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C.G. Ferreira



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    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO20.05 - DISCUSSANT (ID 3907)

      10:50 - 11:05  |  Author(s): C.G. Ferreira

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-045 - Cost-Effectiveness of Carboplatin and Pemetrexed Versus Single Agent Pemetrexed in Patients with Advanced NSCLC and Performance Status of 2 (PS2) (ID 2993)

      09:30 - 09:30  |  Author(s): C.G. Ferreira

      • Abstract

      Background
      Health care expenditures have increased dramatically over the past 20 years. Particularly in oncology new technologies may be accompanied by higher costs but a mild health gain. As part of decision-making process, not only effective, but economic value evidence is mandatory in many developed countries. We have recently shown that the combination of carboplatin and pemetrexed improves survival in a dedicated ECOG PS2 population when compared to pemetrexed alone (Zukin et al. J Clin Oncol 2013). Because combination chemotherapy tends to increase toxicity and costs, a cost-effective analysis was performed in that PS2 dedicated trial.

      Methods
      Clinical data and resource consumptions were obtained from the multicenter phase III randomized trial which tested carboplatin and pemetrexed vs. pemetrexed alone in 205 patients with advanced NSCLC and PS 2. Direct costs were estimated based on Brazilian public health care system. Life time was divided into stable disease stage, progression stage and death. Utilities for each stage were taken from the literature. One-way sensitivity analysis and non-parametric bootstrapping approach were performed to explore the uncertainties regarding the results.

      Results
      Combination chemotherapy demonstrated a gain in 0.22 life years (LY) and 0.15 quality-adjusted life year (QALY) compared to single therapy at an additional cost of $1,667.28 (in 2012 USD). The incremental cost-effectiveness ratio (ICER) was $7,436.79/LY and $10,949.88/QALY. Estimates of ICER were more sensitive to change by the influence of stable disease utility and pemetrexed cost. The probability of being cost-effective at a threshold of $36,000 (3 times Brazilian GDP per capita) per additional QALY was > 99%.

      Conclusion
      Adding carboplatin to pemetrexed therapy for advanced NSCLC patients with PS2 status is cost-effective when compared to pemetrexed alone. To the best of our knowledge this is the first report on cost-effectiveness in a dedicated NSCLC PS2 population. This finding adds up to the efficacy data favoring the combination arm and may support health care policies in that subpopulation. This analysis is particularly relevant for countries with limited health care resources.

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    P2.21 - Poster Session 2 - Diagnosis and Staging (ID 170)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.21-008 - Clinical and Epidemiologic Study of ALK Fusion Genes in Lung Cancer Patients in Latin America: challenges and perspectives (ID 3303)

      09:30 - 09:30  |  Author(s): C.G. Ferreira

      • Abstract

      Background
      Anaplastic Lymphoma kinase (ALK) alterations play a significant role in the pathogenesis of non-small-cell lung cancer (NSCLC), and the ALK pathway has become an important target for novel NSCLC treatment. Despite strong participation in industry-sponsored and recently investigator-initiated multicenter clinical trials, little is known about the prevalence, clinic-pathological parameters and clinical outcomes related to ALK fusion in Latin American (LATAM) NSCLC patients. Preliminary data from previous small studies suggest that the prevalence of other NSCLC driver genes such as EGFR and BRAF may be more frequent in LATAM than in other non-Asian populations. This highlights a clear need for a comprehensive molecular epidemiology investigation in this genetically heterogeneous region.

      Methods
      Collaboration with the Brazilian National Cancer Institute (INCA) and Latin America Oncology Group (LACOG), through a research agreement with Pfizer Inc., was established and 11 sites from 5 different LATAM countries were contacted for participation (Brazil, Mexico, Argentina, Peru and Bolivia). Countries and site selection was based on ethnic, social and cultural characteristics in order to (appropriately) represent the continent’s population. A total of 1,154 patients will be retrospectively enrolled for molecular analysis. Considering that the expected prevalence is no greater than 10%, this sample permits this estimation with a half-width of the 95% confidence interval < 1.7%. Tissue samples will be shipped to INCA (the coordinator center) for central analysis. Clinical data will be collected by local investigators and retrieved by the coordinator center. The primary goal of the study is to estimate the prevalence of ALK fusion gene in LATAM nonsquamous NSCLC patients and build a stable LATAM network for future molecular epidemiology studies. The secondary objective is to perform a comparison of FISH, PCR and IHC methods for ALK fusion gene detection. FISH will be considered the standard method for comparison and performed using the ALK Dual Color Break-Apart probe (Abbott Molecular Inc.). Real time PCR will be performed in collaboration with Fundación Santa Fé, Colombia (probes and primers synthesized at TIB MOLBIO, LLC and designed with Primer 3 software) and IHC performed with Ventana[TM] reagents.

      Results
      The protocol was planned in 2011. Since then, the first LATAM molecular epidemiology network was established with LACOG collaboration, and molecular analysis methodology standardization completed.

      Conclusion
      This trial represents the first cooperative effort for genotype patients in LATAM using sample shipment for central analysis. Enrollment of patients is still pending, waiting for final approval from country regulatory agencies which have different requirements and timeframes for review. Moreover, additional data on tumor specific biomarkers and diagnostic testing across the region may provide a basis to guide future decisions by regulators and treating physicians.

