Author of

• 31446

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  P1.14 - Targeted Therapy (ID 182)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 31495

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    P1.14-43 - A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity (ID 2162)

    09:45 - 18:00  |  Author(s): Balazs Hegedus
    • Abstract
    • Slides

    Background
    

    ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies.

    Method
    

    We established a novel synchronous ALK-translocated lung ADC cell pair from the malignant pleural effusion (PF240-PE) and the pleural carcinosis (PF240-PC) of a 38-year-old female patient following sequential ALK targeted therapy. Immunohistochemistry and mutational analyses were executed in pleural carcinosis tissue specimens and in the tumor cell lines. SRB assays were performed for viability testings following different generations ALK inhibitor treatment alone and combined with SAHA, a pan-HDAC inhibitor. As positive control for all treatment lines we used PF521, another newly established ALK-rearranged but treatment naïve lung ADC cell line. In vivo tumorigenicity was evaluated by performing subcutaneous xenografts.

    Result
    

    We identified two distinct resistance mutations in both tissue specimens: a so far non-characterized E1161K and the already described L1152R. Strikingly, PF240-PC harbored E1161K and PF240-PE carried L1152R. Immunohistochemistry showed changes from epithelial/carcinomatous to mesenchymal/sarcomatous differentiation following resistance acquisition. In vitro testing revealed that both cell lines were significantly different in morphology and sensitivity to different generation ALK inhibitors including crizotinib, alectinib and lorlatinib. However, the novel tyrosine kinase inhibitor entrectinib was effective in both E1161K and L1152R mutant cells. Importantly, combination treatment of crizotinib or alectinib plus pan-HDAC inhibitor SAHA yielded strong synergism. Of note, both novel cell lines were highly tumorigenic in vivo. In vivo treatment response profiles are currently under evaluation.

    

    Conclusion
    

    This is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy.

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• 30601

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  P2.01 - Advanced NSCLC (ID 159)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30707

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    P2.01-94 - Advanced Age and High Modified Glasgow Prognostic Score Are Associated with Increased Complications After Pneumonectomy   (ID 2964)

    10:15 - 18:15  |  Author(s): Balazs Hegedus
    • Abstract

    Background
    

    Pneumonectomy is associated with increased morbidity and mortality compared to parenchyma sparing anatomic lung resections. The aim of this study was to identify risk factors in lung cancer patients undergoing curative intent pneumonectomy.

    Method
    

    All newly diagnosed non-small cell lung cancer patients undergoing pneumonectomy in curative intent as the primary surgical procedure between 1/2013 and 12/2018 were retrospectively analyzed. We reviewed demographic, clinical, functional and surgical variables. Postoperative complications and 30‐ as well as 90‐ day mortality were analyzed to identify risk factors for postoperative morbidity and mortality .

    Result
    

    103 lung cancer patients (67% male; mean age 62.3 ± 8.5) who underwent pneumonectomy with a curative intent have been identified. 62 patients (60%) received neoadjuvant treatment with chemotherapy (n=20) chemoradiation (n=42). Postoperative complications were registered in 35 (34%) patients (34%), with a major complication rate of 12%. Patients older than 65 years had a significantly higher risk for complications (p=0.0039). There was a strong trend in patients with modified Glasgow Prognostic Score >1 for higher postoperative complications (p=0.0715). There was no increase in postoperative morbidity in patients who underwent neoadjuvant treatment. 30‐ and 90‐day mortality was 2.9% and 2.9%, respectively.

    Conclusion
    

    Pneumonectomy for lung cancer can be done with low postoperative morbidity and mortality. Elderly patients should receive a careful preoperative evaluation. Modified Glasgow Prognostic Score can be considered for risk stratification for this procedure.