Author of

• 25900

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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

  • 25991

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    MA11.10 - Identification of Mismatch Repair Deficient Lung Adenocarcinomas Using Targeted Next-Generation Sequencing (ID 12439)

    11:35 - 11:40  |  Presenting Author(s): Navin Rajput Mahadevan
    • Abstract
    • Presentation
    • Slides

    Background
    

    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.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25963

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  P3.09 - Pathology (Not CME Accredited Session) (ID 975)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27589

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    P3.09-12 - Molecular and Immunohistochemical Correlates of RB1 Inactivation in Small Cell Lung Carcinoma (ID 13826)

    12:00 - 13:30  |  Presenting Author(s): Navin Rajput Mahadevan
    • Abstract
    • Slides

    Background
    

    Retinoblastoma (RB1) is a critical negative regulator of cell cycle progression, and serves as a tumor suppressor gene that is inactivated in many tumor types, including small cell lung carcinoma (SCLC). Because biallelic inactivation of RB1 has been observed in virtually all SCLC, loss of RB1 expression in the correct context is considered highly suggestive of SCLC or SCLC-like neuroendocrine carcinomas. However, the relationship between the genomic inactivation of RB1 and expression in SCLC has yet to be fully defined. Here, we characterize the genetic and immunohistochemical correlates of RB1 inactivation in SCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    SCLC (n=57), and combined SCLC cases with a non-neuroendocrine component (CSCLC; n=5), that had undergone targeted next generation sequencing (NGS) (Oncopanel, 309-447 genes) were retrospectively identified. Designation of the molecular mechanism of RB1 inactivation was pursued by integrative analysis of RB1 variant type, variant allele fraction, and heterozygosity of the RB1 locus. RB1 protein status was interrogated in a subset of SCLC (n=25, 19 with biallelic inactivation) and CSCLC (n=2) by immunohistochemistry (IHC).

    4c3880bb027f159e801041b1021e88e8 Result
    

    77% (44/57) of SCLC showed biallelic inactivation of RB1 by NGS, most commonly through a loss-of-function (LOF) variant and associated loss of heterozygosity (LOH, 65%). The most common mechanisms of RB1 genetic inactivation in these cases were nonsense (32%), frameshift (25%), and splice site (23%) variants, respectively. RB1 protein expression was lost in 89% (17/19) of SCLC with biallelic RB1 inactivation; the two remaining cases harbored RB1 splice site variants and displayed weak, patchy RB1 expression. Additionally, 80% (5/6) of SCLC without molecular evidence of RB1 biallelic inactivation showed loss of RB1 expression. Overall, 60% (3/5) of SCLC harboring splice site variants retained weak RB1 expression. 60% (3/5) of CSCLC showed molecular RB1 inactivation in all tumor cells. While one CSCLC showed loss of RB1 expression in both histologic components, the other tumor, which harbored a RB1 splice site variant, retained strong RB1 expression.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Genetic inactivation of RB1 in SCLC may not be identified in ~20% of cases via targeted NGS . While most SCLC with biallelic RB1 inactivation show loss of RB1 expression, retention of weak RB1 expression in SCLC does occur and may be associated with RB1 splice site variants. While additional investigation is needed to interrogate the functional and clinical significance of retained RB1 expression in SCLC, these data suggest that genetic RB1 inactivation does not always result in loss of protein expression, which may have implications for disease classification.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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