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  MTE 06 - Lung Cancer Pathology Update (Sign Up Required) (ID 555)

  • Event: WCLC 2017
  • Type: Meet the Expert
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 07:00 - 08:00, Room 315

  • 22394

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    MTE 06.01 - Lung Cancer Pathology Update (ID 7782)

    07:00 - 08:00  |  Presenting Author(s): Andre L. Moreira
    • Abstract
    • Presentation
    • Slides

    Abstract:
    This session will focus on some new definitions and concepts in the recently published 2015 WHO classification of lung tumors (1), some of which were showcased in the 2011 IASLC/ATS/ERS lung adenocarcinoma classification (2), while others are introduced for the first time. We will focus on resected lung adenocarcinoma as well resected squamous cell carcinoma, large cell carcinoma and the neuroendocrine tumor spectrum. Adenocarcinoma: In the 2015 WHO classification, the definition of adenocarcinoma has been expanded from a malignant epithelial tumor with glandular differentiation or mucin production to include tumors that also express pneumocyte immunomarkers (e.g. TTF1, Napsin A). This means that undifferentiated carcinomas formerly classified as large cell carcinoma that express pneumocyte immunomarkers, like undifferentiated carcinomas that show mucin expression, are now included in the solid adenocarcinoma category. Invasive adenocarcinomas account for >70% of all surgically resected cases and consist of a complex admixture of histologic subtypes. In an effort to represent this morphologic complexity, comprehensive histologic subtyping was introduced in the 2011 IASLC/ATS/ERS classification. A number of recent studies have demonstrated the utility of comprehensive histologic subtyping in identifying prognostically significant groups of tumors . Studies published both before and after the 2011 IASLC/ATS/ERS classification have highlighted the importance of the secondary patterns in addition to the predominant pattern in resected lung adenocarcinoma. Comprehensive histologic subtyping, its pitfalls and the emerging significance of secondary patterns in tumour recurrence and prognosis will be discussed further in this session. Grading: There is no well-established, internationally accepted grading system in resected lung adenocarcinoma. A simple grading system based on predominant histologic subtype has been proposed due to the prognostic significance of predominant histologic subtype. Other suggested grading schemes include different combinations of mitotic count, second predominant pattern and nuclear features with predominant histologic subtype. The emerging concept of an objective grading system for pulmonary adenocarcinomas will be briefly explored in this session. Another newly introduced concept in the 2015 WHO classification is that of tumour spread through alveolar spaces (STAS) which may occur with micropapillary clusters, solid nests or single cells. STAS was found to be associated with an increased recurrence rate in patients with stage I adenocarcinomas <2cm who underwent sublobar resections (3). Tumour size and staging: A recent study confirmed that in resected non-mucinous adenocarcinoma, the size of the invasive component, excluding the lepidic (equated with in situ) component of the tumor, correlates better with patient outcome than total tumour size (4). This finding has been supported by other studies and is expected to be included in the upcoming 8[th] edition TNM staging system for the T descriptor for pathologic staging in resected non-mucinous adenocarcinoma (5). Squamous cell carcinoma (SQCC) is the second most prevalent Non-small cell lung cancer (NSCLC), behind adenocarcinoma. Contrary to the latter where most changes in nomenclature, diagnosis and molecular pathology have occurred, SQCC has a strong association to smoking and remains a challenge for oncologists with few therapeutic advances. To reduce the risk of over diagnosing SQCC, the definition of SQCC became stricter in the 2015 WHO classification. For the diagnosis of this entity it is necessary to have evidence of keratinization and intercellular bridges. For non-keratinizing SQCC it is necessary to demonstrate evidence of squamous differentiation by immunohistochemical (IHC) stain (diffuse positivity for p40 or p63 and absence of adenocarcinoma markers such as TTF-1 and napsin-A). Non-keratinizing SQCC shares a solid pattern of growth with adenocarcinoma; in addition, solid type adenocarcinomas can have squamoid features such as glassy and abundant cytoplasm that can mimic SQCC (6), therefore it is recommended the use of IHC for any NSCLC with solid pattern of growth. Presence or absence of mucin is not a criterion for diagnosis of