In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 11067-11067
Abstract:
11067 Background: Major obstacles limiting the clinical success of EGFR TKI therapy in non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy. Methods: We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA from the paired frozen biopsies and matched normal tissue was analyzed by whole exome sequencing and RNA from the biopsies was analyzed by whole transcriptome sequencing. High-resolution CT images were obtained at the time of each biopsy to compare the degree of molecular and radiographic response observed. Results: Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Selective depletion of each EGFR mutant allele, but not the EGFR wild type allele, was observed upon erlotinib treatment. Gene expression analysis of the paired transcriptomes revealed that erlotinib treatment resulted in significant upregulation of proapoptotic genes including BAD, BAX, BID, CASP3 and growth inhibitory genes including CDKN1A, GADD45B, GADD45G and downregulation of growth-promoting genes including CCNB1 and CCND3. Several unexpected and novel molecular biomarkers were identified by transcriptome analysis and the complete dataset will be presented. High-resolution CT scans revealed no interval radiographic changes in the target lesion and no clinical complications were encountered. Conclusions: This study is the first reported integrated genomic analysis of EGFR-mutant NSCLC immediately following EGFR TKI initiation. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response. Additional, serial integrated genomic analysis is ongoing in the index patient and others on therapy to enhance the management of NSCLC patients on targeted therapy.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.11067
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
detail.hit.zdb_id:
604914-X
