EGFR Exon 20 Mutations: Molecular Spectrum, Incidence and Clinicopathologic Characteristics
Yen-Chun Liu, Khedoudja Nafa, Jamie E Chaft, Natasha Rekhtman, Boris Reva, Maureen F Zakowski, Mark G Kris, Marc Ladanyi, Maria E Arcila. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: The central role that EGFR tyrosine kinase inhibitors such as erlotinib have assumed in lung adenocarcinoma treatment has created the need for a more comprehensive understanding of various EGFR mutations. In contrast to the more common mutations in exons 19 and 21 of EGFR, primary mutations in exon 20 occur at a lower frequency and are not as well characterized. We report the molecular spectrum, clinicopathologic characteristics and incidence of these mutations in a large cohort of lung adenocarcinomas.
Design: A cohort of 3000 lung adenocarcinoma specimens, collected between 2009 and 2012 were subjected to a stepwise genotyping algorithm. Cases were first tested for common mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and, if negative, further analyzed for EGFR exon 20 mutations. All samples underwent extended genotyping for other driver mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, and AKT by mass spectrometry genotyping; a subset was evaluated for ALK rearrangements by FISH.
Results: A total 70 EGFR exon 20 mutated cases were identified, accounting for 11% of all EGFR mutations (70/624) for an overall incidence of 2.3% (95%CI 1.8 to 2.8%). In-frame insertions composed the vast majority of the mutations (89%, 62/70), varying widely in size (range 3 to 12 bps) and position and resulting in 19 unique variants. These EGFR exon 20 mutations were mutually exclusive with other recurrent genetic alterations except for PIK3CA. Molecular modeling predicted potentially different effects on erlotinib binding for the different types of EGFR exon 20 insertions. Insertions were more common in never-smokers (p<0.0001). There was no association with sex, race, or stage. Point mutations were comparatively rare (n=8, 1% of all EGFR mutants), and included S768I (5), R776 (2), and D770N (1); 25% (2/8) occurred in conjunction with other minor EGFR mutations. Morphologically, exon 20 mutated tumors were similar to those with common EGFR mutations.
Conclusions: EGFR exon 20 insertions represent the third most common type of EGFR mutation. Their structural heterogeneity predicts potential differential response to EGFR inhibitors.
Monday, March 4, 2013 1:00 PM
Proffered Papers: Section D, Monday Afternoon