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Walter Weder



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    EP1.03 - Biology (ID 193)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.03-33 - CD26/DPP4 as a Novel Prognostic Marker for Lung Adenocarcinoma (Now Available) (ID 1734)

      08:00 - 18:00  |  Author(s): Walter Weder

      • Abstract
      • Slides

      Background

      CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane exopeptidase expressed on various malignancies in conjunction with activity of epithelial-mesenchymal transition (EMT). We found previously that the activity of CD26/DPP4 in human lung adenocarcinoma is four times higher than in normal lung tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 and EMT markers in samples from non-small cell lung cancer patients to unravel a function of CD26/DPP4 as a prognostic marker and potential therapeutic target for lung cancer.

      Method

      We employed multi-organ tissue micro array (TMA) of non-small cell lung cancer patient samples from two institutions, University Hospital Zurich and Dongsan Medical Center. To identify CD26/DPP4 and EMT markers (Ecadherin, Vimentin, beta-Catenin, Elastin, Periostin, and Versican), immunohistochemistry (IHC) on TMA was performed. Three pathologists scored the intensity IHC from zero to six in a blinded manner. The cohort consisted of 1126 patients (adenocarcinoma: 593; squamous carcinoma: 443; others (large cell carcinoma, adeno-squamous carcinoma): 90). The overall survival rate of patients was considered as a measure of prognosis. To identify a correlation between CD26/DPP4 and EMT related protein expression in lung cancer the Pearson correlation coefficient test was applied.

      Result

      CD26/DPP4 IHC scores revealed that adenocarcinoma expresses significantly higher amount of the protein compared to normal lung or squamous carcinoma or others (p=0.035, p<0.0001, p<0.0001 respectively). In adenocarcinoma, patients with high CD26/DPP4 score (4-6) showed the worst overall survival compared to patients scoring low (1-3) or zero. The correlation analysis of CD26/DPP4 with EMT markers in adenocarcinoma showed that the epithelial marker Ecadherin was negatively correlated (p=0.001), while mesenchymal proteins Vimentin, beta-Catenin, Elastin were positively correlated with CD26/DPP4 (p=0.03, 0.01, and 0.001 respectively). Periostin and Versican showed no correlation with CD26/DPP4 expression.

      Conclusion

      The expression of CD26/DPP4 was significantly higher in adenocarcinoma among non-small cell lung cancers and associated with worse survival of patients. Furthermore, the expression of CD26/DPP4 was significantly correlated with the EMT status. We therefore deem CD26/DPP4 to be a novel prognostic marker for lung adenocarcinoma. In consideration with CD26/DPP4 expression of these cancer samples, inhibition of CD26/DPP4 can potentially improve lung cancer patients’ survival.

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    IBS26 - Treatment Techniques for Localized Therapy in Malignant Pleural Mesothelioma (Ticketed Session) (ID 57)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      IBS26.02 - Role of Extrapleural Pneumonectomy Compared to Pleurectomy Decortication: When and How? (Now Available) (ID 3396)

      07:00 - 08:00  |  Presenting Author(s): Walter Weder

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA01 - Oligometastatic Disease (ID 114)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Oligometastatic NSCLC
    • Presentations: 1
    • Now Available
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      MA01.06 - Prognostic Factors of Oligometastatic Non-Small Cell Lung Cancer Following Radical Therapy: A Multicenter-Analysis (Now Available) (ID 3063)

      10:30 - 12:00  |  Author(s): Walter Weder

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from radical therapy. We aimed to identify factors related to better prognosis, in a multicenter analysis of patients who underwent surgery of primary tumours, in combination with radical treatment of metastatic sites, and chemo- or chemoradiation.

      Method

      We retrospectively reviewed the records of oligometastatic patients who all underwent anatomical resection of primary tumor, treated at 4 centers, (August 2001-November 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery (n=48), radiotherapy (n=36) or a combination (n=41). Univariate analysis and multivariate Cox proportional hazards model were used for identification of prognostic factors on overall survival (OS) and progression-free survival (PFS). Survival was estimated by Kaplan-Meier analysis. P-value < 0.05 was considered significant.

      Result

      We treated 125 patients; 72 (58%) were male, aged 60±9.8 years, with 88 (70%) adenocarcinoma, and following pathological (pN) stage: pNx: 1 (1%), pN0: 57 (46%), pN1: 23 (18%), pN2: 44 (35%). Brain metastasis was most common (n=76; 61%) followed by adrenal (n=13; 11%) and bone (n=12; 10%). Systemic therapy was administered in 102 (82%). Median follow-up was 60 months (95%, CI: 41-86).

