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Shanbo Cao



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    EP1.12 - Small Cell Lung Cancer/NET (ID 202)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.12-37 - Higher Consistency of Mutations Between Tumor DNA and ctDNA in Small-Cell Lung Cancer Compared to Non-Small Cell Lung Cancer (ID 2060)

      08:00 - 18:00  |  Author(s): Shanbo Cao

      • Abstract

      Background

      Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers, patients with SCLC usually have a poor prognosis and limited treatment options. This is primarily due to the lack of adequate tumor tissues to assess and delaying therapy to repeat biopsies is often not possible. Circulating cell-free tumor DNA (ctDNA) based test for EGFR mutations in patients with Non-small cell lung cancer (NSCLC) has been approved by US Food and Drug Administration, however, whether it is feasible to perform genomic profiling of ctDNA from SCLC patients still have been lacking. SCLC is characterized by early hematogenous spread, we hypothesized that ctDNA sequencing in SCLC is more comprehensive as a promising biomarkers than that in NSCLC.

      Method

      To analyze the consistency of gene mutation sites between tumor DNA and perepheral blood ctDNA in patients with lung cancer (SCLC and advanced NSCLC), and further explore the feasibility of ctDNA as a clinical tool in SCLC. Paired tumor and blood samples were obtained from systemic treatment naïve patients with SCLC and advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 808 previously annotated genes related to solid tumors.

      Result

      During February 2017 to April 2018, 8 SCLC and 119 advanced NSCLC patients were enrolled from 3 centers. A total of 256 somatic variations were detected in tumor DNA and ctDNA. TP53 and RB1 are the most frequently mutated genes in SCLC patients and mutations occurred most frequently in NSCLC were EGFR , TP53 , KRAS , ALK. In matched tumor DNA and ctDNA, we observed significant higher concordance of mutations in SCLC (90%) compared to NSCLC (65%). Furthermore, the variant allele frequency (VAF) of shared mutations in SCLC highly correlated to each other (r=0.68). In addition, a subset of mutations was exclusively detected in ctDNA, indicating that the genomic landscape derived from ctDNA reflects that from SCLC to a certain degree.

      Conclusion

      Taken together, our data showed the potential advantage of sequencing ctDNA in SCLC over than that in NSCLC to reveal the global genomic landscape. SCLC ctDNA analysis will be used as a powerful research tool that can shed light on this poorly understood disease and could also provide clinical information that benefits patients.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-45 - Clinico-Molecular Characteristics and Prognostic Outcomes of TP53 Mutated Patients with Advanced Non-Small Cell Lung Cancer (ID 679)

      10:15 - 18:15  |  Author(s): Shanbo Cao

      • Abstract

      Background

      TP53 mutations are the most common molecular alterations in non-small cell lung cancer (NSCLC), but prognostic role of these mutations remains elusive. The aim of this study was to analyze the clinical and molecular characteristics of TP53 mutated NSCLC patients and to evaluate a novel approach called evolutionary action (EAp53) to stratify them into high-risk or low-risk groups.

      Method

      85 advanced NSCLC patients were enrolled. Variations of TP53 and other oncogenic drivers in NSCLC were identified by next-generation sequencing. EAp53 are available at http://mammoth.bcm.tmc.edu/EAp53/.

      Result

      Overall, 77 patients (90.6%) exhibited at least one genetic alteration. TP53 mutations were detected in 51 patients (60.0%) mainly in exons 4, 5, 6, 7, and 8. Notably, TP53 mutations were not observed in exon 4 when they coexisted with EGFR mutations. Mutant allele frequencies (MAFs) of EGFR sensitizing mutations (exon 19 deletion or L858R) were significantly higher than those of other EGFR mutations in patients harboring TP53 mutations (p = 0.012). Among TP53 mutated patients, 39.2% of them carried TP53 truncating mutations (nonsense, splice site, or frameshift), which were correlated with female gender and smokers (p = 0.026 and p = 0.024, respectively), and were potentially associated with young patients (p = 0.078), and were more common in non-DNA-binding domain of TP53 (p = 0.033). Additionally, overall survival time of 37 patients were collected, and patients with high-risk mutations stratified by EAp53 had a significantly worse OS compared to others (HR 23.15; 95% CI 4.30-124.50; p < 0.001).

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      Conclusion

      This study is of great significance in understanding the population characteristics of TP53 mutated NSCLC patients. Furthermore, the data also indicates that evolutionary high risk TP53 mutations can identify a subset of patients with poor prognosis, suggesting that EAp53 is a novel approach and may be useful in clinical prognosis of NSCLC patients with TP53 mutations.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-42 - Emergence of CCDC6-RET Fusion with Maintained EGFR T790M Mutation After Resistance to Osimertinib in NSCLC: A Case Report (ID 1086)

      10:15 - 18:15  |  Author(s): Shanbo Cao

      • Abstract

      Background

      First- and second-generation EGFR-TKIs have been widely used for advanced patients with EGFR mutation-positive non-small cell lung cancer (NSCLC); however, acquired resistance to these inhibitors, such as EGFR T790M mutation, could be present in resistant cases. Several third-generation EGFR-TKIs including osimertinib, have been explored and approved for conquering this resistance, whereas acquired resistance to osimertinib is evident and resistance mechanisms remain complex and incompletely elucidated.

      Method

      A 56-year-old never-smoking Asian woman presenting with back and groin pain for 2 years, and was diagnosed with stage IV lung adenocarcinoma with multiple lung, liver, brain and bone metastases in February 2015. The patient carried EGFR exon 19 deletion and clinically responded to initial erlotinib treatment, who progressed on erlotinib after 20 months, and a T790M mutation was detected by next-generation sequencing (NGS). Osimertinib treatment was administrated for 13 months during which time the patient remained stable according to the Response Evaluation Criteria in Solid Tumors. The patient progressed with bone metastases in January 2018 and no other mutations were detected by NGS, who then started the treatment with osimertinib, bevacizumab, and complementary radiation therapy. However, the patient discontinued the treatment due to the progress with bilateral lung nodules. In order to probe into the subsequent therapy, circulating tumor DNA (ctDNA) was analyzed using NGS with Acornmed Panel in August 2018.

      Result

      The genomic profile of the tumor disclosed actionable mutations including EGFR exon 19 deletion, EGFR T790M mutation, and CCDC6-RET fusion. Osimertinib and bevacizumab discontinued because of the rapid progress, serious adverse effects of gradeⅡsuppression of bone marrow, and shortness of breath. Based on the molecular test results, the patient received treatment with cabozantinib and osimertinib in October 2018, which also failed to slow down the progress of the disease. Further ctDNA test in November 2018 showed EGFR exon 19 deletion, EGFR T790M mutation, and CCDC6-RET fusion were identified again; however, no novel mutations were detected. Unfortunately, the symptoms worsened quickly and the patient died of respiratory failure in December 2018.

      Conclusion

      The specifc mechanisms of acquiring drug resistance for EGFR-TKIs have not been fully elucidated. Based on ctDNA-based NGS, we reported a case maintained EGFR T790M mutation and acquired CCDC6-RET fusion after resistance to osimertinib, which was rare since acquired RET fusion was only found in EGFR T790M lost patients. More studies about the mechanism should be explored to lead to effective treatment strategies in this population.