Lung Research Poster Session

Elio Adib, MD

Postdoctoral Research Fellow
Pulmonary and Critical Care
Elio Adib, MD*, Amin H. Nassar, MD, Sarah Abou Alaiwi, MD, Stefan Groha, PhD, Elie W. Akl, MD, Lynette M. Sholl, MD, Kesi Michael, BS, Mark M. Awad, MD, PhD, Pasi A. JÓ“nne, MD, PhD, Alexander Gusev, PhD, David J. Kwiatkowski, MD, PhD
Variation in Targetable Genomic Alterations in Non-Small Cell Lung Cancer by Genetic Ancestry, Sex, Smoking History and Histology

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.