53P - Heterogeneous characteristics of KRAS mutation subtypes in surgically resected lung adenocarcinomas

Background

KRAS mutations are common driver oncogenes in lung adenocarcinomas (LUADs). Recently, several KRAS G12C-targeted drugs have been developed. The co-mutation of STK11 and KEAP1 drives primary resistance to immune checkpoint inhibitors. This study aimed to elucidate clinicopathological, genetic, and immunological characteristics based on KRAS mutation subtypes of LUADs.

Methods

In total, 1382 patients with surgically resected LUADs were examined for KRAS mutations between February 2010 and July 2016. Co-occurring genetic alterations were analyzed using next-generation sequencing. PD-L1 and PD-L2 expression was evaluated using immunohistochemistry, and their expression statuses were classified using tissue microarrays based on the tumor proportion score as negative (< 1%), weakly positive (1–49%), or strongly positive (≥ 50%). Co-occurring genetic alterations and PD-L1 and PD-L2 expression statuses were analyzed according to KRAS mutation subtypes.

Results

KRAS mutations were identified in 188 LUADs (14%; 121 men and 146 smokers). The median age was 68 years (range 28−86 years). G12C was the most common subtype in 71 LUADs, followed by G12V in 45, G12D in 43, G12A in 15, G13D in 4, G12S in 3, G12F in 2, G12R in 2, G13C in 2, and G13Y in 1. Co-occurring genetic alterations of 97 LUADs were analyzed and detected in 55 LUADs (TP53 in 22, RBM10 in 13, STK11 in 5, KEAP1 in 5, ARID1A in 5, PIK3CA in 4, NOTCH1 in 4). PD-L1 and PD-L2 expression of 158 and 156 LUADs, respectively, was evaluated and was negative in 88 (56%) and 77 (49%), weakly positive in 40 (25%) and 47 (30%), and strongly positive in 30 (19%) and 32 (21%), respectively. Frequencies of co-occurring genetic alterations and PD-L1 and PD-L2 expression status varied across KRAS mutation subtypes.

Conclusions

KRAS mutation subtypes in LUADs are highly heterogeneous regarding co-occurring genetic alterations and PD-L1 and PD-L2 expression status. Therefore, stratification according to KRAS mutation subtypes should be considered when designing future clinical trials.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.