Author of

• 11454

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  P2.01 - Poster Session 2 - Cancer Biology (ID 145)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11473

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    P2.01-019 - Heterogeneity of EGFR mutation detected in a patient treated with gefitinib<br /> as neo-adjuvant chemotherapy (ID 1093)

    09:30 - 09:30  |  Author(s): Y. Nakamura
    • Abstract

    Background
    Epithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show incredible response rate up to around 80 % to non-small cell lung cancer patients with EGFR sensitive mutations, and also contribute to improve overall survival time of such patients. However, it is no doubt that almost all patients have recurrences in time. Some genetic aberrant changes such as the secondary mutation T790M in exon 20 of EGFR are known to have influence on drug resistance, but most mechanisms of drug resistance are still unclear. Recently, Some studies suggested that heterogeneous distribution of EGFR mutations seemed to have correlations with treatment failure of EGFR-TKIs, but others reported that heterogeneity was extremely rare. Heterogeneity of EGFR is still remains to be controversial. In this study, we reported one rare case that resected lung after chemotherapy with gefitinib showed heterogeneous distribution of L858R point mutations and it’s correlation with effects of EGFR-TKIs.

    Methods
    A 68-year-old woman was diagnosed as lung adenocarcinoma (T3N1M0 stageⅢa) with the L858R point mutation. Unilateral Pulmonary Artery Occlusion test before operation showed a high probability that patient’s oxygenation would decrease to near the tolerance limit by right peumonectomy. For the purpose of reducing the tumor volume to avoid the pneumonectomy, she received gefinitib (250mg/body/day) as neo-adjuvant chemotherapy for three months and succeeded. Continuously, she underwent right middle and lower lobectomy and lymph node dissection (ND2a). Pathological examinations of resected lung specimens were done using H&E staining and immunohistochemistry with L858R Mutant Specific Rabbit monoclonal antibody for EGF Receptor. Two different tissue parts were respectively macrodissected from Formalin-Fixed Paraffin-Embedded tissue slides and analyzed genetically by direct sequencing analysis.

    Results
    H&E and immunohistochemical staining specimens showed that this resected identical tumor was divided into two areas. One area consisted of necrotizing and degenerating cell population and was stained with L858R specific antibody. The other area consisted of viable cell population with relatively low nuclear grade and was not stained with L858R specific antibody. Additionally, direct sequencing analysis of each extracted DNA from these two different areas revealed that the former area contained only wild type base sequence in exon 21 of EGFR, but the latter contained a mixture of point mutation of L858R and wild type base sequence in exon21. Secondary T790M mutations were not detected in both areas. The result of direct sequencing analysis supported heterogeneous distribution of L858R point mutations which was found on immunohistchemical staining. Comparing with pathological finding of HE staining, it was implied that therapeutic effect of gefitinib was limited only to the tissue area having L858R point mutation and cells of non-mutated tissue area survived.

    Conclusion
    This study suggested that there may be intratumoral heterogeneity of EGFR mutation and therapeutic effect of EGFR-TKIs could be limited only to mutant cells. As a result, wild-type cells would survive and develop drug resistance against EGFR-TKIs, even if tumors had no secondary T790M mutations in exon 20 of EGFR.