Author of

• 25921

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  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26335

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    P1.01-105 - Lung Cancer Patients with Concurrent EGFR and MET Mutations: A Retrospective Analysis of 29 Cases (ID 12864)

    16:45 - 18:00  |  Author(s): Mingming Yuan
    • Abstract
    • Slides

    Background
    

    It has been reported that about 5%-20% of EGFR-TKIs resistant NSCLC patients harbors MET amplification or activating mutations. However, the extent that MET abnormal activation contributes to EGFR-TKIs resistance remains widely unknown. Here, we describe the clinical and genetic characteristics of 29 lung cancer patients harboring concurrent EGFR and MET mutations.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Genetic mutations were reviewed in 6000 lung cancer patients who underwent genetic testing at our institute from 2016 to 2018. Mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).

    4c3880bb027f159e801041b1021e88e8 Result
    

    The selected patients included 24 lung adenocarcinoma patients, 1 squamous cell lung cancer patient and 3 lung cancer patients with unspecified pathology. Both MET amplification and activating mutations were included for analysis. MET amplification was detected in 90% (27/30) of samples, while activating mutations was present in 13.3% (4/30) of samples, including H1112Y, D1228N, D1246Y and D1246H. 14% (4/29) of patients had not received EGFR-TKIs treatment before genetic testing, which were considered as primary resistance. 79% (23/29) of patients were treated with EGFR-TKIs. Surprisingly, 60% (18/30) of cases had other functional mutations which may also affect the effectiveness of EGFR-TKIs, such as EGFR T790M mutation (3 cases), rare EGFR mutations (I744M, R108K and C769S, 3 cases), EGFR amplification (7 cases), CDK4 amplification (2 cases), loss-of-function mutations of CDKN2A (2 cases) and so on. One patient had two samples tested. He was resistant to gefitinib and osimertinib, and EGFR L858R mutation and MET amplification were detected in the first sample. Later, he was treated with combined gefitinib and crizotinib and reached PR at the 2^nd month. However, his disease finally progressed probably due to an additional MET mutation (D1246Y) that caused resistance to crizotinib.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    MET amplification and activating mutations may lead to primary and acquired resistance of EGFR-TKIs. Moreover, additional potentially resistant mechanisms were detected in most cases. Therefore, it is apparently requisite to provide a comprehensive genetic testing to lung cancer patients.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25943

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  P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall

  • 27049

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    P2.06-39 - Next Generation Sequencing Reveals Genetic Landscape of Malignant Mesothelioma (ID 12702)

    16:45 - 18:00  |  Author(s): Mingming Yuan
    • Abstract
    • Slides

    Background
    

    Malignant mesothelioma (MM) is a rare form of cancer affecting the mesothelium lining. The 5-year survival rate of advanced patients is less than 1% due to the lack of effective medical therapies. To investigate the possibility of targeted therapy for MM patients, a deeper understanding of the genetic basis is required.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    We reviewed 26 samples taken from 22 MM patients who underwent genetic testing at our institute from 2016 to the present. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).

    4c3880bb027f159e801041b1021e88e8 Result
    

    The 26 samples included 8 tumor tissue samples, 17 blood samples and 1 ascetic fluid sample. The most frequently mutated genes were TP53 (11/21), followed by NF2 (6), RB1 (4), NF1 (3), FLT1 (3), BAP1 (2), EGFR (2), FAT2 (2), FGFR4 (2), KIT (2), MAP3K1 (2), MLL4 (2), STK11 (2), APC, ATR, BRAF, BRCA2, CDKN2A, ERBB3, FBXW7, MET, KRAS, PIK3CA and so on. Among these mutations, 5 of NF2 mutations and 2 of NF1 mutations were loss-of-function mutations, which suggests the possible sensitivity of mTOR inhibitors administration. Besides, patients with the active or inactive mutations of KRAS, BRAF, CDKN2A, ERBB3, MET and PIK3CA gene might be sensitive to corresponding targeted drugs. MET exon 14 skipping mutation, commonly identified in non-small-cell cancer (NSCLC) patients, had never been reported in MM patients before. c-Met inhibitors such as crizotinib and cabozantinib may be of efficacy for this patient. Apart from predicting therapeutic effectiveness of MEK inhibitors, the detection of KRAS activating mutation may also provide prognostic information.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    NGS can identify genetic mutations comprehensively and provide predictive and prognostic implications for MM patients. It is a cost-effective tool to describe the genetic landscape of MM, which will facilitate the development of novel therapeutics for the treatment of MM patients.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25955

