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W. Zhong

Moderator of

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    OA01 - Risk Assessment and Follow up in Surgical Patients (ID 371)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Surgery
    • Presentations: 8
    • Now Available
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      OA01.01 - Institutional-Based Differences in the Quality and Outcomes of US Lung Cancer Resections (Now Available) (ID 6124)

      R.U. Osarogiagbon, M.P. Smeltzer, C.C. Lin, A. Jemal

      • Abstract
      • Presentation
      • Slides

      Background:
      Institutional-level differences in NSCLC survival are associated with differences in the quality of oncologic care. We examined stage-stratified and overall survival of patients in different categories of US Commission-on-Cancer (CoC)-accredited institutions, to quantify inter-institutional differences in survival-impactful quality measures and estimate their relative survival impact, in order to identify the most impactful targets for improvement efforts.

      Methods:
      National Cancer Data Base (NCDB) institutions were grouped according to CoC category into: Community Cancer Program (CCP), Comprehensive Community Cancer Program (CCCP), Teaching Research Program (TRP), and NCI Program/Network (NCIP). Resections for stage I-IIIA NSCLC in the National Cancer Data Base from 2004-2013 performed within each category of institution were examined for specific quality parameters. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test.

      Results:
      Of 125,408 NSCLC eligible patients, 8% received surgery at CCP, 52% at CCCP, 28% at TRP, and 12% at NCIP. The pNX rate was 8%, 5.7%, 5.5%, and 3.2% respectively (p<.0001); the median (IQR) nodal count for pN0/1 patients was 6 (7), 7 (7), 8 (9), and 10 (10) respectively, and the CoC quality criterion attainment rate (examination of >10 nodes for stage I/II patents) was 25.5%, 30.2%, 38.7%, and 51.4% (p<.0001). The nodal upstaging rate from clinical (c) N0 to pathologic N-positive was 10.4%, 10.8%, 10.7% and 13.1% (p<.0001); for cN1, nodal upstaging rate was 9.4%, 10.5%, 10.4% and 15.5% (p<.0001). There was no significant inter-institutional difference in 5-year OS for stage I/II patients with pNX resections: 0.47 v 0.50 v 0.51 v 0.54 (log-rank p=.27), whereas stage I/II patients with resections meeting or failing the CoC quality standard had persistent inter-institutional survival differences. For those with <10 nodes, 5-year survival was 0.59 v 0.63 v 0.65 v 0.69 (log-rank p<.0001) and for those with >10 nodes, it was 0.62 v 0.64 v 0.67 v 0.69 (log-rank p<.0001).

      Conclusion:
      Striking differences in the quality and accuracy of NSCLC pathologic nodal staging exist between the different categories of CoC-accredited facilities. Institutions with higher quality staging have significantly better stage-stratified OS. This inter-institutional survival difference disappears in the patients without examination of any lymph nodes, who arguably have similarly bad quality pathologic nodal staging. However, adjustment for other measures of pathologic nodal staging quality failed to eliminate the inter-institutional survival disparity. Further investigation of inter-institutional practice differences is needed to understand the institutional-level difference in survival after lung cancer surgery.

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      OA01.02 - A Lung Cancer Surgical Mortality Risk-Prediction Algorithm to Inform Lung Cancer Screening Shared Decision-Making (Now Available) (ID 4601)

      J.A. Roth, S.D. Ramsey

      • Abstract
      • Presentation
      • Slides

      Background:
      Low-dose computed tomography lung cancer screening has been demonstrated to increase detection of cases at an early-stage and reduce lung cancer mortality (vs. x-ray or no screening). However, screening benefits are greatly reduced in persons who are poor candidates for curative intent surgery in the event of screen-detected early-stage disease. To date, no practical tools have been developed to assess potential suitability for surgical treatment at the time of screening shared decision-making. The objective of this study was to use readily available socio-demographic and medical history variables to develop a prediction model that estimates the risk of 30-day mortality following surgical treatment for early-stage non-small cell lung cancer (NSCLC).

