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William D Travis



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    ES 01 - New TNM and WHO Classification (ID 510)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      ES 01.02 - New Histological Classification (ID 7584)

      11:00 - 12:30  |  Presenting Author(s): William D Travis

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The 2015 WHO Classification had a major impact on the new 8[th] Edition TNM Classification. Compared to the 2004 Classification, major changes include: 1) use of immunohistochemistry throughout; 2) New emphasis on genetic studies and personalized therapeutic strategies; 3) A new classification of lung cancer in small biopsy and cytology samples; 4) adoption of the 2011 IASLC/ATS/ERS lung adenocarcinoma classification; 5) reclassification of large cell carcinoma based upon immunohistochemistry and genetics. Since publication of the 2015 WHO Classification new advances include recognition of ciliated muconodular papillary tumors, SMARCA4 and SMARCB1 deficient neoplasms and digital image analysis as a novel way to assess lung cancer morphology. This presentation will primarily focus on the impact of the new WHO Classification on the 8[th] Edition TNM classification. First the new TNM classification incorporates the introduction of the concepts of adenocarcinoma in situ (AIS) which should be staged as Tis (AIS) and minimally invasive adenocarcinoma (MIA) which should be staged as T1mi. AIS is defined as a lung adenocarcinoma with pure lepidic growth measuring ≤3 cm. MIA is defined as a ≤3 cm lepidic predominant adenocarcinoma with an invasive component measuring 0.5 cm or less. Both AIS and MIA should lack stromal, vascular, or pleural invasion and spread through alveolar space invasion (STAS). Lepidic predominant adenocarcinomas are lung adenocarcinomas with a predominant lepidic component that measure > 3 cm in total size or that have an invasive component measuring >0.5 cm. It is recommended to use invasive size for T-descriptor size in nonmucinous adenocarcinomas with a lepidic component. This is in keeping with a recommendation made in three editions of the UICC TNM Supplement since 2003. It is also supported by a growing amount of evidence showing that invasive size is a better predictor of survival than total size in nonmucinous adenocarcinomas with a lepidic component. Both radiologists and pathologists should report the greatest dimension for tumor size for both clinical and pathologic staging. In addition for nonmucinous lung adenocarcinomas, both the total size and invasive size should be reported with invasive size used for T-factor size determination. By computed tomography (CT) in nonmucinous lung adenocarcinomas, the presence of ground glass versus solid opacities generally correspond to lepidic versus invasive patterns respectively seen pathologically. Since, this is not an absolute correlation, when CT features suggest nonmucinous AIS, MIA and LPA, reporting of the suspected diagnosis and clinical staging, should be made as a preliminary assessment that may need to be revised after evaluation of resected specimens pathologically. Since the mucinous variants of AIS, MIA and invasive mucinous adenocarcinomas usually present by CT as a solid or consolidated nodule, and due to the lack of proven correlation between ground glass/solid CT appearance with lepidic/invasive growth pathologically it is not recommended to apply the total vs solid size assessment by CT in suspected invasive mucinous adenocarcinomas. Furthermore there is insufficient data in invasive mucinous adenocarcinomas that invasive size is a better predictor of survival than total size. Pathologic assessment of total vs invasive tumor size in resected nonmucinous lung adenocarcinomas with a lepidic component can be improved by reviewing CT scans because the lepidic component is often poorly appreciated pathologically on gross exam and size is underestimated. In addition, tumor size can be more accurately assessed after radiologic pathologic correlation in the following settings: 1) Lepidic nonmucinous adenocarcinomas that do not fit onto a single slide, 2) Sausage or bilobed shaped tumors where the maximum single diameter may be better assessed using all three CT views (axial, coronal and sagittal) rather than just axial alone, 3) Tumors removed in multiple parts, 4) Intraoperative defects in tumors, 5) Marked non-neoplastic reactions, 6) Mistaken pathologic assessment. In neoadjuvant tumors, it can be difficult to measure tumor size because tumors that show considerable treatment effect often do not have a uniform response allowing a single focus of viable tumor to be measured. It has been shown that 90% or more treatment effect is the most important prognostic finding instead of tumor size in surgically resected nonsmall cell lung cancer patients following induction therapy. One way to estimate viable tumor size is to multiply the percent of viable tumor cells times the size of the total tumor bed. This can be utilized in the setting of a single focus or multiple foci of viable tumor. Recording the percentage of treatment effect is important in addition to estimating tumor size for T-factor determination. REFERENCES 1. Travis WD, et al The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 2. Travis WD, et al WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 3. Travis WD, et al The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2016;11:1204-23. 4. Tsutani Y, et al Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma. JThoracCardiovascSurg 2012;143:607-12. 5. Maeyashiki T, et al The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg 2013;43:915-8. 6. Yoshida A, et al Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Modern pathology : 2017;30:797-809. 7. Luo X, et al Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis. J Thorac Oncol 2016;12:501-9. 8. Kamata T, et al . Ciliated Muconodular Papillary Tumors of the Lung: A Clinicopathologic Analysis of 10 Cases. The American journal of surgical pathology 2015;39:753-60. 9. MacMahon H, et al Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43. 10. Kamata T, et al. Frequent BRAF or EGFR Mutations in Ciliated Muconodular Papillary Tumors of the Lung. J Thorac Oncol 2016;11:261-5.

