Amphiregulin-2 Immunoreactivity Is Superior to EGFR FISH for Predicting Favorable Response to Tyrosine Kinase Inhibitors in EGFR-Wild Type Lung Adenocarcinoma
J Beheshti, Y Xiao, K Yonesaka, D Jackman, V Joshi, C Lee, P Janne, N Lindeman. Brigham and Women's Hospital, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; Harvard Partners Center for Genetics and Genomics, Boston, MA; Harvard Medical School, Boston
Background: Somatic mutations in the epidermal growth factor receptor (EGFR) are present in 20% of lung adenocarcinomas, where they confer a favorable response to treatment with anti-EGFR tyrosine kinase inhibitors (TKIs: erlotinib, gefitinib). However, in 15-25% of patients with favorable TKI response, no mutation in EGFR is detected. Some of these EGFR-wild type responsive tumors have increased immunohistochemical (IHC) expression of amphiregulin (AR), an alternative ligand for EGFR. It has also been suggested that increases in EGFR copy number may explain the clinical responses to TKIs in wild type tumors, but a direct comparison of EGFR FISH and AR IHC in these tumors has not been performed.
Design: A microarray with 48 lung adenocarcinomas from patients treated with TKIs was immunostained for AR and tested for EGFR mutation by PCR-sequencing and for EGFR copy number by FISH. FISH was scored by the method of Varella-Garcia, et al (Diag Pathol, 2006). An IHC score was calculated by multiplying the modal intensity (0-4+) by the % of tumor cells staining, to give a score from 0-400; >100 was considered positive. Test results were compared with clinical outcome, per RECIST criteria.
Results: 19 samples had wild type EGFR sequence, of which 13 had progression of disease on therapy and 6 had stable disease without progression; no responses were seen in EGFR wild type tumors. Of the six patients with stabilization of cancer on therapy, 5 (83%) had AR IHC positivity, while only 1 (17%) had EGFR FISH positivity. Of the 13 patients with disease progression, 7 had AR IHC positivity and 6 had EGFR FISH positivity. 6/7 (85%) cases with negative AR IHC had progressive disease.
Conclusions: In patients without EGFR mutations who are treated with TKI, positive IHC for AR was a sensitive (83%) test for disease stabilization, and negative AR IHC was a predictive (85%) marker of progression. If corroborated in larger studies, TKI therapy may benefit EGFR mutation negative patients with strong AR staining, but tumors with weak/no AR expression are likely to resist TKIs. EGFR copy number, as measured by FISH, is of no value in predicting likelihood of stable/progressive disease on TKI therapy in EGFR wild type tumors.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 237, Tuesday Afternoon