EGFR/KRAS Mutational Profiling of Lung Adenocarcinomas in a Clinical Practice
S Dacic, SA Yousem, PN Ohori, M Nikiforova. University of Pittsburgh, Pittsburgh
Background: Screening for EGFR and KRAS mutations in patients with lung adenocarcinomas can be used to predict patient's response to EGFR TKIs, but there is a lack of guidelines for testing in a clinical practice. Significance of EGFR FISH testing is uncertain. Recent literature suggests possible correlation between morphology and EGFR/KRAS mutational profile of lung adenocarcinoma, which may be useful selection criteria for molecular testing. We analyzed morphologic and clinicopathologic characteristics of surgically treated primary lung adenocarcinomas in the absence of neoadjuvant or targeted therapies with respect to their EGFR and KRAS mutational profile and EGFR gene amplification.
Design: 337 consecutive newly diagnosed and surgically treated primary lung adenocarcinomas were assessed by PCR amplification and direct nucleotide sequencing for presence of mutations in EGFR exons 19 and 21 and KRAS codons 12/13. Each case was analyzed by FISH for EGFR using a standard method. Amplification was defined as EGFR gene to chromosome 7 ratio 2. High polysomy was defined as 4 or more EGFR gene copies in 40% of the cells. The results were correlated with tumor morphology and clinicopathologic characteristics including tumor stage, size, presence of scar, inflammatory response, angiolymphatic and pleural invasion.
Results: Mutational analysis demonstrated 33 (10%) EGFR+, 78 (23%) KRAS+ and 226 (67%) EGFR-/KRAS- lung adenocarcinomas. EGFR mutations were more frequently seen in women (77%), while equal sex distribution was observed in KRAS+ and EGFR-/KRAS- tumors. Mixed type of adenocarcinoma was the most common histologic type observed in all 3 groups. The primary pattern in EGFR + group was acinar (50%), while papillary (31%) was the most common secondary pattern. The primary and secondary patterns in KRAS+ group were acinar (27% and 32%). Similarly, acinar type was the most common in EGFR-/KRAS- group (42% primary; 29 % secondary). EGFR amplification was seen in only 5 EGFR + tumors which were all positive for exon 19 deletion. 1 KRAS + and 3 EGFR-/KRAS-tumors showed EGFR amplification. High polysomy was seen in 6 EGFR + tumors, 6 KRAS + and 17 EGFR-/KRAS- tumors. There was no difference between the tumor groups in respect to analyzed clinicopathologic characteristics.
Conclusions: Histologic type of lung adenocarcinoma and EGFR FISH status are poor predictors of tumor mutational profile. Determination of KRAS mutational status as the first step, followed by EGFR mutational analysis if necessary, should be considered in a clinical practice.
Monday, March 9, 2009 9:15 AM
Platform Session: Section F, Monday Morning