      One-, 2-, 3-, and 5-years OS was 80%, 58%, 49% and 36% respectively. Several patient-related and treatment-related factors showed a correlation with OS at univariate analysis. Multivariate analysis showed that patients ≤60 years (HR 0.47, 95% CI:0.28-0.78, p=0.004), and/or pN0, compared to pN1,2 (HR 0.38, 95% CI: 0.22-0.66, p=0.001), had a significant survival benefit (Figure 1A). Bone metastasis were associated with worse prognosis (HR 2.122, 95% CI: 1.00-4.48, p=0.05).

      Twenty-eight patients were ≤60 years with pN0, and had 1- and 5-year survival of 100 and 83%.

      PFS at 1-, 2-, 3- and 5-years was 41%, 29%, 25% and 23% respectively. In the multivariate analysis, absence of mediastinal lymphnode involvement (HR: 0.483, 95% CI: 0.305-0.764, p=0.002) and surgical treatment of metastasis (HR: 0.553, 95% CI: 0.347-0.880, p=0.013) remained independently associated with better outcome (Figure 1B). The administration of treatments after first progression was strongly associated with better prognosis (HR: 0.252, 95% CI: 0.076-0.834, p=0.013).

      figure 1.jpg

      Conclusion

      Our experience demonstrates, in a multicenter setting, that radical treatment of selected oligometastatic NSCLC results in excellent 5-year survival. Nodal status correlates with both OS and PFS. Surgical metastasectomy appears to improve PFS, but multimodality treatment, especially in case of recurrence, remains mandatory.

      These data might contribute to develop future combined strategies in the era of immunotherapy.

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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.03 - Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma (Now Available) (ID 2349)

      15:45 - 17:15  |  Author(s): Walter Weder

      • Abstract
      • Presentation
      • Slides

      Background

      Loss of the tumor suppressor NF2 is frequent in malignant pleural mesothelioma (MPM). NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase (CUL4) complex. Here we aimed to evaluate an importance of CUL4 in MPM.

      Method

      We evaluated the expression of CUL4A and CUL4B in tissue microarrays using immunohistochemistry. We tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation, in 13 cell lines and 3 primary cells in 2D and 3D culture. Four groups of SCID mice haboring intraperitoneal (ip.) pevonedistat sensitive (MSTO211H) or resistant (ACC-Meso1) cell lines were treated with pevonedistat (50 mg/kg; ip.) on a 5day on/5day off schedule for 3 cycles. Treatment efficacy was assessed by means of overall survival.

      Result

      CUL4B expression was associated with clinical outcomes (figure 1). Five MPM cell lines (38%) were highly sensitive to pevonedistat (IC50<500 nM). This remained true in 3D spheroid culture. The treatment induced S/G2 cell cycle arrest and accumulation of cells undergoing DNA re-replication (containing >4N DNA content) known to be mediated by p21 and CDT1 accumulation. Indeed the accumulation of p21 and CDT1 was more pronounced in pevonedistat sensitive cell lines after the treatment. Two of primary cells (67%) were sensitive to pevonedistat and also showed higher CDT1 accumulation following the treatment compared to the resistant cells. In vivo, pevonedistat treatment significantly prolonged survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth (phosphorylated histoneH3 positive) in pevonedistat sensitive tumor but increased apoptosis (cleaved–caspase3 positive) in pevonedistat resistant tumor.

      fig1 wclc2019.jpg

      Conclusion

      High CUL4B expression may play a role in MPM progression. Inhibition of cullins by pevonedistat induced growth arrest and DNA re-replication strongly in a subset of MPM. The major mechanism seems to be mediated by p21 and CDT1 accumulation in vitro. Investigation of mechanisms in vivo is ongoing.

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    P1.06 - Mesothelioma (ID 169)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.06-18 - MicroRNA Expression Is Linked to Response of Malignant Pleural Mesothelioma to Cisplatin-Pemetrexed Chemotherapy (ID 2367)

      09:45 - 18:00  |  Author(s): Walter Weder

      • Abstract
      • Slides

      Background

      Treatment of malignant pleural mesothelioma is difficult due to a high intrinsic drug resistance of these tumors. Currently, platinum-based chemotherapy represents the backbone of MPM treatment. However, only approximately 40% of patients respond to this therapy, and true predictors for response have yet to be identified. Towards this end, we here investigate the expression of microRNAs in responders and non-responders to chemotherapy.

