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Jinghui Wang

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    MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      MS14.02 - Subclonal Architecture and Genomic Evolution of SCLC (Now Available) (ID 3520)

      11:30 - 13:00  |  Presenting Author(s): Jinghui Wang

      • Abstract
      • Presentation
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      Small cell lung cancer (SCLC) accounts for 15-20% of all of lung cancer worldwide and it is a highly aggressive and rapidly progressive tumor with rapid growth speed and strongly associated with smoking. SCLC is divided to limited disease and extensive disease. The staging systems for SCLC are Veterans Administration scheme (VA), the AJCC TNM staging systemand NCCN staging, among of these VA is most commonly used. In recent several decades, chemotherapy combined radiotherapy is the main treatment for SCLC. The overall survival (OS) in patients with limited disease-SCLC and extensive disease were 15-18 months and 10-12 months, respectively. Immunotherapy is becoming a promising treatment for SCLC nowadays.

      Targeted therapy based on genotyping in non-small cell lung cancer is a main treatment. However, targeted therapy in SCLC is not successful and studies on the genomic evolution of SCLC are rare. ctDNA (circulating cell-free tumor DNA) is a good tool for monitoring the genomic changing in patients with malignant tumors, especially for monitoring acquired resistance of targeted therapy. ctDNA and CTCs are useful for genomic evolution of cancer. However, isolation and identification of CTCs are not satisfied in lung cancer, though there are more CTCs in small call lung cancer because of tumor cells are more easily to shed to blood stream in SCLC. ctDNA can provide more accurate genomic landscape of SCLC through overcome heterogeneity.

      We conducted a study that aimed to explore the genomic structure and gene evolution pattern of SCLC using next-generation sequencing and who had been followed by dynamic samples after chemotherapy or/and radiotherapy. We found that TP53 and RB1 are the most common mutations in SCLC, and NOTCH1-4, CREBBP, EG300, MYC, MYCL1, and MYCN are also frequently mutated genes and copy number alterations. We also compared the tissue and blood ctNDA genome and we found that a majority of mutations detected in tumor DNA were also detected in paired ctDNA samples suggesting ctDNA sequencing is sensitive and reliable for detecting mutations in SCLC patients. We used the average VAF (Variant allelic frequencies) of mutations from the major clones as a surrogate for overall ctDNA level. We found higher median ctDNA level was associated with shorter progression-free survival (PFS) and overall survival (OS). Dynamic ctDNA levels are correlated with tumor measurements on imaging suggesting that ctDNA sequencing has the potential for monitoring the clinical course of SCLC. The genomic profiles derived from pre-treatment ctDNA to the genomic profiles from ctDNA at different time points during treatment from post-treatment plasma samples available. Some new mutations that were not exist in pre-treatment blood samples.

      Immunotherapy is an important method for lung cancer. PD-L1 expression and tumor mutation burden (TMB) are two common predictors for immunotherapy. In our cohort, tumor mutation burden is not higher based on the large gene panel. PD-L1 expression is about more than 10% in SCLC. The treatment for SCLC is still highly challenging. TMB based on ctDNA is worth further investigation on predicting SCLC immunotherapy. A previous study showed that SCLC with high TMB had a better response to checkpoint inhibitors. Shedding of ctDNA is a complicated process affected by many factors. With the technique development and increasing understanding of tumor biology, the genome of SCLC will be a useful tool for guiding the treatment and predicting the prognosis of SCLC in the future.

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