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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.09 - Circumferential Distribution and Distance from Main Tumor of Tumor Spread Through Air Spaces (STAS) Are Prognostic (ID 10143)

      15:45 - 17:30  |  Author(s): William D Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognostic impact of the presence of tumor spread through air spaces (STAS) has been reported in lung adenocarcinoma (ADC). The aim of this study is to investigate the prognostic impact of the distribution, distance from the primary tumor, and quantification of STAS.

      Method:
      A cohort of 394 patients with pathologic stage I lung ADC (2012-2014) were investigated. The distribution of STAS around the tumor was classified into focal or circumferential. The distance of STAS was evaluated by counting the number of air spaces between the farthest STAS and the tumor edge. STAS was quantified by counting the number of STAS areas in the three most STAS- dense 20x high power fields (HPFs). The recurrence free probability (RFP) was analyzed by the Kaplan-Meier method with a log-rank test.

      Result:
      STAS was present in 211 (54%) cases. The presence of STAS was associated with a higher risk of recurrence (5-y RFP in STAS-positive vs. STAS-negative; 78% vs 90%, p<0.001, Fig 1A). Circumferential STAS was associated with a higher risk of recurrence than focal STAS (5-y RFP in circumferential vs. focal; 67% vs 87%, p=0.027, Fig 1B). A longer distance of STAS was associated with a higher risk of recurrence (5-y RFP >7 alveoli vs.≤7 alveoli, 69% vs. 91%, p=0.003, Fig 1C). Quantification of STAS was not prognostic (5-y RFP in >3/HPFs vs. ≤3/HPFs, 75% vs. 88 %, p=0.15). Figure 1 X



      Conclusion:
      Beyond just the presence of STAS, the distribution and distance of STAS can further stratify the risk of recurrence in stage I lung ADC.

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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.13 - Impact of Histologic Subtype of Locally Advanced Lung Adenocarcinoma on Outcomes After Definitive Chemoradiation (ID 10382)

      15:45 - 17:30  |  Author(s): William D Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      Micropapillary and solid subtypes of lung adenocarcinoma have significantly worse outcomes and survival after surgical resection for early-stage disease. These subtypes have recently been shown to have higher locoregional and metastatic progression after definitive stereotactic radiation therapy (SBRT) as well. However, the potential impact of histologic subtype on locally advanced disease treated with definitive concurrent or sequential chemoradiation (CRT) has not been previously explored. We sought to identify high-risk subtype patients treated with CRT, and compare their outcomes with those not known to have high-risk histologic subtypes.