      Methods:
      We used logistic regression to develop a risk-prediction model for 30-day mortality following surgical treatment for Stage I/II NSCLC in patients age 65 to 79 using SEER-Medicare linked databases (2007-2012). Additionally, all patients had at least 1 year of Medicare enrollment prior to NSCLC diagnosis and received initial surgical treatment within 6 months of diagnosis. We developed the model with a training sample of 1,571 surgical cases and conducted internal validation exercises with a sample 4,632 independent surgical cases. Models included age, sex, race, country of birth, urban-rural status, and comorbidities in the year prior to NSCLC diagnosis. The Hosmer-Lemeshow test (by decile) and area under the receiver-operating characteristic curve (AUC) were assessed as measures of model calibration and discrimination, respectively.

      Results:
      Within the full sample of 6,203 cases, 201 deaths were identified within 30 days of surgical treatment (3.2% of sample). In the training and internal validation sets, the AUC was 0.831 and 0.734, respectively. The observed risk of 30-day mortality was 9.3-fold greater in the highest decile of predicted risk (8.3%) vs. the lowest decile (0.7%), and the Hosmer-Lemeshow test indicated satisfactory model fit (p=0.92). The model had similar performance in women, men, whites, and non-whites; and also had similar calibration and discrimination for 60- and 90-day mortality.

      Conclusion:
      Our risk-prediction model has good ability to identify patients at increased risk of mortality following surgical treatment for early-stage NSCLC, and pending additional development and validation, can potentially be applied in clinic to inform lung cancer screening shared decision-making with minimal time or resource impacts.

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      OA01.03 - Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Stage I NSCLC Patients: A Competing Risk Analysis (Now Available) (ID 4952)

      T. Eguchi, S. Bains, K.S. Tan, M.S. Bains, R.J. Downey, J. Huang, J.M. Isbell, B.J. Park, V. Rusch, D. Jones, P.S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background:
      At the time of diagnosis, two-thirds of patients with lung cancer are ≥65 years of age with significant comorbidities. We sought to determine the short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who underwent resection for stage I non-small cell lung cancer (NSCLC).

      Methods:
      Of 5371 consecutive patients who had undergone curative-intent resection of primary lung cancer (2000–2011), 2186 patients with pStage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were considered, including, Charlson comorbidity index, predicted postoperative (ppo) diffusion capacity of the lung for carbon monoxide (DLCO), and ppo–forced expiratory volume in 1 second (FEV1). Association between factors and cause-specific mortality was performed using competing risks approach.

      Results:
      Of 2186 patients, 1532 patients (70.1%) were ≥65 years of age, including 638 patients (29.2%) ≥75 years of age. In patients ≥65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID, the higher noncancer-specific early-phase mortality was enhanced in patients ≥75 years of age compared with 65-74 years of age (Figure 1a). Multivariable analyses adjusted by age, sex, smoking status, comorbidities, tumor size, and surgical procedures showed that low ppoDLCO was an independent predictor for severe morbidity (p<0.001), 1-year mortality (p<0.001), and noncancer-specific mortality (p<0.001), whereas low ppoFEV1 for lung cancer–specific mortality (p=0.002). PpoDLCO can be used for estimation of 5-year cumulative incidence of noncancer death (Figure 1b, right, red curve) because of its linear relation, whereas ppoFEV1 for lung cancer-specific death (Figure 1b, left, black curve).

