Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

SIMPLE SUMMARY: RAS mutation is the most frequent oncogenic alteration in human cancers and KRAS is the most frequently mutated, notably in non-small cell lung carcinomas (NSCLC). Various attempts to inhibit KRAS in the past were unsuccessful in these latter tumors. However, recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target KRAS G12C-mutated tumors, which seems promising for patient treatment and should soon be administered in daily practice for non-squamous (NS)-NSCLC. In this context, it will be mandatory to systematically assess the KRAS status in routine clinical practice, at least in advanced NS-NSCLC, leading to new challenges for thoracic oncologists. ABSTRACT: KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment.