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Nan Li
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-26 - Uncommon EGFR Mutations Sensitive to First-Generation EGFR-TKI, Icotinib (Now Available) (ID 2091)
08:00 - 18:00 | Author(s): Nan Li
- Abstract
Background
The first-generation EGFR-TKIs are the standard of care for non-small cell lung cancer patients withEGFR activating mutations. Patients with EGFR L858R (p.L858R) or exon 19 deletions are the most prevalent subgroup sensitive to EGFR-TKIs. Previous reports showed that the minority of lung cancer patients with rare EGFR mutations still achieved clinical benefit with EGFR-TKIs. Here, we profiled the landscape of gene mutations in lung cancer patients who responded to Icotinib (a first- generation EGFR-TKI approved in China) treatment without classic EGFR activating mutations.
Method
We performed a comprehensive sequencing study by a NGS-based panel on a cohort of eleven lung adenocarcinoma patients without common EGFR sensitive mutations and receiving Icotinib treatment in a previous clinical trial (ICOGEN, NCT01040780). The pre-treatment FFPE tissues from all eleven patients were sequenced using a 500-gene panel.
Result
Six patients responded to Icotinib treatment including three patients with partial response (PR) and three patients with stable disease (SD). The other five patients showed immediate disease progression (PD) after the treatment of Icotinib. Rare EGFR mutations in the EGFR tyrosine kinase domain , including EGFR mutations W731C (exon 19), M793I (exon 20), and V845L (exon 21), were detected in the PR and SD groups but not in the PD group. EGFR somatic mutation M793I has been detected in the lung tissue of a patient according to the COSMIC record (COSM1716335). In the PR and SD groups, ERBB2 I655V and JAK2 R215Q were identified as potential mutations which could relate to Icotinib sensitivity.
Conclusion
This study uncovered potential new biomarkers predicting the clinical benefit to Icotinib. With further validation and evidence, it may expand the current patient populations which benefits from the first-generation EGFR-TKIs.
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P1.15 - Thymoma/Other Thoracic Malignancies (ID 184)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.15-05 - Genomic Variation Landscape of Thymoma and Thymic Carcinoma in Chinese Patients (Now Available) (ID 2147)
09:45 - 18:00 | Author(s): Nan Li
- Abstract
Background
Background: Thymoma and thymic carcinoma (TC) are rare diseases of thymus with relatively good prognosis. Though pathological sub-types of thymoma and TC show clear differences on clinical characteristics, morphology, molecular markers, and prognosis, little is known on either the etiology or the molecular mechanism of the two tumor types.
Method
Method: In this study, 27 thymoma and thymic carcinoma patients with most common thymic epithelial tumor subtypes were enrolled, including 2 type A, 6 type AB, 3 type B1, 1 type B1/B2, 5 type B2, 2 type B2/B3, 5 type B3, and 3 type TC patients in total. The Masaoka stage status of the cohort was 15 stage I, 5 stage II, 3 stage III, and 4 stage IV patients. DNA samples extracted from the frozen tissues were sequenced using a 500-gene NGS panel.
Result
Result: Forty-seven non-synonymous somatic variants in 38 genes were identified from the sequencing data. The average tumor mutation burden was low (0.83 mut/MB), which was consistent with the previous findings in the TCGA thymic epithelial tumor cohort study (0.48 mut/MB). The KEGG pathway enrichment analysis showed that the function of the mutated genes was closely related to cancer signaling pathways: 15 genes in “pathway in cancer”, 9 in “Ras signaling pathway”, and 10 in “PI3K-Akt signaling pathway”. GTF2I L424H mutation was observed in one type A (50% of type A), six type AB (100% of type AB), and four type B (25% of type B) samples. We observed the significantly higher GTF2I mutant prevalence on type B samples in our cohort than that in the TCGA cohort (p=0.024). NF1 and ATM were highly mutated genes in our cohort. Three type B samples had NF1 mutations (D1067V, P1087L, and G1090*). Two type B and one type A samples had ATM mutations (S169F, P424H, and R493G). Neither NF1 nor ATM was identified as frequently mutated genes in the TCGA cohort. One KRAS (A59del) and one NRAS (Q61K) mutations were detected in two type AB samples respectively. No KIT or EGFR mutation was found.
Conclusion
Conclusion: This study provided a comprehensive somatic mutation landscape of thymic epithelia tumor in a Chinese cohort. We compared our data to the TCGA cohort, most of which were Caucasian people. We identified higher mutation prevalence of GTF2I on type B samples in the Chinese cohort. Moreover, NF1 and ATM mutations were found to be highly mutated in our cohort but not in the TCGA cohort.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-27 - Discovery of WNK1-ROS1 Fusion in a Lung Adenocarcinoma Patient and the Precise Guidance for Targeted Therapies (ID 2122)
10:15 - 18:15 | Author(s): Nan Li
- Abstract
Background
Lung cancer can be driven by activation of tyrosine kinases including EGFR mutations, ALK, ROS1, RET, or NTRK fusions. New partners of gene fusions remain to be identified and their response to targeted therapy need be carefully evaluated in the clinical practice.
Method
A targeted next-generation sequencing (NGS) panel was used to analyze DNA extracted from tumor tissue and plasma samples from a lung adenocarcinoma patient. The fusion detected by NGS panel was confirmed by Sanger sequencing.
Result
Using a targeted NGS lung cancer panel, we identified a novel ROS1 fusion from a 39-year old Chinese female with lung adenocarcinoma. No EGFR, MET, KRAS, ALK, ROS1 or other driver mutations of lung cancer were detected in the patient. Intron 25 of WNK1 was translocated to intron 33 of ROS1 (Figure blow), which resulted in an in-frame fusion transcript of WNK1-ROS1 at the breakpoints of exon 25 and exon 34, respectively. Sanger sequencing confirmed the fusion and the breakpoints. This novel WNK1-ROS1 fusion encoded a chimera protein of which the transmembrane and kinase domains of ROS1 remained intact. The patient received treatment with crizotinib targeting to ROS1, and partial response was achieved 3 months later. Resistance to crizotinib occurred at 5 months after the treatment. Analysis of the ctDNA from the patient’s plasma sample identified ROS1 G2032R mutation, a well-known mechanism of ROS1 resistance to crizotinib. The patient was subsequently treated with TPX-0005, which is effective to ROS1 G2032R mutant. Decreased CEA level was observed 2 months after TPX-0005 treatment, suggesting the patient was responsive to the targeted therapy.
Conclusion
We identified a lung adenocarcinoma patient with a novel WNK1-ROS1 fusion who was sensitive to crizotinib and developed crizotinib resistant ROS1 G2032R mutation at progression but appeared to be responsive to the new generation of TPX-0005 therapy. These results suggest that WNK1-ROS1 fusion is a new molecular mechanism leading to lung adenocarcinoma and targetable to ROS1 tyrosine kinase inhibitors.