SQCC. Similar to adenocarcinoma, there is no grading system for SQCC. There is evidence that tumour budding is associated with worse prognosis (7). Basaloid carcinoma is now classified in the same group of SQCC and no longer part of large cell carcinoma. In contrast, Lymphoepithelioma-like carcinoma of the lung that share IHC profile with squamous cell carcinoma is grouped in the category of other undifferentiated tumours that also include NUT carcinoma. Large cell carcinoma: remains a separate category; however, the diagnosis of this entity is greatly reduced. Large cell carcinoma is an undifferentiated carcinoma (positive for cytokeratin markers), which lacks evidence of differentiation by morphology and lineage specific immunohistochemical profile (TTF-1/Napsin-A and p40 negative). This classification is supported by molecular profile (8). High Grade Neuroendocrine Carcinomas. This tumour category remains largely the same from previous classification with the exception that Large Cell Neuroendocrine Carcinoma (LCNC) is now grouped with neuroendocrine tumours. It is no longer part of a Large Cell Carcinoma category. Recent studies have suggested that LCNEC is a heterogeneous group ranging in the spectrum from NSCLC-like to small cell carcinoma-like tumours (9). LCNEC that resemble NSCLC have higher incidence of KRAS mutations, whereas those morphologically closer to small cell carcinoma have higher incidence of RB mutation. The significance of these findings for tumour classification and especially for therapeutic options are still unknown as more studies need to be done. There have been several studies on the genetic and epigenetic profile of small cell carcinoma that could lead to new therapeutic options (10). However, the diagnosis and classification of this tumour remains the same. Carcinoid Tumours: Typical and atypical carcinoid tumours maintained the same morphological criteria for diagnosis and classification. Recent molecular studies have showed however that these tumours have distinct molecular profiles from the high grade relatives (LCNC and small cell carcinoma) (10). References: Travis WD, Brambilla E, Nicholson A, Noguchi M, et al, (eds). (2015) WHO Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. 4[th] ed., Lyon: IARC. Travis WD, Brambilla E, Noguchi M, et al. (2011). International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6: 244-85 Nitadori J, Bograd AJ, Kadota K, et al. (2013) Impact of micropapillary histologic subtype in selecting limited resection vs lobectomy for lung adenocarcinoma of 2cm of smaller. J Natl Cancer Inst. 105:1212-10. Yoshizawa A, Motoi N, Riely GJ, et al. (2011). Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 24: 653-64. Travis WD, Asamura H, BAnkier AA et al. (2016) The IASLC Lung cancer Staging Project: Proposal for coding T category 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. 11:1204-23. Rekhtman N, Paik P, Arcila M, et al (2012). Clarifying the spectrum of driver oncogene mutations in pure, biomarker-verified squamous cell carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res. 18:1167-76. KAdota K, Nitadori J, woo KM et al. (2014). Comprehensive pathological analyses in lung squamous cell carcinoma:single cell invasion, nuclear diameter, and tumor budding are independent prognostic gfactors for worse outcomes. J Thorac Oncol. 9:1126-39 Rekhtman N, Tafe LJ, Chaft JE et al. (2013) Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large cell carcinoma. Modern Pathol. 26:511-22. Rekhtman N, Pietanza MC, Hellman M, et al. (2016) Next-Generation Sequencing of Pulmonary Large cell neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like subsets. Clin Cancer Res. 22:3618-29. Bunn PA, Minna J, Augustyn A et al. (2016). Small cell Lung Cancer: can recent advacnes in biology and molecular biology be translated into improved outcomes? J Thorac Oncol. 11:453-74
    
    

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• 20182

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  P3.03 - Chemotherapy/Targeted Therapy (ID 719)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Chemotherapy/Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 24052

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    P3.03-007 - LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor (ID 8338)

    09:30 - 09:30  |  Author(s): Andre L. Moreira
    • Abstract
    • Slides

    Background:
    The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.
    
    Method:
    904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.
    
    Result:
    Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.
    
    Conclusion:
    Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe
    
    

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