      Method:
      We identified 249 consecutive patients with stage IIIA-B lung adenocarcinoma who had undergone CRT at our institution from 2008 to 2015. All patients had pathology reviewed by pathologists at our institution with subspecialty expertise in thoracic pathology. Twenty-five patients had elements of micropapillary and/or solid subtype on core biopsy, according to the 2015 World Health Organization classification. The remaining 224 patients were considered non-high-risk (8 patients had core biopsy with no high-risk subtypes identified; 216 patients either did not undergo core biopsy or did not have subtyping performed). Local, nodal, regional, and distant failure were estimated using cumulative incidence (CI) curves and compared using the log-rank test. Time to each event was measured from the date of diagnosis until the event of interest or the last follow-up visit.

      Result:
      With median followup of 19.7 months, there was a trend towards greater 2-year CI of local failure in the high-risk vs. non-high-risk group (40.7% vs. 26.7% p=0.060). The 2-year CI of nodal, regional, and distant failure in high-risk versus non-high-risk groups was 30.9% vs. 32.6% (p=0.576), 24.7% vs. 20.1% (p=0.468), and 63.9% vs. 59.8% (p=0.272), respectively, though statistical power was limited due to the small number of known high-risk patients.

      Conclusion:
      Though only a limited proportion of patients had demonstrated high-risk subtypes in this cohort, there was a trend towards earlier local failure in locally advanced adenocarcinoma patients treated with definitive concurrent or sequential chemoradiation, similar to what has been observed for early-stage tumors treated with SBRT. Hence, high-risk histologic subtype may be a prognostic factor for early treatment failure in locally advanced adenocarcinoma patients treated with CRT. We suggest that core biopsies, which are required for histologic subtyping, should be obtained more often in these patients, to allow for further study of the hypothesis that histologic subtype predicts outcomes after definitive chemoradiation.

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    OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA 03.03 - Phase II Trial of Cetuximab and Chemotherapy Followed by Surgical Resection for Locally Advanced Thymoma (ID 10288)

      11:00 - 12:30  |  Author(s): William D Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      The mainstay of treatment for thymoma is surgery with neoadjuvant chemotherapy recommended to patients with locally advanced disease. EGFR is overexpressed in thymoma. Clinical responses to single-agent cetuximab have been reported in patients with advanced cetuximab. We conducted this two-site prospective phase II trial of cetuximab combined with a standard induction chemotherapy regimen of cisplatin, doxorubicin and cyclophosphamide (PAC) in patients with locally advanced thymoma prior to surgical resection.

      Method:
      Patients with clinical Masaoka stage III-IVA thymoma were treated with cetuximab (250mg/m[2] weekly x 4 weeks) followed by cetuximab (250 mg/m[2] weekly) combined with cisplatin (50mg/m[2]), doxorubicin (50 mg/m[2]) and cyclophosphamide (500mg/m[2]) 3 weeks x 4 cycles). Radiographic response was assessed by CT using RECIST 1.1 and FDG-PET using PERCIST. All patients went on to surgery after completion of induction therapy. The primary endpoint was major pathologic response (MPR, >90% treatment effect). Planned enrollment was 18 patients in first stage of a two stage design. If 1 MPR was observed, then enrollment would expand to 28 patients.

      Result:
      Eighteen patients were enrolled: 8 women, median age 53 (range 32-73). WHO Histologic subtype A: 2, AB: 3, B1: 3, B2: 7, B3: 3. Final Masaoka stage I: 2, II: 2, III: 5, IVA: 9. There were no responses to cetuximab alone by RECIST criteria, although 1 patient had a 25% reduction in indicator lesions. Response rate (CR+PR), in evaluable patients after complete treatment course was 50% (8/16, 95% CI 28-72%). Partial responses by PERCIST criteria were seen on PET in 11/18 (61%) evaluable patients. There were no MPRs. R0 resection was obtained in 7 patients; 5 had R1 and 6 had R2 resections.

      Conclusion:
      The addition of cetuximab to PAC chemotherapy did not lead to pathologic complete responses in the neoadjuvant setting. Cetuximab alone appears to have little effect during 4 weeks of treatment. There was no apparent increase in radiographic response rate with the addition of cetuximab to PAC chemotherapy compared to historical series.

