difference (α < 0.05, 2-sided) between E alone versus E+D treatment days.

      Results
      Nine patients enrolled (3 in cohort 1 and 6 in cohort (-1)). The study was suspended due to excess of DLTs. Best response was evaluable in seven patients. Two unevaluable patients on follow-up scan were on E monotherapy for ~1 month. Four patients discontinued due to grade 3 AEs (syncope (n=1), fatigue (n=1), and pulmonary embolism (n=2)). Three patients had progressive disease and 4 had stable disease (duration: 6 cycles(C), 8 C, and 1-2 C for two patients who stopped due to AE). Two patients required a dose delay in D (one for grade 2 LFT elevation, the other for grade 3 fatigue) and one required dose reduction of E to 100 mg prior to initiation of D (dose-corrected for PK analysis). Six patients had data available for PK analysis. During E alone, erlotinib exposure (average C~max~ 2308 +/- 697 ng/ml and AUC~ 0-24 ~41.0 +/- 15.6 μg*h/ml) was similar to previous reports for multiple daily doses of 150 mg. During D co-administration, the concentrations of E were reduced. C~max~ on average decreased by 83% (p= 0.022) and AUC~0-24 ~by 94% (p= 0.0039). OSI-420 exposure was also reduced during D co-administration.

      Conclusion
      Our small study demonstrates a potential significant PK interaction with decrease of E and its metabolite in the presence of D. This decrease is higher than that reported in combination studies with other CYP1A1 or CYP3A4 inducers. Dovitinib PK data is pending. Given the toxicity and the potential PK interaction, further investigation with this drug combination will be challenging.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-049 - Palliative Care and Anti-Cancer Care Integration: Description of three models of care delivery at a tertiary medical center (ID 3182)

      09:30 - 09:30  |  Author(s): M. Das

      • Abstract

      Background
      The American Society of Clinical Oncology issued a Provisional Clinical Opinion on the integration of palliative care (PC) with anti-cancer care which states, “Based upon strong evidence from a phase III RCT, patients with metastatic non-small-cell lung cancer should be offered concurrent palliative care and standard oncologic care at time of initial diagnosis.” There is both a national shortage of PC providers, as well as a lack of guidelines on the best operational ways to integrate PC into oncologic care. Here we describe different models of palliative care integration into anti-cancer care models performed at the Stanford Cancer Institute.

      Methods
      Three methods of PC integration into oncology care at Stanford Hospital and Clinics, a tertiary medical center, are being tested. These include a low resource model using a social work (SW) only intervention for advance care planning and goals of care, as well as two high resource models using an MD, advance nurse practitioner, and social worker. The first high resource model is concurrent care with joint PC and oncology visits, and the second is a traditional model of separate PC and oncology visits. Observations around successes and barriers within these various models, as well as resources needed, will be described. Data evaluated include volume, referral patterns, advance care planning, symptom assessment, and resource utilization.

      Results
      The SW only intervention was run as a pilot in thoracic oncology. Resources required for appropriate implementation included information technology (IT) for appropriate cohort identification, operations support, data management support, and team cooperation from the physician and nursing team. Process outcomes measured included % of patients seen by SW within 3 visits, documentation of advance care planning within the medical record, and co-signature of advance care planning documentation by the physician. The joint visit model utilized a high resource team (physician, nurse practitioner, and social worker) which was present concurrently with the oncology visit for advance care planning and symptom management. In addition to the resources required for the SW only intervention, this model also included a care coordinator for visit coordination. Process outcomes measured included lead time to arrange for the joint visit and documentation of advance care planning. End outcomes included discharge to hospice, hospital utilization patterns, and effective symptom management. Other outcomes included volume and number of referring providers. Our third model was a traditional clinic visit with the PC team only, not coordinated with the oncology team. Resources and outcomes were the same as for the joint visit model. A total of 529 consults were seen in the first year. 61% were seen in a traditional clinic model and 39% were seen in the concurrent model. Volume of consults have increased over time. There were 10 consults per month in January of 2012. Currently over 100 consults are seen per month.

      Conclusion
      Appropriate integration of PC into oncology care for thoracic oncology patients is still under investigation. Here we describe the strengths and weaknesses of three separate models of integration of PC with oncology care at an academic medical center.