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Jonathan Nowak

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    MA11 - Biomarkers of IO Response (ID 912)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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      MA11.10 - Identification of Mismatch Repair Deficient Lung Adenocarcinomas Using Targeted Next-Generation Sequencing (ID 12439)

      11:35 - 11:40  |  Author(s): Jonathan Nowak

      • Abstract
      • Presentation
      • Slides


      Mismatch repair (MMR) deficiency/microsatellite instability (MSI) results from the inactivation of DNA mismatch repair proteins. Due to the defect in DNA repair, MMR-deficient (D) tumors display an elevated tumor mutation burden (TMB) and a characteristic increase in small insertions/deletions within homopolymer tracts (“homopolymer indels”), a signature that can be detected using next generation sequencing methods. MMR-D/MSI predicts response to immune oncology (IO) agents (Le et al., 2017) and is an approved biomarker for pembrolizumab therapy in the relapse setting irrespective of histologic diagnosis. In this study, we retrospectively analyzed a large cohort of non-small cell lung carcinomas using targeted next generation sequencing to examine the prevalence and clinicopathologic associations of MMR-D in this tumor type.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      TMB and MSI status was derived from a 309-447 gene targeted next generation sequencing panel (OncoPanel) using an internally validated method (Nowak et al., 2017), that relies on an empirically defined homopolymer indel cutoff of >=1.52/Mb to identify candidate MMR-D tumors. MMR/MSI status was confirmed using MSI PCR (5 marker panel) and/or immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. When indicated, MLH1 promoter methylation status was evaluated by methylation-specific PCR.

      4c3880bb027f159e801041b1021e88e8 Result

      2242 lung tumors, including 1835 non-squamous non-small cell lung carcinomas (NSCLC), were interrogated. A total of three lung tumors (all adenocarcinoma) with confirmed MSI/MMR-D by orthogonal methods were identified, for a prevalence of 0.1% of all lung tumors and 0.2% of non-squamous NSCLC. The TMB of these tumors averaged 42.5 mutations/Mb with 7-10 homopolymer indels /Mb. All three tumors showed loss of MLH1 and PMS2 staining by IHC; two cases had somatic loss-of-function MLH1 variants and one showed MLH1 promoter methylation. All were from female patients whose mean age was 68 years (range: 53-83). All showed a poorly-differentiated histology with moderate to brisk lymphoid infiltrates. One patient was a never-smoker; her tumor had a concomitant EML4-ALK rearrangement. The other two patients had moderate/heavy smoking histories (12.5-80 pack-years) both showed RASA1 and NF1 inactivating mutations. One tumor evolved in the context of usual interstitial pneumonia.

      8eea62084ca7e541d918e823422bd82e Conclusion

      MMR-D is very rare in lung tumors, where it appears to arise as somatic event and is enriched in adenocarcinoma. MMR-D may coexist with other relatively uncommon driver alterations, including those not traditionally associated with IO response. Additional investigation is needed to determine if MMR-D confers sensitivity to IO in lung carcinomas.


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