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L. Wang



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    MINI 27 - Biology and Other Issues in SCLC (ID 152)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      MINI27.11 - Comprehensive Mutation Analysis of Never-Smokers with Small Cell Lung Cancer (SCLC) (ID 3135)

      17:45 - 17:50  |  Author(s): L. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Although most patients with SCLC are current or former smokers, this disease has been reported in never-smokers. In our prospective genomic profiling of SCLC patients, we have identified four never-smokers. Here, we report next generation sequencing (NGS) results for these four SCLC patients and describe how they differ from those of smokers.

      Methods:
      We are evaluating pathologically confirmed SCLC tumors in patients undergoing treatment. Formalin-fixed, paraffin-embedded surgical resections, core biopsies, and fine needle aspirates are being evaluated using a targeted, hybrid capture-based, NGS assay, MSK-IMPACT, which identifies single nucleotide variants, indels, and copy number alterations in 341 cancer-associated genes. We determined never-smoking status prospectively: all smoked <100 cigarettes in their lifetime. Clinical data on stage [extensive (ES), limited (LS)], treatment, and response were collected.

      Results:
      Four never-smokers have been identified within the 50 patient samples that have undergone NGS evaluation thus far. The median age at diagnosis of the four never-smokers is 58 (range, 47-75); 50% are male; and one presented with LS-SCLC. None of these four patients developed SCLC as acquired resistance to EGFR tyrosine kinase inhibitors after treatment for EGFR-mutant lung cancers. The tumors from the four never-smokers displayed a median of 3 non-synonymous somatic mutations, while those from moderate (<20 pack years) and heavy (20+ pack years) smokers contained 4.5 and 8 mutations, respectively (P<0.05). None of the four never-smoker samples contained smoking associated G-to-T transversions (see Table). Inactivation of RB1 and TP53 occurred in 75% and 50% of the samples, respectively. Only patient 4 had platinum-refractory disease. The median survival of these patients was 20.7 months (range, 17 to 25).

      Sample Gene altered Alteration Present Protein Alteration Base Pair Alteration
      Patient 1 PHOX2B Missense Mutation P82L G-to-A
      NOTCH1 Frame-Shift Insertion P2485fs
      RB1 Splice Site R500_splice G-to-A
      TP53 Frame-Shift Deletion V218fs
      TP53 Frame-Shift Deletion V73fs
      TERT Amplification
      Patient 2 CBL Missense Mutation C401S G-to-C
      GNAS Missense Mutation M102V A-to-G
      MYCL Amplification
      Patient 3 TP53 Nonsense Mutation R342 G-to-A
      RB1 Frame-Shift Insertion T197fs
      CDKN2C Amplification
      MYCL Amplification
      Patient 4 RB1 Nonsense Mutation C666
      ETV1 Amplification


      Conclusion:
      Using a targeted NGS assay, we have shown that the molecular characteristics differ between never-smokers and smokers, while the majority of the tumors demonstrate RB loss. Whole exome sequencing of the tumors from these never-smokers is underway. Ongoing comprehensive, multiplexed genotyping is needed to fully characterize the molecular diversity of SCLC in this unique population.

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