期刊
CLINICAL LUNG CANCER
卷 17, 期 1, 页码 56-61出版社
CIG MEDIA GROUP, LP
DOI: 10.1016/j.cllc.2015.08.001
关键词
ALK rearrangements; Crizotinib; EGFR mutations; Erlotinib; KRAS mutations
类别
资金
- Fondo di Ricerca Ente Ospedaliero Cantonale, Switzerland
- University of Insubria, Varese, Italy
We investigated mutations and copy number of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) on 42 selected anaplastic lymphoma receptor tyrosine kinase (ALK)-positive adenocarcinomas. Eight cases showed concomitant mutations in EGFR or KRAS genes, and were classified as double-positive (DP). Four DP patients were treated with tyrosine kinase inhibitors (TKIs). EGFR-mutant DP patients had better response to crizotinib versus erlotinib. KRAS-mutant DP patients experienced the poor response to crizotinib. Patients with ALK/EGFR might benefit from crizotinib rather than erlotinib administration, and the efficacy of TKIs in ALK/KRAS cases remains unclear. An integrated targeted therapy should be considered for DP adenocarcinomas. Introduction: In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs). Materials and Methods: We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DP patients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. Results: Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DP patients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DP patients experienced opposite responses to crizotinib. Conclusion: The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC. (C) 2016 Elsevier Inc. All rights reserved.
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