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  P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27466

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    P3.01-106 - Real-World Data to Evaluate the Clinical Benefit of NGS for Directing Lung Adenocarcinoma Treatment (ID 12870)

    12:00 - 13:30  |  Author(s): Mingming Yuan
    • Abstract
    • Slides

    Background
    

    Since mid-2017, multiple NGS-based companion diagnostic tests have been approved in NSCLC to select patients eligible for targeted therapy and immunotherapy. Here, we retrospectively analyzed the benefit of NGS for advanced lung adenocarcinoma in routine clinical practice.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    From 2016 to 2018, the samples taken from 9 lung adenocarcinoma patients were sent to Geneplus-Beijing Institute for genetic testing. Mutation profiles were analyzed using hybridization capture based NGS, which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes). The tumor response was evaluated using RECIST v1.1.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Six tumor tissue samples, two blood samples and one pleural effusion sample were analyzed (Table 1). No actionable mutation was detected in patient 1 and then he left hospital without additional treatment. The KRAS mutation present in patient 2 suggested that he might be resistant to EGFR-TKIs. Therefore, he received chemotherapy. According to the genetic testing results, all the other patients received EGFR-TKIs and the disease control rate was 100% at the 2^nd month. Apart from EGFR T790M mutation, EGFR amplification was present in patient 8 with disease progression following gefitinib therapy. She received osimertinib and achieved PR at the 2^nd month. The response has maintained for over 7 months up to now, which made us reconsidering the controversial correlation between EGFR amplification and EGFR-TKI effectiveness. Rare EGFR mutation and MET amplification were detected in patient 9, and then he was treated with icotinib.The best response was SD at the 4^th month. However, he died of pulmonary embolism or cerebral infarction, making the duration of response 4 months.

    Table 1. Clinical and genetic characteristics of 9 patients
    Patient No	Age/Gender	Sample	Previous Targeted Therapy	Actionable Mutations	Following Treatment	Response Evaluation (2nd month)	Duration of response (months)
    1	72/Male	Blood	No	No	No treatment	Not applicable	Not applicable
    2	62/Male	Tissue	No	KRAS p.G12A, STK11 p.D53Gfs*110	Chemotherapy	Not available	Not available
    3	62/Male	Tissue	No	EGFR p.L747_T751del (EX19del)	Gefitinib	PR	20+
    4	63/Female	Tissue	No	EGFR p.L858R (EX21)	Gefitinib	PR	5+
    5	75/Female	Tissue	No	EGFR p.L858R (EX21)	Icotinib	SD	11+
    6	63/Male	Blood	Icotinib	EGFR p.L858R (EX21),CHEK2 c.445-1G>A	Combined gefitinib and bevacizumab	SD	6+
    7	79/Male	Tissue	No	EGFR p.L747_T751del (EX19), NF1 c.587-1G>C, ATM c.2124+1G>T	Gefitinib	PR	2+
    8	80/Female	Pleural effusion	Gefitinib	EGFR p.L858R (EX21), EGFR p.T790M (EX20), EGFR amplification	Osimertinib	PR	7+
    9	81/Male	Tissue	No	EGFR p.G719A (EX18), MET amplification, CDK4 amplification	Icotinib	SD	4

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    NGS-based genetic testing comprehensively predicts the effectiveness of targeted therapy. It can be widely used in routine clinical practice.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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