EGFR and KRAS mutations in patients with bronchioloalveolar carcinoma treated with erlotinib in a phase II multicenter trial

Abstract

7029 Background: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene have been associated with sensitivity to erlotinib (Tarceva™). Virtually all patients whose tumors harbor these mutations respond. Mutations in KRAS, which encodes a signaling protein downstream of EGFR, appear to be mutually exclusive of EGFR mutations (Shigematsu H. JNCI 2004) and are associated with sensitivity and resistance to erlotinib (Pao W. PLoS Medicine 2005). We now report the association of EGFR and KRAS mutations with partial radiographic response, BAC histologic types, and smoking history in patients with BAC treated with erlotinib in this ongoing phase II trial. Methods: Patients with stage IIIB/IV BAC received erlotinib 150 mg PO daily. We performed standard PCR-based sequencing using tumor-extracted genomic DNA to detect mutations in EGFR (exons 18–21) and KRAS (exon2) on the first 37 specimens available from this trial planned to enroll 100. The analysis includes 36 specimens previously reported by Pao cited above. Results: We found mutations in EGFR in 9 of 37 (24%) and KRAS in 4 of 34 (12%). In the 11 patients with partial responses, mutations in EGFR were found in 9 (82%) and in KRAS in none. Two patients with partial response had neither mutation. EGFR mutations were found in 1/8 (13%) with “pure BAC” (WHO defined) and 8/29 (28%) with AdenoCa with BAC features. All 4 KRAS mutations were found in the latter group. EGFR mutations were found in 0/5, 4/25 and 5/7 current, former and never smokers, respectively. KRAS mutations were detected in 1/5, 2/24 and 1/5 current, former and never smokers. Conclusions: In these patients with BAC: 1) All 9 tumors with EGFR mutations and 2 without showed partial responses. None of the 4 tumors with KRAS responded. 2) EGFR mutations are more common in AdenoCa with BAC features than “pure” BAC. 3) EGFR mutations were most frequent in never smokers. 4) Since EGFR and KRAS mutations are associated with sensitivity and resistance to erlotinib, these data may help decide when to prescribe it and may define the biological basis of clinical observations. We plan to study additional tumors from the 89 patients accrued. Support: P50 CA90949, Genentech, Inc. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech