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Michael J. Mann



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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA06.09 - Timing of Driver Mutation Development and the Genetic Evolution of Semi-Solid Lung Nodules into Early NSCLC (Now Available) (ID 2980)

      13:30 - 15:00  |  Author(s): Michael J. Mann

      • Abstract
      • Presentation
      • Slides

      Background

      The genetic changes that drive the appearance of a ground glass opacity and subsequent development of an invasive solid component within a semi-solid lesion (SSL) are not well understood. Biomarkers that predict the transition to invasive cancer are needed to determine when ground glass lesions will evolve into invasive cancer.

      Method

      From a prospective database 65 patients with surgically resected SSL between 2011-2018 were identified. Clinical characteristics and disease free survival was compared between SSL and 155 stage I adenocarcinomas resected during the same time period. Paraffin tissue blocks were obtained from 22 of the SSL and areas of normal lung (NL) ground glass (GG) and solid (S) tumor were identified and microdissected separately from within the same lesion. Next generation sequencing (NGS) was performed on DNA extracted from 19 nineteen matched GG and S samples on twenty-five common lung cancer driver mutations. Affymetrix microarray of over 48,000 transcripts was performed on S, GG, and NL samples from eight patients with SSL.

      Result

      No patients with a resected SSL has recurred to date with significant differences in 5-year disease free survival verses stage I adenocarcinomas from the same time period (100% vs 80.9%, log-rank p-value 0.007). Driver mutations in the solid component of SSL were EGFR mutation (43%; L858R 26% and exon 19 deletion 11%), KRAS mutation (21%), and no mutation identified (42%). All driver mutations present in S component of SSL were also identified in GG regions of the same lesion with very similar gene expression profiles. Only 32 transcripts were significantly different between GG and S areas of the same tumor. The greatest difference observed between GG and S portions of the same tumor was significantly higher expression of secreted phosphoprotein 1 (SPP1) in the invasive solid portion suggesting that SPP1 may serve as a biomarker of invasive potential.

      Conclusion

      This is the first study to examine the systems genetics of mutations and gene expression from the microenvironments of solid and ground glass areas within the same tumor. Mutations are present in the ground glass portion of a semi-solid tumor suggesting early development of driver mutations. Increased expression of SPP1 emerged as the most promising biomarker of invasive potential of a semi-solid lesion. In other studies SPP1 has been shown to correlate with poor prognosis and is a biomarker that warrants further study.

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