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J. Jen



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    MA 13 - New Insights of Diagnosis and Update of Treatment (ID 674)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Early Stage NSCLC
    • Presentations: 1
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      MA 13.01 - Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA (ID 8686)

      15:45 - 17:30  |  Author(s): J. Jen

      • Abstract
      • Slides

      Background:
      Analysis of circulating tumor DNA (ctDNA) represents a potential strategy for the early detection of lung cancer. Despite significant interest, few studies have evaluated ctDNA levels in early stage lung cancer patients and the feasibility of ctDNA-based screening remains unclear.

      Method:
      We applied lung cancer-focused Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to assess ctDNA levels in 55 localized lung cancer patients treated with curative intent (stage I: n=22, stage II: n=7, stage III: n=26) and 50 healthy controls. Histological subtypes included: adenocarcinoma (n=30), squamous cell carcinoma (n=19), NSCLC NOS (n=4), and small cell lung cancer (n=2). Sensitivity and specificity of ctDNA detection were evaluated in all patients and in a subset of NSCLC patients with node negative (N0) stage I-II disease. Additionally, for patients with stage I adenocarcinoma in whom ctDNA was not detectable using the standard population-based CAPP-Seq approach, we designed personalized CAPP-Seq assays covering a median of 320 mutations/patient based on tumor exome sequencing from the respective patients.

      Result:
      We detected ctDNA in the pre-treatment plasma of 43/55 (78%) patients at a median allele fraction (AF) of 0.48% (range: 0.004%-26.1%). ROC analysis revealed an area under curve of 0.91, with sensitivity and specificity of 78% and 98%, respectively. Among patients with non-adenocarcinoma histologies, 92% (23/25) had detectable ctDNA (median AF: 0.90%), compared to 67% of patients with adenocarcinoma (20/30; median AF: 0.23%; P=0.046). However, tumor volumes were significantly smaller in adenocarcinomas (P=0.01) and in multivariate analysis ctDNA detection was significantly associated with tumor volume (P=0.01) but not histological subtype (P=0.16). In N0 stage I-II NSCLC patients (n=22), ctDNA was detected in 64% of patients (7/14 adeno vs 7/8 non-adeno) with a specificity of 98% and median AF of 0.022% (median AF of 0.018% vs 0.030% in adeno vs non-adeno patients, respectively). Using personalized CAPP-Seq assays, we detected ctDNA in 3/4 patients with stage I adenocarcinoma in whom ctDNA was not detected using our standard lung-cancer focused CAPP-Seq assay. In these 3 patients, tumor volumes ranged from 11.6-14.7 mL and the ctDNA AF ranged from 0.0014%-0.003%. Taken together, we detected ctDNA in 17/22 (77%) N0 stage I-II tumors.

      Conclusion:
      These data suggest tumor volume is a stronger determinant of ctDNA levels than histology in localized lung cancers. Additionally, our findings suggest that the majority of localized lung cancers shed ctDNA and that ultra-sensitive assays will be required for early detection of lung cancer using ctDNA

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.07 - Contraction of T Cell Clonality in Lung Cancer Metastases (ID 7542)

      11:00 - 12:30  |  Author(s): J. Jen

      • Abstract
      • Presentation
      • Slides

      Background:
      Clonal evolution and the heterogeneity of non-small cell lung cancer (NSCLC) may affect patient outcomes through variations in treatment planning, response to therapy, and drug resistance. Even less is known about the diversity of the adaptive immune response to primary and metastatic lesions in this disease. We sought to characterize the richness, abundance and overlap of T cell clones between paired primary NSCLC lesions and brain metastases.

      Method:
      We identified 20 patients with NSCLC with paired, fully resected primary lesions and brain metastases with sufficient tissue available in our clinical archives. DNA was purified from formalin-fixed paraffin-embedded specimens. The complementarity determining region 3 of T-cell receptor β was profiled by next generation sequencing to identify unique T cell clones. Sample richness (including iChao1 and Efron-Thisted Estimator), and clonal abundance (Simpson’s diversity index) were compared between paired lesions with the paired t test. Overlap in clonality was measured with the Morisita index.

      Result:
      There was a significant contraction of T cell clonality in paired metastases compared to primary lesions (mean of differences -2803, 95% CI -4202 to -1405; p=0.0005). The decreased richness in clonality in brain metastases was also supported by significant differences in iChao1 (mean of differences -20355, 95% CI -29561 to -11149; p=0.0002) and the Efron-Thisted Estimator (95% CI -21331 to -7216; p=0.0004). Simpson’s diversity index was higher in brain metastases than primary lesions (mean of differences 0.002, 95% CI 0.001 to 0.004; p=0.05), but low overall. Only a fraction of T cell clones in primary lesions were also found in brain metastases (mean Morisita Index 0.23).

      Conclusion:
      There is greater richness but less abundance of T cell clones in primary NSCLC lesions compared to paired brain metastases. Although the blood brain barrier may restrict T cell trafficking to tumors, the minimal overlap in T cell clones may reflect the genetic divergence of metastatic tumor clones.

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