      Method

      FFPE tumour samples were available from 32 MPM patients, who showed either partial response (PR, N=21) or progressive disease (PD, N=11) following 3-4 cycles of cisplatin-pemetrexed chemotherapy. RT-qPCR based microRNA profiling was performed on chemo-naïve tissue of 5 PD and 5 PR patients using TaqMan Low Density Arrays (TLDAs, Thermo Fisher), which cover the expression of 754 microRNAs. Candidate microRNAs with differential expression (P≤0.05 Mann-Whitney Test) were then measured in the remaining samples using microRNA-specific RT-qPCR. Expression of these microRNAs was also assessed in post-chemotherapy specimens (obtained during extrapleural pneumonectomy) and compared to that in chemo-naïve samples. In addition, for two candidates, preliminary in vitro experiments investigating the effect of microRNA overexpression (transfection with microRNA mimics) on cell growth were performed.

      Result

      TLDA-based profiling identified 35 microRNA with differential expression between patients with PD and PR following cisplatin-pemetrexed chemotherapy. The majority of these microRNAs showed higher expression in patients who showed no reponse to therapy. In an initial step, 8 candidates identified from the profiling (miR-145, miR-193a-3p, miR-30a-3p, miR-24, miR-380-5p, miR-494, miR-625-3p, miR-221-3p) were further evaluated in additional 16 PR and 6 PD samples. This confirmed a trend towards differential expression for miR-145 (p=0.08). Interestingly, when comparing expression pre- and post-chemotherapy, levels of miR-145 significantly decreased in patients with PD, while they remained stable in PR. Lack of validation of other microRNAs could be the result of the low number of cases with PD in this preliminary validation set, and additional samples will included. For miR-221-3p and miR-380-5p, preliminary analysis in vitro showed that overexpression in established MPM cell lines results in an increased sensitivity towards cisplatin.

      Conclusion

      Taken together, our data show that several microRNAs show trends towards differential expression between responders and non-responders to chemotherapy. Overall, higher expression appears to be linked to PD under cisplatin-pemetrexed, however further in-depth investigations are required. Furthermore, preliminary in vitro data suggest that altering expression of specific microRNAs has the potential to increase sensitivity of MPM to chemotherapy.

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    P1.13 - Staging (ID 181)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Staging
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.13-02 - Should Aortic Lymph Nodes be Considered Hilar Lymph Nodes in Patients with Completely Resected NSCLC? A Multicenter Study (ID 380)

      09:45 - 18:00  |  Author(s): Walter Weder

      • Abstract
      • Slides

      Background

      It has been suggested that aortic lymph nodes (stations #5 and #6, aortic-LNs) may have a similar prognostic significance as hilar-LNs (stations #10 and #11). Therefore we compared survival of lung cancer patients with aortic-LNs metastasis to those with N1 disease at the hilar-LNs.

      Method

      Between 2008 and 2017, 865 patients with left upper lobe (LUL) lung cancer underwent complete resection in three centers. Overall survival was assessed retrospectively and compared in four groups according to pN status: N0 (n =429, 49.6%), N1 (n=259, 29.9%), N25,6+ (only metastasized to stations 5 and/or 6 with/without N1 disease, n=126, 14.6%), and N27+ (only metastasized to station 7 with/without N1 disease, n=51, 5.9%). pN1 was divided two subgroups according to location; N1peripheral (n=124), N1hilar (n=135).

      Result

      Five-year survival rate was significantly better for N25,6+ than N27+ patients (32.7% vs 22.1%) (p=0.05) (Figure 1). Skip metastasis for aortic-LNs (n = 39) was a factor of better prognosis as compared to non-skip metastasis (n = 87) (42.5% vs. 26.3%) (p=0.03) although five year survival rates were similar for N2single (5+ or 6+) (n=96) and N2multiple (both 5+ and 6+) (n=30) patients (32.8% vs 32.3%, p=0.8). There was no statistically significant difference between the N25,6+ and N1hilar (p = 0.4), although N1peripheral had a significantly better survival than N25,6+ (p < 0.0001) (Figure 2).

      fig 1 and 2.png

      In multivariate analysis, age (p<0.0001), N2 versus N0/1 (p<0.0001), N1hilar versus N1peripheral (p=0.006), N25,6+ versus N1peripheral (p=0.0001), N27+ vs N25,6+ (p=0.05), and N2non-skip 5 and/or 6+ vs N2skip 5 and/or 6+ (p=0.01) were significant independent negative prognostic factors (Table 1).table.png

      Conclusion

      The prognostic significance of aortic-LNs is similar to hilar-LNs even if LUL tumors with hilar-LNs metastasis is associated with statistically not significant prognosis than aortic-LNs metastasis. In order to generalize this result, it needs to be validated in a bigger database.

