[1782] Molecular Profiles of EGFR and KRAS Mutations in Non-Small-Cell Lung Carcinoma: A Survey of 344 Cases

SS Chen, R Luthra, LJ Medeiros, Z Zuo. University of Texas MD Anderson Cancer Center, Houston, TX

Background: Activating mutations of the epidermal growth factor receptor (EGFR) predict clinical response to EGFR inhibitor (EGFRi) therapy in non-small-cell lung carcinoma (NSCLC) patients, whereas mutations of the Kirsten rat sarcoma viral oncogene (KRAS) predict primary resistance to EGFRi therapy. EGFR and KRAS mutations are generally mutually exclusive, with rare reports documenting coexistent mutations. There is also limited data about the coexistence of multiple EGFR mutations in a single tumor sample. For instance, the development of the secondary resistance mutation T790M has been identified in NSCLC with the primary sensitive mutation L858R following treatment with EGFRi.
Design: 334 randomly selected NSCLC cases were analyzed for EGFR and KRAS mutations. Samples tested included surgical biopsy and cytology fine needle aspiration specimens. For EGFR analysis, exons 18-21 were assessed using Sanger sequencing. For KRAS analysis, codons 12, 13, and 61 were assessed using Pyrosequencing.
Results: EGFR mutations were identified in 66 of 327 (20.2%) samples and were distributed as follows: 5 (6.7%) in exon 18, 29 (38.7%) in exon 19, 13 (17.3%) in exon 20, and 28 (37.3%) in exon 21. These mutations included 26 (34.7%) in-frame deletions in exon 19, 4 (5.3%) in-frame insertions in exon 20, and 45 (60%) point mutations in exons 18, 19, 20, and 21. Multiple EGFR mutations coexisting in the same tumor sample were rare. KRAS mutations were identified in 66 of 327 (20.2%) samples and were distributed as follows: 55 (83.3%) in codon 12, 6 (9.1%) in codon 13, and 5 (7.6%) in codon 61. 320 samples were analyzed for both EGFR and KRAS mutations: 195 (60.9%) had no mutations, 60 (18.6%) had EGFR mutation, 61 (19.1%) had KRAS mutation, and 4 (1.3%) had both EGFR and KRAS mutations. The coexistent EGFR and KRAS mutations were: KRAS G13C + EGFR Y801A, and KRAS G12C + EGFR V726M or R748G or K875R.
Conclusions: EGFR and KRAS mutations rarely (∼1%) coexist in cases of NSCLC. Similarly, multiple EGFR mutations rarely coexist in these tumors. The clinical relevance of coexisting EGFR and KRAS mutations and that of multiple mutations in EGFR to clinical response to EGFRi therapy needs further evaluation, which may lead to a better understanding of the mechanisms explaining therapeutic response to patients with NSCLC treated with EGFRi.
Category: Pulmonary

Tuesday, March 23, 2010 9:30 AM

Poster Session III # 260, Tuesday Morning

 

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