The Predictive Value of EGFR/KRAS/BRAF Genotyping and TP53 Expression in a Series of 54 Patients with Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitors.
Solene Houlle, Anne Perel, France Blanchard, Aude Lamy, Philippe Courville, Luc Thiberville, Jean-Christophe Sabourin. Rouen University Hospital, France
Background: Adenocarcinomas (ADK) represent 30 to 40% of lung carcinomas. Tyrosine kinase inhibitors (TKI) are used to treat patients with advanced carcinomas harboring activating mutations of the EGF receptor (EGFR). Recent studies have demonstrated that TKI efficacy depends on the mutational status of specific molecular markers such as EGFR and TP53 while other activating mutations in KRAS or BRAF lead to resistance. The aim of our study is to retrospectively analyze lung ADK tumor samples to correlate these 4 molecular markers with clinical and histological data.
Design: 72 patients with lung adenocarcinoma (17 surgical specimens and 55 biopsies) were analyzed; 25 metastasis and 7 recurrences were also studied. Among the 72 patients, 54 patients were treated with TKI. The molecular analysis of EGFR was performed by sequencing exons 18, 19, 20 and 21, KRAS and BRAF genotyping by SNaPshot® multiplex on codons 12, 13 and 61 for KRAS and exon 15 for BRAF. TP53 gene expression was quantified by immunohistochemistry on 28 patients with TKI treatment.
Results: 6.9% of EGFR mutations and 48.6% of KRAS mutations (no mutation in the codon 61 was reported) were identified while no BRAF mutation was found. Interestingly we observed only one case with both EGFR and KRAS mutations. EGFR mutations are frequently diagnosed in women and also in none mucinous ADK whereas KRAS mutations are predominantly found in mucinous ADK. 64.3% of tumors are TP53 positive. The study of the overall survival of patients with EGFR/KRAS mutations and TP53+ is under analysis. Mutational discordances between primary tumors and metastasis or primary tumors and recurrences represent 8% for EGFR and 24% for KRAS. Different mutations between primary tumor and metastasis were sometimes encountered emphasing the heterogeneity of these tumors.
Conclusions: The identification of molecular alterations in EGFR/KRAS genes and TP53 expression seems to be important for the outcome of patients treated with TKI. Today, the use of these inhibitors merely requires detection of activating mutations in EGFR. The detection of KRAS mutations (more frequent, technically easier to perform and mostly exclusive to EGFR) might also be necessary for TKI administration. Our results suggest that BRAF is not implicated in the carcinogenesis of these tumors. Mutational discordances between primary tumor site and metastasis encourage the analysis of the metastasis site if accessible.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 265, Tuesday Afternoon