Molecular and Clinicopathologic Characteristics of HER2 Mutant Lung Adenocarcinoma (ADC)
Sinchita Roy Chowdhuri, Jamie Chaft, Khedoudja Nafa, Mark Kris, Maureen Zakowski, Marc Ladanyi, Maria Arcila. Memorial Sloan-Kettering Cancer Center, New York
Background: Activating mutations within the tyrosine kinase domain of the ERBB2/HER2 gene have been previously reported in a small subset of lung ADCs. Amplification of HER2 has also been reported in some mutant cases. HER2 mutations are mutually exclusive with EGFR and KRAS mutations and are associated with increased sensitivity to specific kinase inhibitors in preclinical models. Previous studies have been mainly carried out on East Asian patients. The frequency and clinicopathologic characteristics of HER2 mutations and amplification have not been defined in the US population.
Design: Consecutive clinical cases of lung ADC (n=501) known to be negative for mutations in EGFR (exons 18-21) and KRAS exons 2 (codons 12-13) and 3 (codon 61) were selected based on DNA availability. HER2 mutation analysis was done by fragment analysis for small indels in exon 20. A subset of tumors was tested for ALK fusions and for HER2 amplification by FISH.
Results: HER2 mutations were present in 5% (25/501) of EGFR neg / KRAS neg lung ADCs. Twenty-four (96%) were exon 20 insertions and 1 (4%) was a point mutation (L755S). None of the 23 HER2-mutants tested for an ALK fusion by FISH were positive. HER2 amplification was not detected in any of the 10 mutant cases tested. The incidence of HER2 mutations in the “triple negative” (EGFR/KRAS/ALK) group was 7.6% (23/303). Morphologically, 84% (21/25) were mixed ADCs moderately or poorly differentiated. One tumor was well differentiated and 3 could not be graded due to small sampling but had high grade morphology. Eight tumors had a bronchoalveolar component and 2 had a mucinous component.
The patients (68% female) had a median age of 64 at diagnosis (range 41-87); 13 patients presented with advanced disease; 17 patients were never smokers. The prevalence of HER2 mutations was significantly higher (p<0.0001) in never smokers (15.9%; 17/107) than in current/former smokers (2.2%; 8/369) but there was no significant difference between females (6.5%; 17/260) and males (8/216; 3.7%).
Conclusions: HER2 mutations in lung ADCs are mutually exclusive with EGFR and KRAS mutations as well as ALK fusions. Compared to EGFR mutant ADC's, HER2 mutant tumors are morphologically highly heterogeneous with moderate to poor differentiation. While the overall prevalence of these mutations is low, estimated at 2.2% of all lung ADCs, testing of “triple negative” patients identifies HER2 mutations in 7.6%, thereby more efficiently screening for this subset of patients who could potentially benefit from alternate targeted therapies.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 286, Tuesday Morning