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    OA 18 - Lung Cancer Pathology and Genetics (ID 687)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 18.06 - Three-Dimensional Assessment of Spread Through Air Spaces in Lung Adenocarcinoma: Insights and Implications (ID 8826)

      14:30 - 16:15  |  Author(s): William D Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor spread through air space (STAS) is a newly recognized form of invasion in lung adenocarcinoma and squamous cell carcinoma and growing evidence shows it is associated with recurrence and survival. The observation that tumor STAS clusters/nests or single cells within air spaces on two-dimensional H&E slides raised the question of how these cells could survive within air spaces without a vascular supply and this has led some to speculate STAS is an artifact. Herein, we perform the high resolution-high quality 3D reconstruction and visualization of normal lung and tumor in a lung adenocarcinoma to investigate the invasive pattern of STAS.

      Method:
      A formalin-fixed paraffin embedded block of invasive adenocarcinoma with micropapillary pattern and extensive STAS was studied. Following our histology 3D reconstruction standard procedure, 3D reconstruction was performed for analysis from 200 serial sections of H&E stained 20x (0.5um/pixel resolution) whole slide images. The relationship to alveolar walls between micropapillary structures within the tumor and STAS clusters in lung parenchyma distant from the tumor was evaluated.

      Result:
      3D reconstruction and analysis demonstrated the following novel features – a) in the main tumor area, micropapillary structures within airspaces were connected to alveolar walls, b) unlike in 2D evaluation where STAS appeared as ‘free-floating’ micropapillary clusters, in 3D evaluation many STAS clusters within air spaces are attached to alveolar walls, and c) STAS clusters that appear ring-like in 2D by 3D evaluation they are actually balls of tumor cells surrounding a central space.

      Conclusion:
      Our 3D reconstructed image analysis for the first-time demonstrates that most STAS cells are not ‘free-floating’, rather attached to the alveolar walls. In addition within the main tumor micropapillary clusters are attached to alveolar walls. These findings raise an intriguing hypothesis that STAS cells are clusters of tumor cells spread within alveolar spaces in a non-contiguous fashion to reattach to the alveolar walls at a distance possibly by co-option of alveolar wall capillaries to support their growth. This form of spread is analogous to the phenomenon of vascular spread where tumor cells spread freely within blood vessels to distant sites where they attach to endothelium and extravasate through the vessel walls to form metastases. It is possible the ball-like configuration of STAS clusters may facilitate movement through alveolar spaces distant from the main tumor. The frequent alveolar wall attachment of STAS observed on serial 3D imaging disputes the concept this is an artifact.

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    P1.13 - Radiology/Staging/Screening (ID 699)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.13-003 - Recurrence Dynamics in Resected Pathological Stage I Lung Adenocarcinoma Depend on the IASLC/ATS/ERS Histological Subtype (ID 9423)

      09:30 - 16:00  |  Author(s): William D Travis

      • Abstract
      • Slides

      Background:
      Current practice guidelines recommend uniform follow-up protocol for all stage I lung adenocarcinoma (ADC) patients who underwent surgical resection. We hypothesized that the annual recurrence hazard of resected pathological stage I lung ADC patients vary according to the IASLC/ATS/ERS histological subtype.

      Method:
      Pathological stage I lung ADC patients who had undergone complete resection (R0) without induction therapy (N=1572, 1995-2012) were analyzed.

      Result:
      Among 1572 patients, 271 (18.5%) recurrences were identified (median follow-up 64.0 months) with highest peak of recurrence within first two years following resection. Patients who had undergone sublobar resection showed higher recurrence rate than those who had undergone lobectomy (Fig. 1A). The recurrence hazard increased as a function of the percentage of micropapillary (MIP) pattern (Fig. 1B), while the solid pattern contributed to the early recurrence (Fig. 1C). According to the presence of MIP and/or solid (SOL) pattern, the recurrence hazard is well stratified. Tumors without micropapillary and solid subtype show no peak with 2% of annual recurrence hazard within 10 years following resection, while tumors with both MIP and SOL patterns have the highest peak within 2 years compared to other MIP and SOL combinations.

