Frequency of actionable genomic alterations in early-stage lung adenocarcinoma (LA) detected by next-generation sequencing (NGS).

Abstract

e17541 Background: Early stage LA (≤T1N0) has a variable natural history. Although many patients are cured (~2/3) with surgery, many tumors recur and better methods are needed to distinguish these subsets and tailor therapy accordingly. We undertook a pilot study of NGS in such tumors to characterize the frequency and diversity of actionable genomic alterations in this setting. Methods: Formalin-fixed paraffin embedded (FFPE) tissues from 21 archival samples collected from 2007 to 2011 were obtained commercially with accompanying clinical and pathologic data. Clinical characteristics: female (17)/male (4); T1N0 (18), AIS (2), MIA (1). Pathologic LA subtype: acinar (n=8), mucinous (n=4), lepidic (n=4), and mixed (n=2) in addition to AIS (n=2) and MIA (n=1). Targeted NGS performed in a CLIA laboratory (Foundation Medicine) gave evaluable results in all cases. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 640X with 99% of bases covered >100X. Results: Forty-one driver mutations were identified in 17 genes among the 21 patients (avg= 1.9) including 28 base substitutions, 5 indels, 4 amplifications, 3 homozygous deletions and 1 rearrangement. Notably, 90% of cases (19/21) harbored at least one alteration that can be classified as actionable-linked to an approved therapy in LA or another tumor type or a clinical trial. Examples include alterations in EGFR (n=6), NF1 (n=2, PI3K/mTOR inhibitors), CDNK2A (n=1, CDK inhibitors), EML4-ALK (fusion, n=1, ALK inhibitor), ERBB2 (n=1, TKI inhibitors), STK11 (n=1, mTOR inhibitors), and MDM2 (n=1, nutlins). Conclusions: NGSidentified drivergenomic alterations in T1N0 LA, MIA and AIS. On average, two known driver mutations were identified per tumor, many of which are associated with existing or emerging targeted therapies. This provides rationale for future investigation of larger series of T1N0 LA, AIS and MIA, using NGS to evaluate the prognostic value of these changes and could presage adjuvant trials in higher risk patients.