Background: Genomic alterations in 8 genes are now targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established.
Methods: We characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (Discovery cohort: DFCI; validation cohort: Duke, Memorial Sloan-Kettering, Vanderbilt). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, sex, and histologic subtypes using multivariable logistic regression.
Results: We identified variation in the prevalence of KRASG12C, sensitizing EGFR mutations, ALK and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental and Ashkenazi-Jewish ancestries from panel sequencing enabled quantitative correlation between Asian ancestry and EGFR mutations, and anti-correlation between Asian ancestry and KRASG12C mutation. Both mutations were enriched in female patients. We also uncovered low tumor mutational burden in patients of high Ashkenazi-Jewish ancestry. Among never/light smokers, targetable alterations in LUAD were significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we showed that 5% of patients with squamous cell (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbored targetable alterations.
Conclusions: Among patients with NSCLC, there was significant variability in the prevalence of targetable alterations according to genetic ancestry, histology, sex and smoking. Patients with LUSC and LCLC have >5% rates of targetable alterations supporting consideration for sequencing in those subtypes.