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    P2.22 - Poster Session 2 - Epidemiology, Etiology (ID 167)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.22-013 - Evaluation of elderly patients with non-small-cell lung cancer in a private Cancer Center in Brazil. (ID 3298)

      09:30 - 09:30  |  Author(s): C.G. Ferreira

      • Abstract

      Background
      At diagnosis approximately 25-40% of patients with non-small-cell lung cancer (NSCLC) are older 70 years. There is a scarcity of data on this elderly subpopulation. The aim of this study was to report clinical characteristics of this subpopulation, highlighting some challenges in their clinical management.

      Methods
      In this retrospective cohort, data from 631 patients with lung cancer diagnosed from 1995 to 2011 at a private Cancer Center in Brazil were analyzed.

      Results
      At diagnosis, 33% patients (n=214) were older than 70 years. Within this elderly group most patients (n=193; 90%) were classified as NSCLC and became the focus of our analysis. As expected, performance status (PS), staging and smoking were associated with survival (table1). Metastatic disease was present in 60% of this subpopulation, and most patients had good PS (PS0-1: 83%) and 84% were smokers. Additionally, 70% of this group with NSCLC had at least one comorbidity. The median overall survival time was 15 compared to 22 months for patients aged <70 years (p<0.001). In the metastatic group the majority of patients (62%) received only one cycle of chemotherapy (CT) and only 10% received more than 3 cycles. Of note, in patients with stage II and III adjuvant CT was correlated with survival (14 months vs 69 months in no adjuvant CT and adjuvant CT group respectively; p=0,02), although this therapy was administered in only 30% of patients with stage II and 20% of those with stage III. Figure 1

      Conclusion
      These data show that in this cohort elderly patients with NSCLC do constitute a special subpopulation with associated comorbidities. However, despite most of them had good PS at diagnosis, limited oncology treatment options were offered leading to suboptimal treatment. The fact that oncologists do not feel confortable to offer standard oncology treatment for this population may be due to the fact most of clinical trials exclude elderly patients. Although these data were generated in a private Cancer Center in Brazil we believe it mirrors the stiatuation across the country. These results highlight the urgent need for clinical trials focused on elderly patients, in order to provide a better care for those patients.

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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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      P3.01-004 - Pre-clinical evaluation of Death Receptor-5 activation as a feasible option for K-ras mutant NSCLC therapy (ID 3399)

      09:30 - 09:30  |  Author(s): C.G. Ferreira

      • Abstract

      Background
      Activating mutations of K-ras are one of the most common alterations associated with tobacco exposure-related lung cancer(LC). There are two major types of LC - small-cell LC(SCLC) and non-small cell LC(NSCLC) - and the later accounts for 80% of the cases. NSCLC can be divided into three histological subtypes: Adenocarcinoma, large cells and squamous cell carcinoma. First-line treatment comprises surgical resection of tumor, followed or not by chemo/radiotherapy. In non-surgical cases, platinum compounds remain the cornerstone for both early and advanced NSCLC stages management, in spite of its toxicity, high rate of chemo-resistance and poor long term results. Several attempts to develop therapies based on molecular targets, such as K-ras, have been developed and thus far failed, clearly stating the need for new approaches to bring clinical benefits to patients. Among its several aberrations, NSCLC harbors alterations in the apoptotic pathways, leading to impaired pro-apoptotic signaling and positive modulation of anti-apoptotic pathways. Therapeutic strategies targeting such pathways can emerge as an alternative to the cytotoxic therapies selected to wild-type EGFR-patients – especially for K-ras mutated patients, comprising about 20% of this population.

      Methods
      Here we have analyzed a representative panel of NSCLC cell lines (A549, H460, Calu-1 and LC319), that display distinct sensitivities towards cisplatin, mutational profiles and histological subtypes, to test a pre-clinical therapeutic strategy engaging the TNF-related apoptosis-inducing ligand (TRAIL) receptor (Death receptor 4 and 5).

      Results
      TRAIL is a member of the TNF family of cytokines that induces apoptotic cell death in a variety of tumor cells by means of activation of its specific receptors, DR4 and DR5, while displaying low toxicity towards normal cells. We sought to investigate if DRs activation could subvert the relative resistance to cisplatin intrinsically presented by NSCLC cell lines. NSCLC cell lines treated with suboptimal concentrations of cisplatin (IC30) for 48h had their gene expression analyzed by qPCR and the results showed an increased expression of DR4 and DR5 in these cells. These results were confirmed at protein level by Western blot analysis. NSCLC cells are naturally regarded as resistant to TRAIL-induced cell death. Such resistance can rise, among other reasons, from low expression of DRs or increased expression of decoy receptors and/or anti-apoptotic proteins. LBY135 (Novartis) is a DR5 agonist monoclonal antibody that mimics TRAIL and induces cell death in DR5 expressing cells. As cisplatin modulated DR5 protein expression, we have combined it with LBY135 as a strategy to improve cell death induction upon NSCLC cells. LBY135 monotherapy did show some effects when analyzed by MTT assay, although it did not induce cell death accessed by Annexin/PI FACS analysis. However, when cisplatin IC30 and LBY135 were combined, we observed a significant decrease in MTT measurements and increased cell death incidence, suggesting a synergistic effect of these drugs. Such pro-apoptotic effect was blocked by zVAD-fmk, a pan-caspase inhibitor.

      Conclusion
      The synergistic effect observed was more pronounced in cell lines bearing the classical G12K-ras mutation, suggesting an alternative way to subvert chemo-resistance of K-ras mutated NSCLC and restore cisplatin-induced apoptotic signaling leading to cell death.