Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with <i>EGFR</i>-Mutant Lung Cancers

Clinical Cancer Research - Tập 19 Số 8 - Trang 2240-2247 - 2013
Helena A. Yu1,2,3, Maria E. Arcila1,2,3, Natasha Rekhtman1,2,3, Camelia S. Sima1,2,3, Maureen F. Zakowski1,2,3, William Pao1,2,3, Mark G. Kris1,2,3, Vincent A. Miller1,2,3, Marc Ladanyi1,2,3, Gregory J. Riely1,2,3
1Authors' Affiliations: 1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; 2Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College; 3Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; and 4Division of Hematology Oncology, Vanderbilt Ingram Cancer Center, Nashville, Tennessee
2Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
3Division of Hematology Oncology, Vanderbilt Ingram Cancer Center, Nashville, Tennessee

Tóm tắt

Abstract Purpose: All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Results: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%–4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR.

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Clinical Cancer Research

Tập 19 Số 8

2240-2247

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