Molecular profiling of key driver genes improves staging accuracy in multifocal non–small cell lung cancer

Objective: Multifocal non-small cell lung cancer has historically been separated into synchronous primary lung cancers or intrapulmonary metastases with the use of histopathology. We hypothesize that using targeted next-generation sequencing of key driver mutations in multifocal non-small cell lung cancer will improve our ability to differentiate intrapulmonary metastases from synchronous primary lung cancers. Methods: We identified patients who underwent surgery for non-small cell lung cancer between 2013 and 2018 with multifocal tumors. Archived specimens were reviewed with a 4-gene next-generation sequencing panel identifying mutations of EGFR, KRAS, BRAF, and NRAS. Synchronous primary lung cancers were classified as lesions with different histopathologic subtypes or driver mutations. Tests of hypotheses were performed with the Fisher exact test. Calculations were performed in Stata (v13.0; StataCorp LLC, College Station, Tex). Results: A total of 18 patients had non-small cell lung cancer tumor specimens (n = 41) available from 2 or more sites. The pathologic diagnosis was predominantly adenocarcinoma (39/41 specimens). We detected a driver mutation in 68.3% (28/41) of all tumors. The most common mutations observed were in KRAS (n = 17/41) and EGFR (n = 7/41). Eleven patients had synchronous primary lung cancers, and 4 patients had intrapulmonary metastases based on combined histopathologic and molecular profiling results. Three lacked driver mutations in either lesion. Eight synchronous primary lung cancers (8/18, 44%) were downstaged when compared with their original diagnosis (P =.08). Of these, 4 patients received adjuvant chemotherapy unnecessarily in hindsight. Conclusions: Molecular non-small cell lung cancer profiling using a 4-gene next-generation sequencing panel allows for better distinction between synchronous primary lung cancers and intrapulmonary metastases than histopathology alone. Routine use of next-generation sequencing for multifocal lesions prevents unnecessary adjuvant treatment for patients with histologically similar synchronous primary lung cancers.