Young lung adenocarcinoma: Molecular analysis pointing to early acquisition of aggressive mutations.
Authors: Pruitt Aaron , Liu Jinpeng , Faisal Abu Saleh Mosa , Lei Feitong , Huang Bin , Durbin Eric B. , Jeong Jong Cheol , Levens Justin , Kolesar Jill , Arnold Susanne M. , Villano John L. , Zinner Ralph , Hao Zhonglin 
Published: June 2024

e20089 Background: Lung adenocarcinoma in young adults (≤50) has an aggressive course even in the presence of targetable mutations. Prior US studies were conducted predominantly in the Northeast where smoking prevalence is low compared to Kentucky. To assess the mutation spectrum in this high-risk population we performed a descriptive analysis of mutations in patients 50 years old and younger (YA), compared the survival of YA patients with and without NGS, and compared the survival of YA to patients older than 50 seen at an NCI designated Comprehensive Cancer Center situated in the tobacco belt. Methods: Using the Kentucky Cancer Registry (KCR) we identified 139 YA patients with lung adenocarcinoma seen at our institution between 01/2015 to 11/2023, 54 had NGS testing. 933 patients over age 50 were identified for comparison. Adenocarcinoma specimens were analyzed using next-generation sequencing of DNA (DNA-592-gene panel or whole exome) or RNA (whole transcriptome or +1,500-gene panel) at Caris Life Sciences or Foundation Medicine. Hazard ratios (HR) for survival were calculated using the Cox proportional hazards model. The cutoff for statistical significance was a p-value < 0.05 as calculated by the Chi-square test. Results: Of the 54 YA patients with NGS, 28 (52%) were female, 48 were white (88%), 3 Black (6%), and 3 Asian (6%). Only 18% were never smokers (median 28 pack years), and 44% had a family history of lung cancer. Targetable mutations were noted in 27 (50%). EGFR was mutated in 9 patients (17%), 2 with exon 19 deletion, 2 with exon 20 insertion, and 5 with exon 21 L858R. ALK rearrangement was seen in 3 patients (5%), while 3 (5%) had ERBB2 mutations. There was a mutation of KRAS in 17 patients (31%), and 16 of the 17 were transversion mutations. (13/17 G12C, 1/17 G12R, 1/17 G12V and 1/17 G13C). TP53 was mutated in 44 patients (81%), and 16 patients (30%) had mutations in homologous recombination repair (HHR) genes. The tumor mutation burden was high in 28 (52%) of patients. PD-L1 expression was > 50% in 22/54, 1-49% in 18/54, and 0% in 10/54 (4/54 NA). Survival was not significantly different between YA patients with and without NGS nor between YA and older patients. Conclusions: We identified a high prevalence of KRAS G12C, previously associated with increasing age and environmental insults, and EGFR exon 21 L858R in a YA population. Alterations in HHR genes and TP53 were present at high rates. Acquisition of aggressive forms of KRAS and EGFR mutation, as well as the high prevalence of TP53 and HHR defects, may contribute to early disease development. This highlights the importance of early tobacco cessation efforts and the need to assess germline mutations. Lung cancer remains a therapeutic challenge even in young patients with actionable mutations, as outcomes remain poor, equivalent to older patients.