Comparison of Clinicopathological Features and Prognosis between ALK Rearrangements and EGFR Mutations in Surgically Resected Early-stage Lung Adenocarcinoma

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.

Mucinous lung adenocarcinoma, particularly referring to EGFR‐mutated mucinous adenocarcinoma

“…As demonstrated by several studies, EGFR mutations are associated with female sex, w/d histological grade such as lepidic adenocarcinoma, and Asian ethnicity . However, the current study, wherein EGFR ‐mutated adenocarcinoma was divided into two subtypes (i.e., mucinous adenocarcinoma and nonmucinous adenocarcinoma), clearly revealed that EGFR ‐mutated mucinous adenocarcinoma was related to more males and smokers as well as lower histological grades than that without mucin.…”

Clinical, Conventional CT and Radiomic Feature-Based Machine Learning Models for Predicting ALK Rearrangement Status in Lung Adenocarcinoma Patients

“…In spite of this, the improved efficacy of the integrated model by adding clinical characteristics for lesions in the primary cohort suggests that clinical information was effective to improve the radiomic-based model for detecting ALK-mutated status. Adding more ALK-associated clinical variables such as carcinoembryonic antigen (CEA) level and histological growth pattern may further enhance the performance of the model (35,36). Previously, the best predictive model for the detection of ALK mutations was from Yamamoto's study (AUC = 0.846), in which it contained age as the only selected clinical feature and several conventional CT features (14).…”

Expanding anaplastic lymphoma kinase therapeutic indication to early stage non-small cell lung cancer

“…Supporting this hypothesis, also early stages ALK+ lung cancers appeared to be more spread than what initially thought: a recent retrospective analysis, performed on resected lung adenocarcinoma with clinical N0 (absence of computed tomography or positron emission tomography detectable lymph node involvement), revealed an higher percentage of pathological N1 or N2 stage (37%) in ALK+ cases compared to other subgroups (EGFR+, KRAS+ or WT) (22). ALK+ lung cancer patients are younger, never or light smoker, diagnosed mainly on advanced stage of the disease, bearing adenocarcinoma histology with peculiar aspects: solid or sheet-like pattern, with "signet-ring" cells and invasive mucinous aspects, similar to other fusionpositive subgroups (i.e., ROS+ or RET+) (13,(17)(18)(19); thus, identifying a subgroup of tumors with morphological aspects denoting itself a more aggressive phenotype (23,24).…”

“…Identification of the right comparator group seems to be relevant: results of an European platform screening, conducted mainly in a smoker population, identifies ALK positivity (either by IHC or FISH) as predictor of better OS, whereas in other studies, evaluating never-smoker populations, the presence of ALK translocations resulted to be associated with poor disease free survival (DFS) (25)(26)(27). Similarly, other studies conducted on resected lung cancers highlight the association between ALK positivity and reduced recurrence free survival (RFS) or DFS compared to EGFR+ patients, although no differences in OS have been reported (13,28,29). Multiple factors can potentially jeopardize the prognostic interpretation of ALK fusions in surgical patients: retrospective nature of these studies, heterogeneity of comparator (smokers/never-smokers, oncogenic drivers, different stages) and limited number of ALK+ patients.…”

“…Genomic complexity of lung adenocarcinoma is well characterized, supporting the evidence of different tumor entities with different biology, natural history and clinical behavior (11). Within oncogene-addicted tumors itself, fusions-positive lung cancers retain peculiar aspects, compared to mutation-driven cancers (e.g., EGFR+) (12,13). Thus, a deep understating of ALK fusionsrelated clinical implications in early stage of the disease is mandatory, to precisely determine their prognostic relevance and, consequently, promote therapeutic strategies' implementation that could impact on PFS and, more relevant, on overall survival (OS).…”