Spectrum of KRAS variants in primary lung mucinous adenocarcinoma: implications for diagnosis, testing, and therapy

INTRODUCTION: Primary lung mucinous adenocarcinoma (PLMAC) frequently harbors KRAS mutations; however, the distribution of KRAS variants in PLMAC remains under-characterized. This study aimed to investigate the KRAS mutational profile in PLMAC. MATERIALS AND METHODS: Cases of PLMAC (2018-2022) and primary lung nonmucinous adenocarcinomas (PLNMAC) (Oct-Dec 2022) were identified from pathology archives. Molecular testing was performed using a next-generation sequencing lung cancer hotspot gene panel. Specimen types, molecular results, demographic data, and smoking status were recorded. Statistical significance was assessed using an online Z-score calculator. RESULTS: A total of 117 PLMAC and 185 PLNMAC cases were identified. KRAS mutations were more common in PLMAC (62/86, 72%) compared to PLNMAC (61/154, 40%). In PLMAC, the most common KRAS variants were G12V (39%), followed by G12D (32%), while G12C was found in 19%. In PLNMAC, G12C was the predominant variant (47%). Among 27 (23%) never-smoking PLMAC patients, 17 were tested, and 12 (71%) harbored KRAS mutations-all non-G12C. Among 26 (14%) never-smoking PLNMAC patients, 20 were tested, and only one had a KRAS mutation, which was G12C. CONCLUSIONS: In our cohort, KRAS mutations were more prevalent in PLMAC than PLNMAC (72% vs. 40%, P < 0.05). However, the KRAS G12C variant was significantly less frequent in PLMAC compared to PLNMAC (19% vs. 47%, P < 0.05), suggesting that patients with PLMAC are less likely to benefit from KRAS G12C-targeted therapy. These findings underscore the importance of comprehensive KRAS genotyping and highlight the need for developing additional KRAS variant-targeted therapy for patients with PLMAC.