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Ruoying Yu

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-46 - Comprehensive Investigation of ERBB2 Transmembrane Domain Mutations (V659/G660) in 12,833 Chinese Lung Cancer Patients (ID 13466)

      16:45 - 18:00  |  Author(s): Ruoying Yu

      • Abstract
      • Slides


      The ERBB2/HER2 receptor tyrosine kinase belongs to the human EGFR family and is a known oncogenic driver in many cancers including lung cancer. Majority of ERBB2 mutations are within its kinase domain in non-small cell lung cancer (NSCLC). Rare transmembrane domain (TMD) mutations of ERBB2 have also been identified at V659/G660 residues, which potentially stabilize ERBB2 heterodimerization with EGFR, favour a kinase activating conformation, and have shown to respond to afatinib (Ou et al, JTO 2017).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We interrogated next-generation sequencing data from 19,800 Chinese cancer patients, including 12,833 lung cancers between 2014 and 2017. Sample types include formalin-fixed paraffin-embedded (FFPE) or fresh tumor samples, and/or circulating tumor DNA (ctDNA) from pleural effusion or plasma. Patients’ demographic and clinical data were further analyzed.

      4c3880bb027f159e801041b1021e88e8 Result

      ERBB2 TMD mutations at V659 were identified in twelve adenocarcinomas patients (five with V659D and seven with V659E), accounting for 0.14% of lung adenocarcinomas and 0.09% of all lung cancers. However, no G660 mutations were observed in this patient cohort. There is no gender preference for patients carrying such mutations (50%:50%). The median age of these patients is 56 with a trend to be younger in female patients. Two cases also carry other known driver alterations, EGFR L858R mutation and PIK3CA amplification, respectively. One case has two tumor tissue samples from the right upper and lower lobe of the lung, respectively. One lobe harbors EGFR exon19del mutation and EGFR amplification, whereas the other lobe carries ERBB2 V596D and EGFR G719A mutation. No other driver mutations were identified in the remaining cases. Interestingly, a novel TMD mutation I649R on ERBB3 was found in two patients together with ERBB2 V659D mutation, which might involve in the regulation of heterodimerization between ERBB2 and ERBB3. All these ERBB2 TMD mutations present at a relatively high mutant allele frequency (MAF) in tumor tissues, ranging from 15% to 71%, as well as liquid biopsy samples up to 47.5% of MAF, indicating a high tumor burden in these patients and potential ERBB2 amplification. Three patients received afatinib treatment though with progressive disease for various potential reasons, and the details of their treatment course will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Among Chinese patients, ERBB2 TMD mutation V659D/E is rare and unique to lung adenocarcinomas (0.14%). The efficacy of ERBB2-specific targeted therapy on these patients especially ERBB2 antibody and/or TKI need to be further investigated.


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