Background

EGFR alterations have important therapeutic implications in lung cancer (LCa). The incidence of these alterations, their subtypes, and co-mutational status is well described in Caucasian and East Asian but not in African American populations. This study aims to fill this gap by using the Tempus database to analyze real-world data from EGFR mutant LCas across races, assessing alteration subtypes and co-mutational profiles.

Methods

De-identified records with primary LCa diagnosis tested via Tempus xT assay, which includes a 595-648 gene DNA panel, were included if they had ≥1 pathogenic EGFR mutation (short variants (SVs), copy number amplifications (CNAs), or fusions). Race was determined based on recorded clinical records and stratified by Causcasian (CA), Black or African American (BAA), Asian or Pacific Islander (API), other races, and unknown. Somatic pathogenic co-mutations were restricted to genes with ≥5% frequency in at least one race. Statistical analyses were performed using chi-squared tests with Bonferroni or false discovery rate adjustments for multiple testing.

Results

Of 17,482 LCa samples sequenced with Tempus xT assay, pathogenic EGFR alterations occurred in 8.9% of CA 7.6% of BAA, 39% of API, 15% of other races, and 12% of unknown races. The frequency of exon 19 deletions differed significantly across races (p=0.017), with the highest frequency in other races. L858R mutations also differed (p < 0.001), being significantly higher in CA compared to BAA (p=0.034) and in API compared to CA (p=0.006). EGFR copy number variants (CNVs) differed across races (p<0.001), with the highest frequency in BAA. TP53 alterations occurred at a higher frequency in patients with a history of smoking, those with high tumor mutational burden (TMB), and high PD-L1. KMT2C co-mutations were significantly more common in BAA (13%) compared to CA (3%) and API (4%) (q=0.003). Similarly, GLI1 co-mutations were most frequent in BAA (5.8%) compared to 1.5% in CA and 0% in API patients (q=0.025).

Conclusions

Significant racial differences in the prevalence of EGFR alterations were observed, with specific co-mutations like KMT2C and GLI1 occurring more frequently in BAA compared to CA and API patients. KMT2C may be linked to higher TMB and immunotherapy response, while GLI1 is associated with erlotinib and osimertinib resistance. Regardless of race, TP53 mutations were more frequent in smokers, patients with high TMB, and those with elevated PD-L1 expression, suggesting that additional factors may drive tumors with these alterations. A deeper understanding of the mechanisms contributing to these genetic changes could lead to more effective treatment strategies for lung cancer patients.

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