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P. Gascón



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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      MA17.09 - Premature Fibroblast Senescence in Large Cell Carcinoma Provides Enhanced Growth and Invasive Advantages to Cancer Cells in Culture and in vivo (ID 5352)

      15:20 - 15:26  |  Author(s): P. Gascón

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.

      Methods:
      We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.

      Results:
      We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.

      Conclusion:
      Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-033 - Long-Term Safety and Efficacy of Darbepoetin Alfa in Subjects with Advanced Stage NSCLC Receiving Multi-Cycle Chemotherapy (ID 3765)

      14:30 - 14:30  |  Author(s): P. Gascón

      • Abstract

      Background:
      Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) that has been shown to increase hemoglobin levels and reduce the rate of transfusions in patients with chemotherapy-induced anemia (CIA). Most studies have not shown an association between ESA use and poor outcomes, but some clinical trials have reported increased mortality and/or tumor progression. This trial was therefore designed to address the safety of DA for CIA in patients with non-small cell lung cancer (NSCLC).

      Methods:
      Study 20070782 is a randomized, double-blind, noninferiority trial to compare DA with placebo, and is enrolling patients with NSCLC with CIA. Eligible patients are ≥ 18 years old with Eastern Cooperative Oncology Group (ECOG) status ≤ 1, stage IV NSCLC, no prior adjuvant/neoadjuvant NSCLC therapy, ≥ 2 cycles first-line chemotherapy planned (≥ 6 weeks total), and screening hemoglobin ≤ 11 g/dL. Approximately 3,000 patients from up to 500 global sites will be randomized 2:1 to DA (500 mcg) or placebo every 3 weeks (Q3W) until disease progression or end of chemotherapy. At hemoglobin > 12 g/dL, study drug is withheld until hemoglobin ≤ 12 g/dL. Transfusions are allowed when necessary. Endpoints include overall survival (OS; primary) and progression-free survival (PFS; secondary), and will be analyzed when ~2,700 deaths have occurred. Additional safety endpoints include tumor response and rate of thromboembolic events. Superiority of DA to placebo in transfusion rates will be tested if noninferiority is achieved for OS and PFS.

      Results:
      As of April 15, 2016, a total of 2,215 patients have enrolled. The independent data monitoring committee has conducted 9 reviews of unblinded data (which included a planned formal interim analysis at 40% of planned total number of 2,700 deaths to test for harm), and has recommended continuation of the trial without changes.

      Conclusion:
      Study 20070782 is the largest clinical trial in NSCLC to date, and will provide comprehensive data on the safety and efficacy of DA in patients with CIA.