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Frances Allison



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    MA22 - New Therapeutics, Pathology, and Brain Metastases for Small Cell and Neuroendocrine Tumour (ID 925)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 206 BD
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      MA22.06 - Preinvasive Multifocal Neuroendocrine Lesions with Primary Typical Carcinoid Lung Tumors: A Negative Prognostic Factor? (ID 12432)

      15:50 - 15:55  |  Author(s): Frances Allison

      • Abstract
      • Presentation
      • Slides

      Background

      Impact on survival in patients with surgically resected multifocal neuroendocrine lesions (MNET), such as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) or tumorlets, along with primary typical lung carcinoid (TC) is unclear. Aim of this study is to analyze whether synchronous preinvasive multifocal neuroendocrine lesions of the lung with primary TC tumors (MTNET+TC) may represent a negative prognostic factor.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective study, prospectively collected, for TC from two institutional databases was evaluated with a lifelong follow-up from surgery. Patients who did not receive surgery, underwent bronchial resection or lung transplant were excluded. Pathology specimens were all reclassified according the 2015 WHO and the eight AJCC Staging system. Kaplan-Meier(KM) method and Log-rank test reports significance between TC and were MTNET+TC were used. Hence a 1:1 propensity score matching analyses was done by adjusting the imbalance and comparing the overall survival and progression free rate between matched groups with a Cox proportional hazards regression model. A p value of 0.05 or less was considered significant.

      4c3880bb027f159e801041b1021e88e8 Result

      From January 1983 to December 2013 a total of 234 patients was outlined from the databases (TABLE). A total of 41 patients (17.5%) with MNET+TC were identified. Overall KM progression free survival achieved at 5 and 10 years respectively MNET+TC 93.2% and 83.8% compare to TC 98.4% and 96.1% (p =0.00039). Thirty-six MNET+TC were matched pairs vs. TC alone. Univariate Cox proportional hazards model for matched patients MNET+TC compared to TC was 2.78 (95% CI=0.84-9.3, p=0.095). Difference in progression free rate between matched groups was p<0.001.

      table_net_daddi.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Synchronous multifocal neuroendocrine preinvasive lesions (MNET) with primary typical carcinoid (TC) lung tumors can be a negative prognostic factor. Careful search of MNET should be always performed in clinical and pathological staging of a suspected primary TC. The increased risk of progression of MNET+TC warrants an accurate and lifelong follow-up.

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    MA27 - Novel Drugs and PDX Models (ID 931)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD
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      MA27.01 - Establishment of PDX From Tumors Characterized by EGFR Mutations or ALK Fusion Genes from Resections, Biopsies and Pleural Fluids (ID 12144)

      13:30 - 13:35  |  Author(s): Frances Allison

      • Abstract
      • Presentation
      • Slides

      Background

      Patient-derived xenograft (PDX) models allow for cancer tissue expansion, providing an effective method to evaluate tumor biology and mechanisms of response or resistance. Our study aims to establish models in patients enriched for lung adenocarcinoma (LUAD) with EGFR mutations or ALK fusion genes which respond initially to oral targeted therapy, but typically develop resistance and disease relapse within 2 years. The PDXs will be evaluated for their potential to model therapy outcomes, to determine resistance mechanisms and to evaluate novel therapy strategies to overcome resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      From August 2015 to January 2018, we collected 109 samples from patients with EGFR- or ALK-driven LUAD and from never-smoker LUAD patients with unknown mutation status. Five samples with low tissue viability (i.e. necrotic) or very low tumor content (<100 malignant cells) were excluded. Adequate samples were implanted into the subcutaneous tissue of NOD-SCID mice. At this time, 16 samples have reached the study endpoint (tumor growth ≥1.5cm3) and 60 showed no tumor-growth following implantation (median follow-up: 8m). Results are currently pending for 18 models.

      4c3880bb027f159e801041b1021e88e8 Result

      Samples were collected from surgical resections (31, 36%), CT-guided biopsies (12, 14%), EBUS (19, 22%) and pleural fluid effusions (24, 28%). Most patients were female (51/86, 59%), never smokers (62/85, 73%), and had stage III or IV cancer (55/79, 70%). Mutations in EGFR and ALK were found in 55/81 (68%) and 12/84 (14%) primary cancers, respectively. Early-passage xenograft engraftment (XG) was observed in only 16 (19%) PDXs, including 9/55 (16%) EGFR- and 1/12 (8%) ALK-mutant cancers. The phenotype and molecular changes (EGFR and ALK) were consistent within the PDX model and its corresponding patient sample. Samples collected from surgical-resection specimens showed a trend towards higher engraftment rates (p=0.084). Conversely, the presence of EGFR or ALK mutations showed a trend towards non-engraftment (noXG, p=0.075). Patient smoking status and tumor stage did not influence engraftment rate. To identify reasons for no tumor-growth, we conducted histological analysis in the subcutaneous fat-pads (nodes in the implant sites) of 28 noXG mice. Interestingly, we identified small non-palpable foci of carcinoma in 8 animals (4 EGFR+ and 2 ALK+).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Environmental or molecular factors may impair engraftment rates of EGFR+ and ALK+ LUAD samples in PDX models. Nevertheless, these models recapitulate the primary disease and could be useful for population-based drug-screening studies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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