Author of

• 16051

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  ORAL 42 - Drug Resistance (ID 160)

  • Event: WCLC 2015
  • Type: Oral Session
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:R.C. Doebele, J.V. DeGregori
  • Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 4a-4f

  • 16053

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    ORAL42.02 - Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer (ID 572)

    18:41 - 18:52  |  Author(s): H. Mizuuchi
    • Abstract
    • Presentation
    • Slides

    Background:
    Acquisition of resistance to EGFR- tyrosine kinase inhibitors (TKIs) is one of important issues in lung cancer researches. Several resistance mechanisms have been identified. However, inter-tumor heterogeneity in acquisition of resistance to EGFR-TKIs is currently unclear.
    
    Methods:
    Eleven autopsied patients who developed acquired resistance to EGFR-TKI monotherapy were included in this study. All patients harbored activating EGFR mutations (exon 19 deletion or L858R mutation), and developed acquired resistance to EGFR-TKI after initial response to the drug. Details of patient characteristics are summarized in Table 1. The resistance mechanisms of seven patients have been reported in our previous analyses (Suda K, et al. Clin Cancer Res 2010, and Suda K, et al. APLCC 2014). In this study, we analyzed acquired resistance mechanisms in twenty-eight tumor samples obtained from the four additional patients using target sequencing technique by next-generation sequencer.
    
    Results:
    Among eleven patients, four developed T790M EGFR secondary mutation in all TKI-refractory lesions. One patient developed MET amplification in all TKI-refractory lesions. Three patients harbored both TKI-refractory lesions with T790M mutation and those with MET amplification. The other three patients showed respective resistance mechanisms (Table 1).

    Table 1. Summary of resistant mechanisms in eleven patients.

    Pt. ID	Age/Sex	Pack-Year	Resistant Mechanisms	TTF (m)
    C1	57/F	0	T790M or MET	13.8
    C2	48/F	0	T790M or MET	11.0
    C3	58/M	34	MET	14.5
    C4	75/M	0	T790M	43.9
    C5	93/F	0	T790M	14.8
    C6	62/M	26	T790M	9.1
    P1	86/F	0	T790M	10.8
    P2	72/M	27	T790M or MET	3.8
    P3	89/F	0	EGFR loss with MET or Unknown	9.0
    P4	84/F	0	Unknown	22.6
    A1	76/F	0	SCLC transformation or T790M	5.0

    In the target sequence analysis, allele count data were further analyzed in tumor samples with T790M mutation, and we observed diverse T790M/activating EGFR mutation allele ratio ranging from 2 – 51%. In the analysis for time to treatment failure (TTF), we observed longer TTF in patients who developed single resistance mechanism compared with those who developed multiple resistance mechanisms (Fig. 1; p = 0.055). Figure 1
    
    
    
    Conclusion:
    In this study, we observed qualitative heterogeneity and quantitative heterogeneity of T790M allele ratio in acquisition of resistance to EGFR-TKIs in lung cancers. Qualitative heterogeneity in resistance mechanisms would have a correlation with TTF of EGFR-TKIs.
    
    

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