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    P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.15-04 - Multimodality Treatment of Chest Wall Tumors: Induction Therapy Reduces Recurrence Rates (Now Available) (ID 1937)

      09:45 - 18:00  |  Author(s): Walter Weder

      • Abstract
      • Slides

      Background

      Chest wall resections are associated with significant morbidity. The present analysis reports a the outcome of a large series of chest wall tumor resections.

      Method

      Patients with primary and secondary chest wall malignancies undergoing resection and reconstruction were retrieved from our institutional database. Clinical and pathological parameter were correlated with long-term outcome

      Result

      The study includes 169 patients, who underwent chest wall resection and reconstruction for primary or secondary chest wall tumors between 1999 and 2018. The median age was 60 (range 10-87) years. 48 (28%) were primary tumors, whereas 121 (72%) were secondary tumors. Primary malignancies were predominantly sarcomas 39 (23%). For secondary malignancies, the largest subgroups were non-small cell lung cancer 65 (38%), breast cancer 24 (14%), and mesothelioma 20 (12%). Resection margins were free in 103 (61%), R1 in 60 (36%), R2 in 4 (2%). Perioperative complications occurred in 67 patients (40%). The 30-days mortality was 4% (n=7). 46 patients (27%) received preoperative chemotherapy, 52 patients (31%) preoperative radiotherapy. The median follow-up time was 21 (range 0-218) months. The median OS was 44 months (95% confidence interval (CI): 33-55 months[SI1] ). At the time of last follow-up 71% (n=120) of the patients were recurrent. Local recurrence rate was significantly lower in patients receiving preoperative therapy (16%) compared to patients receiving postoperative therapy (42%) or pre- and postoperative therapy (44%) (p=0.01). In patients receiving a preoperative chemotherapy, a R0 resection was significantly more often achieved (77%) than in patients receiving no preoperative chemotherapy (56%) (p=0.02). Preoperative radiotherapy had no influence on R0 resection (p=0.2). Defect size and resection status had no influence on OS (p=0.4 and p=0.8, respectively).

      Conclusion

      Surgical therapy is the cornerstone for the treatment of primary and secondary chest wall malignancies and can be performed with reasonable morbidity. Induction chemo- and/or radiotherapy improves the probability of free resection margin and has positive influence in survival.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-28 - NeoCOAST: Neoadjuvant Durvalumab Alone or with Novel Agents for Resectable, Early-Stage (I–IIIA) Non‑Small Cell Lung Cancer (ID 56)

      10:15 - 18:15  |  Author(s): Walter Weder

      • Abstract
      • Slides

      Background

      Resectable, early‑stage non‑small cell lung cancer (NSCLC) is a potentially curable disease.The current standard of care is surgery with or without adjuvant or neoadjuvant platinum‑based doublet chemotherapy. However, over half of patients eventually relapse after surgery and die from NSCLC. Clinical studies have shown that neoadjuvant programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) checkpoint inhibitors may yield clinically meaningful pathological responses in patients with resectable NSCLC.1–3 The NeoCOAST trial is a multidrug platform study to assess the PD-L1 checkpoint inhibitor durvalumab alone or in combination with novel agents, with the goal of identifying new treatment strategies to improve clinical outcomes of patients with resectable, early-stage NSCLC.

      Method

      NeoCOAST (NCT03794544) is a phase 2, open-label, randomized trial that will initially evaluate the clinical activity and safety of neoadjuvant durvalumab alone or in combination with the novel agents oleclumab (MEDI9447), monalizumab (IPH2201) and danvatirsen (AZD9150), in patients with resectable, stage I (>2 cm) to IIIA NSCLC. New treatment arms evaluating other durvalumab combinations may be added based on emerging preclinical and clinical data. The primary endpoint is major pathological response rate in the resected tumor specimen after treatment with neoadjuvant durvalumab alone or in combination with novel agents. Secondary objectives include feasibility of tumor resection surgery within 14 days of the end of the 4-week treatment period, safety, pathological complete response rate, pharmacokinetics and immunogenicity. Correlative translational analyses include tumor genomics, changes in the tumor microenvironment, and T cell populations. NeoCOAST is open for accrual with an estimated total target enrollment of up to 40 patients per treatment arm.

      References

      1Forde PM, et al. N Engl J Med. 2018;378:1976–86.

      2Rusch V, et al. MA04.09. Presented at IASLC 19th World Conference on Lung Cancer, 23–26 September 2018, Toronto, Canada.

      3Cascone T, et al. LBA49. Presented at European Society of Medical Oncology Congress, 19–23 October 2018, Munich, Germany 2018.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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