      Conclusion:
      In patients undergoing curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with increasing impact as patient age increases. Figure 1



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      OA01.04 - Discussant for OA01.01, OA01.02, OA01.03 (Now Available) (ID 6961)

      A. Brunelli

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA01.05 - The Impact of Lung Age on Postoperative Complications in Patients with Lung Cancer Combined with Pulmonary Fibrosis and Emphysema (Now Available) (ID 4319)

      M. Naito, Y. Kondo, H. Yamazaki, H. Nakashima, Y. Matsui, K. Shiomi, Y. Satoh

      • Abstract
      • Presentation
      • Slides

      Background:
      Postoperative complications after pulmonary resection may cause morbidities such as prolonged hospitalization. Recently, combined pulmonary fibrosis and emphysema (CPFE) have reportedly been linked to a high risk for postoperative complications following lung cancer surgery. Moreover, some studies have claimed that lung age (LA) is associated with postoperative complications. Here we clarify the relationship between LA and postoperative complications in lung cancer patients with CPFE.

      Methods:
      Among a total of 1166 consecutive patients who underwent curative resection for lung cancer from January 2004 to April 2016 at the Kitasato University Hospital, Japan, a dataset of 36 patients with CPFE was retrospectively analyzed. Lungs with CPFE were defined based on preoperative chest computed tomography (CT) findings. LA was determined using the methods advocated by the Japanese Respiratory Society. The difference between “real age” (RA) and LA was calculated as “RA−LA,” and patients were classified into three groups: group A, RA−LA > 0 (n = 10); group B, −15 ≤ RA−LA ≤ 0 (n = 13); group C, RA−LA < −15 (n = 13).

      Results:
      The average age was 70 (males, 69.1; females, 73.2) years. Thirty two patients were male and four were female. Almost all patients were ex- or current smokers. The average postoperative hospital stay was 16 (range, 7–56) days. There were no significant differences in age, gender, smoking history, and postoperative hospital stay among the three groups. The surgical procedures were lobectomy (n = 29), segmentectomy (n = 2), and wedge resection (n = 5). Histologically, the tumors were squamous cell carcinoma (n = 22), adenocarcinoma (n = 9), and other types (n = 4). Postoperative complications were arrhythmia (4 cases), hypertension (4 cases), air leakage (3 cases), pneumonia (5 cases), hypoxemia (3 cases), and others (5 cases). There were no significant differences in postoperative complications among the groups (p = 0.69). However, cardiovascular complications in group C were significantly higher than those in the other groups (p = 0.008). There were 26 patients with postoperative acute exacerbation, but there were no significant differences among the groups.

      Conclusion:
      LA accurately predicted postoperative cardiovascular complications in lung cancer patients with CPFE.

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      OA01.06 - Early Post-Operative Ambulation after Thoracic Surgery - The WAVE Experience (Now Available) (ID 5194)

      S.J. Khandhar, C.M. Powers, C. Schatz, C. Rosner, A. Mahajan, P. Kiernan

      • Abstract
      • Presentation
      • Slides

      Background:
      The occurrence of minimally invasive thoracic surgery interventions has grown steadily since the early 1990s, yet practice patterns for peri-operative management of these patients has lagged behind technical progress. Our thoracic program has created WAVE (Walking After VATS Experiment) which focuses on a multidisciplinary approach to early ambulation after thoracic surgery. A report from our first 3 years of data (July 2010 - July 2013) was presented at the 2013 IASLC meeting in Sydney, Australia. In response to the positive comments, we have continued our endeavor and in addition, investigated 30 day outcomes and length of stay for the homogeneous subset of anatomic lobectomy.

      Methods:
      Data was collected from a single surgeon at a single center and includes all consecutive thoracic surgical patients recovered through the WAVE program from July 2010 - July 2016. We excluded patients undergoing tracheostomy, endoscopic only procedures, and mediastinoscopy. Data was collected prospectively and analyzed retrospectively.

