Dissecting the clinicopathological, genomic, and prognostic significance of ALK rearrangement in resected lung adenocarcinoma.

OBJECTIVES: The ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD). METHODS: We retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathological characteristics, molecular profiles, and outcomes was explored. RESULTS: Among 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and non-smokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (e.g., TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in stage I patients who did not receive adjuvant chemotherapy while with prolonged RFS in stage II and III patients who received adjuvant chemotherapy. Notably, six patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. Additionally, the administration of ALK inhibitors significantly improved post-recurrence survival in ALK-positive patients. CONCLUSIONS: ALK positivity was associated with specific aggressive pathological features and inferior RFS in stage I LUAD. ALK-positive patients seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

Prognostic value of KRAS G12V mutation in lung adenocarcinoma stratified by stages and radiological features.

OBJECTIVE: KRAS G12V is one of the most common KRAS mutation variants in lung adenocarcinoma (LUAD), and yet its prognostic value is still unrevealed. In this study, we investigated the clinicopathologic characteristics and prognostic value of the KRAS G12V mutation in LUAD. METHODS: Data of 3829 patients who underwent LUAD resection between 2008 and 2020 were collected. Mutations were classified as wild-type, G12V, or non-G12V. The clinicopathologic characteristics, postoperative outcomes, and recurrence pattern were analyzed among groups. RESULTS: In total, 3554 patients were wild-type and 275 patients harbored a KRAS mutation: 60 patients with G12V (22.2%) and 215 patients with non-G12V (77.8%). The KRAS G12V mutation was more frequent in male patients, older patients (≥60 years), former/current smokers, those patients with radiologic solid nodules, and those with highly invasive histologic subtypes. Tumors carrying KRAS G12V mutation exhibited elevated programmed death-ligand 1 expression in comparison with wild-type tumors. KRAS G12V was more prevalent in older patients and had less lymphovascular invasion compared with other mutation types. FGF3, RET, and KDR co-mutations occurred more frequently in the KRAS G12V group. Multivariate analysis demonstrated that the KRAS G12V mutation was an independent prognostic factor in stage Ⅰ tumors, whereas the KRAS non-G12V mutation was not. KRAS G12V was associated with early recurrence and locoregional recurrence. CONCLUSIONS: The KRAS G12V mutation was associated with aggressive clinical-pathologic phenotype and early recurrence. To note, this mutation exhibited a significantly worse prognosis in patients with part-solid and stage Ⅰ lung adenocarcinoma. Meanwhile, the prognostic significance of KRAS G12C and G12V variants was comparable.