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Lynette M Sholl



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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): Lynette M Sholl

      • 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.

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    MA19 - Genomic Markers of IO Response (ID 922)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 201 BD
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      MA19.01 - Efficacy and Genomic Correlates of Response to Anti-PD1/PD-L1 Blockade in Non-Small Cell Lung Cancers Harboring Targetable Oncogenes (ID 12921)

      15:15 - 15:20  |  Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) are associated with improved outcomes in a subset of patients with advanced non-small cell lung cancer (NSCLC). NSCLCs with targetable oncogenes are thought to be less responsive to ICI therapy, possibly due to association with never smoking status and reduced tumor mutational burden (TMB), but this has not been comprehensively characterized. We evaluated the responsiveness of NSCLCs with targetable oncogenes to ICIs, and if mutation type or TMB influence response.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Clinicopathologic, radiographic response, and sequencing data for patients with advanced NSCLC treated with ICI therapy was acquired from two separate cohorts (DFCI Oncopanel, n=296; MSKCC MSK-IMPACT, n=202). Durable clinical benefit (DCB) was defined as responsive/stable disease > 6 months. Samples with activating mutations in EGFR, ALK, ROS, BRAF, MET, and RET were identified. TMB was calculated as the sum of nonsynonymous mutations divided by the coding region captured in each panel. Objective response rates (ORR), DCB, and TMB were compared in targetable oncogene positive (TOP) vs oncogene negative (TON) patients. TMB was considered within each cohort to avoid confounding for differences in NGS panel technique.

      4c3880bb027f159e801041b1021e88e8 Result

      Targetable oncogenes were identified in 16% (82/498) of patients; 44(9%) EGFR, 15(3%) MET exon 14 splice site mutated, 8(2%) BRAF V600E, 6(1%) ROS1 rearranged, 5(1%) ALK rearranged, and 4(1%) RET re-arranged. Response to ICIs was similar in TOP vs TON patients, with ORR of 18% and 20%, and median PFS of 2.7 vs 2.8 months in TOP vs TON patients respectively. Among TOP patients, response rates differed by mutation type; ORR rate was 11%(5/44) in EGFR mutated, 40%(6/15) in MET mutated, 25%(2/8) in BRAF mutated, 33%(2/6) in ROS1 rearranged, and 0% in RET and ALK rearranged cancers (0/4, 0/5 respectively). Compared to WT, TMB was lower in TOP tumors (OncoPanel median 9vs11, p=0.0064; IMPACT median 4vs8, p=2.25e-06). TMB did not correlate with objective response or DCB in TOP tumors when considered collectively or by mutation type (OncoPanel median TMB 10vs8 in DCB vs NDB, p=0.52; IMPACT median TMB 3vs5 in DCB vs NDB, p=0.31)(Mann-Whitney U for all).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite lower TMB in oncogene positive NSCLC, these patients still derive clinical benefit from ICIs. ICI responsiveness is likely mutation specific, and is most pronounced in MET and BRAF mutated cancers. Among targetable oncogene positive NSCLC, TMB did not distinguish benefit. Taken together, low TMB in the presence of oncogenic driver mutations should not preclude ICI therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA19.11 - Discussant - MA 19.08, MA 19.09, MA 19.10 (ID 14642)

      16:20 - 16:35  |  Presenting Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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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
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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  |  Author(s): Lynette M Sholl

      • 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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    PC06 - Controversies in Immunobiomarker Testing (ID 845)

    • Event: WCLC 2018
    • Type: Pro-Con Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 13:30 - 15:00, Room 106
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      PC06.03 - Tumor Mutation Burden - PRO (ID 11627)

      14:10 - 14:30  |  Presenting Author(s): Lynette M Sholl

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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