      Results:
      From July 2010 - July 2016, 1152 patients were included for analysis. Within the 6 year period, 798/1152 patients (69%) walked any distance within one hour of extubation, 945/1152 patients (82%) walked 250 feet at any time while in the PACU, 721/1152 patients (63%) successfully walked the targeted distance of 250 feet within one hour of extubation and only 37/1152 patients (3%) were unable to ambulate at all in the PACU. There were no adverse events. The subset of anatomic lobectomies included 290 patients of which 197/290 patients (68%) walked any distance within one hour of extubation, 239/290 patients (82%) successfully walked 250 feet at any time while in the PACU, 175/290 patients (60%) achieved the target distance of 250 feet within one hour of extubation and only 5/290 patients (1.7%) were unable to ambulate at all in the PACU. The rate of 30 day post-operative complications compares favorably with the literature and are as follows: 4.1% atrial arrhythmia, 1.0% pneumonia, 6.6% air leak > 5 days, 0.7% DVT, 0.3% acute renal failure, 0.3% pulmonary embolism, 0% stroke, 0% myocardial infarction, 4.8% readmission and 0% mortality. Mean length of hospital stay was 1.6 days with a median of 1 day.

      Conclusion:
      Our “WAVE” experience reveals that aggressive early ambulation is effective in reducing post-operative complications and shortening length of stay. The platform is simple, reproducible and feasible for any thoracic surgical program. Key features for successful implementation include patient and family engagement, a multi-disciplinary team and administrative support.

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      OA01.07 - Alternative Follow-Up Methods Based on Recurrence Patterns after Surgery for Non-Small Cell Lung Cancer (Now Available) (ID 4323)

      K. Watanabe, T. Nishii, K. Sakamaki, T. Yamamoto, A. Gorai, T. Nagashima, K. Ando, Y. Ishikawa, T. Woo, H. Adachi, Y. Kumakiri, T. Maehara, H. Nakayama, M. Masuda

      • Abstract
      • Presentation
      • Slides

      Background:
      There is no consensus for the appropriate follow-up of patients after complete resection of non-small cell lung cancer (NSCLC). Our study was designed to visually represent postoperative recurrence patterns for NSCLC with the use of event dynamics and to optimize postoperative follow-up schedule based on risk factors for recurrence.

      Methods:
      A total of 829 patients with NSCLC who underwent complete pulmonary resection were studied. There were 538 men and 291 women with a mean age of 69.2 at the time of operation. The majority of the patients had adenocarcinoma (62.5%), underwent lobectomy (85.9%) and pathological stage IA (47.3%). Event dynamics, based on the hazard rate, were evaluated and only first events (distant metastases or local recurrence) were considered. The effects of sex, histological type and pathological stage were studied.

      Results:
      On non-parametric kernel smoothing, the resulting hazard rate curves indicated that the recurrence risk pattern was definitely correlated to sex, with a sharp peak in the first year for men and broad peak during the 2 to 3 years for women. This finding was also confirmed by the analysis of histological type. Although pathological stage IA patients lacked such a large peak in both sexes during the follow-up period, gender difference was shown in pathological stage IB and stage IIA to IIIB patients. Figure 1



      Conclusion:
      The use of recurrence dynamics allows the times of peak recurrence to be visualized. The hazard rate and the peak times of recurrence differed considerably between genders in pathological stage IB or higher. Postoperative follow-up methods should be based on currently recommended follow-up guidelines, give adequate consideration to the recurrence patterns, and be modified individually.

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      OA01.08 - Discussant for OA01.05, OA01.06, OA01.07 (Now Available) (ID 7007)

      T. Klikovits

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
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      JCES01.18 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (ID 7060)

      W. Zhong

      • Abstract
      • Slides

      Background:
      Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.

      Methods:
      Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.

      Results:
      288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.

      Conclusion:
      Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.

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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA15.10 - Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma (ID 4885)

      W. Zhong

      • Abstract
      • Slides

      Background:
      Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade remains elusive. This study was sought to identify the potential biomarkers that predicted response to PD-1 blockade immunotherapy in lung adenocarcinoma.

      Methods:
      We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from cohorts of both lung adenocarcinoma public database including The Cancer Genome Atlas (TCGA), GEO repository (GSE72094) and Broad dataset, and clinical immunotherapeutic patients in our center. Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.

      Results:
      We observed distinct function of TP53 and KRAS mutation in regulating immune tumor microenvironment (TME). It is TP53 mutation but not KRAS mutation in lung adenocarcinoma that significantly increased expression of immune checkpoints, facilitated CD8+T cell infiltration and activated T-effector and interferon-γ (IFN-γ) signature. Interestingly, TP53 and KRAS co-mutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. More importantly, TP53 or KRAS mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell cycle regulating, DNA replication and damage repair. Finally, clinical immunotherapeutic data were further confirmed that TP53 or KRAS mutation lung adenocarcinoma patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 blockade immunotherapy. Figure 1



      Conclusion:
      This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.

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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      MA17.05 - Evolutionary Trajectories of Molecular Progression in Different Subtypes of Primary Lung Adenocarcinomas (Now Available) (ID 5712)

      W. Zhong

      • Abstract
      • Presentation
      • Slides

      Background:
      Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

      Methods:
      Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

      Results:
      Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1



      Conclusion:
      We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

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    OA09 - Locally Advanced NSCLC: Innovative Treatment Strategies (ID 384)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA09.03 - Randomized Controlled Study Comparing Adjuvant versus Neo-Adjuvant Chemotherapy  in Resectable Stage IB to IIIA NSCLC (Now Available) (ID 5843)

      W. Zhong

      • Abstract
      • Presentation
      • Slides

      Background:
      Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival(DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC.

      Methods:
      Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued.

      Results:
      Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1.Figure 1



      Conclusion:
      Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.

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    OA15 - Sublobar Resections for Early Stage NSCLC (ID 396)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Surgery
    • Presentations: 1
    • Now Available
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      OA15.08 - Discussant for OA15.05, OA15.06, OA15.07 (Now Available) (ID 7091)

      W. Zhong

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 2
    • Now Available
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      P1.05-046 - Randomized Study of Adjuvant Docetaxel vs. Observation for Completely Resected StageⅠB-Ⅲa NSCLC with 11 Years' Median Follow-Up (ID 5722)

      W. Zhong

      • Abstract

      Background:
      Although previous meta-analyses have verified the significance of adjuvant chemotherapy, the role of adjuvant carbopatin plus docetaxel(DC) among patients with completely resected NSCLC with long periods of follow-up remains unclear.

      Methods:
      Eligible patients were randomly assigned to 4 cycles of DC or observation after complete resection. The primary end point was DFS; secondary ones were OS, the toxicity and safety of drugs. An increase of 15% in 1-year survival rate (observation arm 70%) with a sample size of 270 patients was considered significant.

      Results:
      This trial was suspended prematurely in June 2005 due to the negative survival benefits from chemotherapy in stage IB patients in the JBR10 trial. 82 patients were enrolled between 2002 to 2005(43 and 39 in each arm).Two arms were well-balanced on age, gender, histology, smoking history and staging. Median follow-up was 11 years(10.5-13y). DFS was marginally significantly longer in DC arm than observation (10.4 vs. 3.7y; HR=0.58; 95% CI, 0.33-1.03; P=0.06), as was 5-year DFS rates(63% vs. 41%, P=0.057). No statistical significance existed in OS (NR vs. 7.1y; P=0.103) or 5-year survival rates(76% vs. 61%; P=0.148). Multivariable analysis revealed patients receiving adjuvant DC(HR=0.54,95%CI 0.30-0.96,P=0.036) and with stage IB disease(HR=0.34,95%CI, 0.19-0.61,P<0.001) bore lower recurrence risk. In DC arm, 84% of patients received at least one cycle of DC, and 53% of patients finished four. Grades 3 adverse events occurred in 5%(2/43) in chemotherapy group. The time-varying endpoints showed adjuvant DC could delay the recurrence and mortality in the first postoperative 5ys, while two arms tended to be equivalent after 5ys. Figure 1



      Conclusion:
      This is the first randomized trial used DC as adjuvant chemotherapy suggesting a potentially significant role for completely resected early stage NSCLC with safety and compliance. Additionally, at least 10ys’ follow-up for each patient was vital to investigate the long-term time-varying recurrence and mortality pattern.

