Abstract
BACKGROUND: A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic significance of mutations in the epidermal growth factor receptor gene (EGFR) and rearrangements in the anaplastic lymphoma kinase gene (ALK) in patients with surgically resected primary LAC. PATIENTS AND METHODS: We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in EGFR and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) by reverse transcription (RT)-PCR, and investigated ALK rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS). RESULT: ALK rearrangements and EGFR mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases. ALK rearrangements and mutations in EGFR and KRAS were mutually exclusive. Compared with patients with EGFR mutations, ALK rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically, EGFR mutations were more common than ALK rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas ALK rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas. ALK-positive patients had a significantly worse DFS than those with EGFR mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in EGFR-mutated versus WT patients. No significant differences were found in patients with ALK-positive tumors compared with EGFR-mutated and WT patients. CONCLUSION: Clinicopathological features of LAC with ALK rearrangements differ from those of LAC with EGFR mutations. Patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. Thus, ALK rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while EGFR mutations are associated with a better prognosis.