Druggable driver gene alterations in redefined large cell carcinoma in Chinese patients: an observational study

Few reports have investigated the genetic status of large cell carcinoma (LCC) in Chinese patients under the 2015 World Health Organization (WHO) classification. We aimed to analyze the distribution of druggable driver gene alterations, including mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), proto-oncogene B-Raf (BRAF), and phosphatidylinositol-4,5 biphosphate 3-kinase catalytic subunit alpha (PIK3CA) and translocations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and ROS proto-oncogene 1 (ROS1), in a large population of patients with LCC under the 2015 WHO classification, and to assess the clinical outcomes of patients with LCC harboring these genetic alterations.

A cohort of 322 patients with LCC resected between June 2015 and December 2018 was included in this study. The clinical characteristics of the patients and data on the distribution of EGFR, KRAS, BRAF, PIK3CA, EML4-ALK, and ROS1 alterations were retrospectively collected. The disease-free survival (DFS) of patients with LCC was analyzed using the log-rank test.

Among the patients with redefined LCC, the proportion of males was much higher than that of females. Detection of LCC was more frequent in patients >60 years of age (71.4%). Mutations of EGFR were found in 3.6% of the LCC participants, predominantly in non-smokers. Mutations in KRAS were observed in 7.8% of the LCC patients, mainly in males and smokers. Mutations in PIK3CA and EML4-ALK translocations comprised 2.1% and 0.52% of the identified alterations, respectively. No alterations were identified in ROS1 and BRAF. After molecular stratification, no significant difference in DFS was identified between wild-type (WT) and mutation groups (29.91±3.83 vs. 25.33±6.04 months, P=0.48).

Under the 2015 WHO criteria, LCC was more frequently detected in elderly male patients with inferior prognoses. The frequency of EGFR and KRAS mutations was found to be the highest. Mutations in EGFR occurred more frequently in non-smokers, whereas KRAS mutations occurred predominantly in males and smokers. The PIK3CA mutations and EML4-ALK translocations were rare in patients with LCC. Our data revealed that the identification of clinically actionable molecular alterations in LCC may help guide personalized cancer treatment decisions in the future.