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      P1.05-072 - Predictors and Patterns of Lymph Node Metastasis in Small Peripheral Non Small Cell Lung Cancer (Now Available) (ID 4268)

      W. Zhong

      • Abstract
      • Slides

      Background:
      Lobectomy is the standard treatment of early stage non-small cell lung cancer (NSCLC) and wheather sublobar resection is appropriate for small peripheral small NSCLC or not is unclear. PET-CT is a powerful imaging modality for the detection of lymph node metastasis with a relatively low false-negative rate. We identified predictors and patterns to identify false-negative N(+) disease in PET-CT.

      Methods:
      A total of 435 consecutive cN0 peripheral NSCLC underwent curative-intent resections following PET-CT scans from January 2008 to December 2014 in our hospital, we analysed patients’ clinicopathological data retrospectively. 171 patients with tumour size≤2cm were enrolled to identify predictors and patterns of lymph node metastases by multivariable analysis. The cut‑off values, sensitivity and specificity for the predictors were calculated using a receiver operating characteristic curve. The patterns of lymph node metastases were also analysed.

      Results:
      In total, 9.4% (16/171) PET-CT-diagnosed N0 NSCLC cases were pathologically N1/N2 disease. The preoperative CEA was a unique independent risk factor for lymph node metastasis (OR = 0.914, 95 CI% = 0.85–0.98, P = 0.009). According to ROC curve, we divided the patients into two groups by CEA: the N(+) rates in the CEA ≤1.67 and CEA> 1.67 groups were 1.6% (1/64) and 14.0% (15/107), respectively (P =0.007). In 16 patients with lymph node metastasis, 7 were N1 disease, and 6 out of 9 N2 diseases were skip N2 disease. 93.5%(15/16) lymph node metastases were found in adenocarcinoma and 11 of them were single station metastases. The metastases rates in solid and subsolid lesions were 12.8%(16/125) and 0%(0/46)(P=0.007), retrospectively. Solid/mucinous/ micropapillary predominant adenocarcinoma were associated with LN metastases(31.2% vs 7.1%, P=0.01).

      Conclusion:
      The preoperative CEA was an independent risk factor for lymph node metastases in cN0 NSCLC with T ≤ 2cm. In patients with CEA>1.67, sublobar resection should be avoided before thorough lymph node sampling that include intrapulmonary lymph node while patients with CEA ≤ 1.67 may be candidate for sublobar resection, especially in GGO lesions. In patients with solid/mucinous/ micropapillary predominant adenocarcinoma, sublobar resection should be avoided due to high LN metastases rate.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • Now Available
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      P1.07-038 - Typical Morphological Features Revealed Unfavorable Survival Benefits in High-Grade Neuroendocrine Carcinomas (Now Available) (ID 5718)

      W. Zhong

      • Abstract
      • Slides

      Background:
      The 2015 WHO classification of lung cancer has proposed an revision about high-grade neuroendocrine carcinomas(HGNEC). Neuroendocrine(NE) markers are necessary for differentiations in cases lacing in typically morphological features, but their roles in survival benefits remain unclear.

      Methods:
      A total of 700 consecutive patients diagnosed with pNET were re-diagnosed during 2008 to 2015 and 632 were HGNECs. NE markers, such as Syn(synaptophysin), CgA(chromogranin A) and CD56, were stained by immunohistochemistry(IHC) if morphological features were not enough for diagnoses.

      Results:
      Four were excluded due to clinical identification of transformation from adenocarcinomas to SCLC. Nine HGNECs were previously diagnosed with AC. TTF1 stained 77.4%(459/593) HGNEC patients, of which 50.6% in LCNEC, 80.9% in SCLC and 62.5% in poorly differentiated HGNEC(P<0.001). Syn staining(94.1%, 571/607) were not statistically significant in three groups(89.1% vs. 94.6% vs. 100.0%, respectively; P=0.30). The same situation was in CgA(52.6%, 319/607), with a frequency of positive staining as 46.9%, 53.6% and 25.0%(P=0.26), respectively in three diagnoses. The number of positive NE markers were generally balanced(P=0.62). Cases with zero to three positive NE markers indicated marginal significant differences of overall survival(OS)(P=0.05). Meanwhile, no differences of mOS existed in positive and negative staining of Syn(14.7 vs. 32.53 mons, P=0.14) or CgA(14.6 vs. 15.9 mons, P=0.82); but patients with typical morphological features for diagnose and thus without IHC staining Syn or CgA (mOS, 9.13mons) bore significantly poorest OS benefits than those with positive(Syn, HR=2.71, 95%CI=1.24-5.86, P=0.01; CgA, HR=2.72, 95%CI=1.25-5.92, P=0.01) or negative(Syn, HR=3.44, 95%CI=1.39-8.52, P<0.01; CgA, HR=2.76, 95%CI=1.26-6.05, P=0.01) staining. The same condition occurred especially inⅠto Ⅲa patients(P<0.01). Figure 1



      Conclusion:
      The number of positive NE markers were necessary for precise diagnoses but not significant for survival benefits. Typical morphological features of NE tumor cells were unfavorable factors for OS. Further studies are imperative to identify its crucial role in HGNEC patients.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02b-095 - Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs (Now Available) (ID 6057)

      W. Zhong

      • Abstract
      • Slides

      Background:
      With the marketing of osimertinib, epidermal growth factor receptor (EGFR) T790M mutation has become a clinically significant biomarker for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) after acquired resistance to previous EGFR TKIs. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated.

      Methods:
      We retrospectively reviewed T790M status and clinical courses of 93 patients who underwent multiple (≥2) rebiopsies after acquired resistance to first or second generation EGFR TKIs from 2010 to 2015 in Guangdong General Hospital. Patients underwent synchronous rebiopsies at the same lesion or paired tissue and plasma rebiopsies were enrolled to evaluate the spatial T790M heterogeneity. Patients received heterochronous rebiopsies at the same lesion or different lesions were enrolled to evaluate the temporal and spatiotemporal T790M heterogeneity respectively.Tissue EGFR detection was performed by SNAPSHOT or Amplification Refractory Mutation System (ARMS). Plasma EGFR was detected by ARMS.

      Results:
      A total of 99 evaluations were performed with 6 of 93 enrolled patients underwent both synchronous and heterochronous rebiopsies. Among 20 patients who underwent synchronous rebiopsies at the same lesion, 13 revealed T790M heterogeneity. Among 17 patients who had paired tissue and plasma rebiopsies, 8 showed T790M heterogeneity. Spatial T790M heterogeneity ratio was 57% (21/37) in general. 33% (10/30) patients who received heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who received heterochronous multiple sites rebiopsies. Of abovementioned patients with heterochronous T790M heterogeneity, T790M status in 67% (18/27) switched from negative to positive after chemotherapy or continuation of EGFR TKIs and in 33% (9/27) switched from positive to negative after chemotherapy or combined regimens of chemotherapy and EGFR TKIs.

      Conclusion:
      T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs. Repeated rebiopsies both at the same lesion and various lesions might be valued particularly in T790M-negative cases in this subset of patients.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02c-060 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (Now Available) (ID 4502)

      W. Zhong

      • Abstract
      • Slides

      Background:
      Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.

      Methods:
      Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.

      Results:
      288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups. Figure 1



      Conclusion:
      Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.

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