      Conclusion:
      Patients with resected pathological stage I lung ADC show structured recurrence dynamics well stratified with the high risk histological subtypes, providing clinically useful prognostic information for patients and physicians. Figure 1



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    P2.05 - Early Stage NSCLC (ID 706)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P2.05-021 - Occult Nodal Metastasis Following Lobectomy for Clinical Stage I Lung Adenocarcinoma: Implications for Sublobar Resection (ID 9436)

      09:30 - 16:00  |  Author(s): William D Travis

      • Abstract
      • Slides

      Background:
      We investigated the incidence and location of occult nodal metastasis (ONM) in patients who had undergone lobectomy and lymph node dissection for clinical stage I lung adenocarcinoma (ADC). We performed a risk regression analysis to identify any associated radiologic and pathologic factors.

      Method:
      Clinical stage I lung ADC patients (stage II and III were excluded by CT and FDG-PET/CT scans) who underwent lobectomy and systematic lymph node dissection (N=715, 2005-2011) were included in the analysis. ONM were defined as pathologically diagnosed metastatic lymph nodes that are not suspected to be involved by cancer on both CT and PET scans.

      Result:
      Among 715 patients, 75 (10.5%) ONM were identified: 64 (85%) hilar or peribronchial and 32 (43%) mediastinal. Multivariable risk regression analysis identified tumor diameter, SUVmax, and lymphovascular invasion as risk factors (P<0.01). The incidence of subcarinal lymph node (LN) metastasis was very low among patients whose primary tumors were in the right upper lobe or left upper division (N=1/439, 0.2%). Lower mediastinal LN metastasis was rarely identified only when the primary tumor was located in the right lower or left lower lobe (N=2/210, 1.0%).

      Conclusion:
      One in ten patients with clinical stage I lung adenocarcinoma showed occult nodal metastases, with the highest incidence in hilar lymph nodes; this observation may be relevant for clinicians when considering sublobar resection for these patients. Figure 1



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    P3.13 - Radiology/Staging/Screening (ID 729)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P3.13-019 - Preoperative Needle Biopsy Does Not Increase the Risk of Pleural Recurrence in ≤3cm Lung Adenocarcinoma (ID 9526)

      09:30 - 16:00  |  Author(s): William D Travis

      • Abstract

      Background:
      Percutaneous transthoracic needle biopsy (NB) has been widely used for the preoperative diagnosis of lung nodules. It has been proposed that the risk of pleural recurrence is high following lung resection in patients who underwent preoperative NB for sub-pleural nodules (Kashiwabara, et al. Cancer Invest 2016; Wang, et al. Sci Rep 2017). The aim of this study is to investigate the prognostic impact of preoperative NB for pleural recurrence in patients with early-stage lung adenocarcinoma (ADC).

      Method:
      Patients who underwent lung resection for pathologic stage I (≤3cm) lung ADC were included in the analysis (1995-2014, n=992; NB group 626 patients and no-NB group 366 patients). We compared the clinicopathologic characteristics and recurrence free probability (RFP, separately analyzed for any, locoregional, pleural, and distant recurrence) between NB and no-NB groups. The risk of pleural recurrence was evaluated in tumors both with and without visceral pleural invasion (VPI).

      Result:
      The NB cohort was associated with older age and larger tumor size compared to the no-NB cohort (p<0.05). There was no statistical difference in the incidence of VPI (VPI in NB, 12% vs. VPI in non-NB, 15%, p=0.2). In RFP analysis by Kaplan-Meier method with log-rank test, there was no statistical difference between NB and no-NB groups (NB vs. non-NB: 5-year RFP for any recurrence, 86% vs. 86%, p=0.8; locoregional recurrence, 93% vs. 94%, p=0.7; pleural recurrence, 98% vs. 96%, p=0.14; and distant recurrence 94% vs. 93%, p=1). In tumors both with and without VPI (n=128 and n=864, respectively), the risk of pleural recurrence was not higher after NB (Figure; 5-year RFP for pleural recurrence [NB vs. no-NB]: VPI positive, 93% vs. 83%, p=0.3; VPI negative, 98% vs. 97%, p=0.4). Figure 1



      Conclusion:
      Preoperative needle biopsy was not associated with an increased risk of pleural recurrence following lung resection.