Author of

• 15382

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  P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 15420

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    P3.04-038 - Molecular Topography of Early-Stage Lung Adenocarcinomas (ID 2799)

    09:30 - 09:30  |  Author(s): L. Jimenez
    • Abstract

    Background:
    Intratumor heterogeneity may have implications for targeted therapies. Despite the well known morphologic intratumor heterogeneity of lung adenocarcinomas (ACs), the heterogeneity of druggable alterations throughout individual primary tumors is still controversial and has remained poorly defined. The purpose of our work was to comprehensively characterize histological intratumor heterogeneity in primary lung ACs.
    
    Methods:
    A total of 83 consecutive patients with stage I-IIIA primary lung AC who underwent surgery at HM Sanchinarro University Hospital were considered. All tumors were always included in toto for histological analysis, regardless of size, by the same pathologists. We carefully reviewed all slides to identify and quantify (with the help of digital pathology, [iScan, Ventana Medical Systems, USA]) the different histological patterns according to the revised International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of lung ACs. Every pattern from each specimen was macrodissected, and a new paraffin block per pattern was constructed. Afterwards, we performed targeted next-generation sequencing (Ion AmpliSeq[TM] Cancer Hotspot Panel v2, Life Technologies, USA) to detect actionable somatic mutations and copy number variations (CNVs) in 50 genes in every different histological pattern of each tumor. The raw data were processed using the RUbioSeq and MuTect softwares. After a filtering process, the detected variants were then annotated with the Ensembl Variant Effect Predictor. The annotations were used to compute a variant score and rank the mutations according to their clinical significance.
    
    Results:
    All 83 tumors were primary invasive ACs. Detailed histological analysis revealed that 63 tumors (76%) had more than one histological pattern. Among them, 52 (82,5%) exhibited two patterns, and 11 (17,5%) showed three components. An initial pilot study of 20 cases showed that 45% of the tumors had heterogeneous results regarding the presence of somatic mutations and CNVs between different histological patterns within a given tumor. We observed intratumor heterogeneity predominantly regarding the mutational status of several genes (e.g. 2 out of 11 TP53 mutated tumors, 1 out of 6 KRAS positive tumors, 1 out of 3 STK11 mutated cases, and 3 out of 3 CDKN2A mutated tumors). Solid patterns accumulated more molecular alterations than other patterns, and also showed events not present in other components (i.e. CDKN2A or NOTCH1 mutations, copy number gain of ALK, HER2, FGFR2 or NOTCH1). RET and GNAS mutations were exclusively observed in papillary patterns. EGFR and HER2 mutations were not heterogeneous.
    
    Conclusion:
    In early stage lung ACs there is a significant degree of intratumor heterogeneity. Our preliminary results indicated a trend towards a high somatic events rate in solid patterns. The comprehensive approach presented herein links routine pathology practice with targeted clinical molecular annotation of lung ACs. Therefore, it could be used prospectively to assess the implications of studying single tumor regions. Acknowledgements This study was partially funded by Instituto de Salud Carlos III (ISCIII), Fondo de Investigaciones Sanitarias (FIS) [Fondos FEDER, Plan Nacional de I+D+I 2008-2011 (PI11-02866) and Plan Estatal de I+D+I 2013-2016 (PI14-01176)].