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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
P1.02-054 - Genomic Complexity in KRAS Mutant Non-Small Cell Lung Cancer (NSCLC) by Smoking Status with Comparison to EGFR Mutant NSCLC (ID 6134)
14:30 - 15:45 | Author(s): E.S. Chambers
Background: KRAS is the most frequently mutated oncogene in NSCLC and lacks an effective targeted therapy. Notably, KRAS mutations occur in both never/light-smokers and smokers. However, the relationship between smoking status and a KRAS+ tumor’s genomic complexity (mutation burden, copy number changes, concurrent mutations in key oncogenic pathways) is unclear. Similarly, the relationship between genomic complexity in tumors from never/light smokers but with a KRAS v EGFR activating mutation is also unknown.
Methods: Targeted next-generation sequencing (NGS) data at our institution from 7/13-1/16 was reviewed to identify KRAS+ NSCLC tumors. All patients with a <10 pack-year (py) smoking history (NS) and a subset of heavy smokers (HS) (>40 py) were identified, with clinical and genomic analysis. A comparison cohort of 48 patients with EGFR+ NSCLC was also identified. Fisher’s exact test was used to compare frequency of gene mutations.
Results: 41 NS and 104 HS KRAS patients were evaluated. NS patients were more likely to be female (34/41 v 66/104, p<.01) and diagnosed with Stage I disease (14/41 v 13/104, p<.01). Compared to KRAS NS patients, tumors from KRAS HS patients were also genomically more complex, with increased total nucleotide variants (median=10 v 7, p<.001) and total copy number variations (median=22.5 v 5, p<.01). Intriguingly, in the cohort of EGFR tumors, total nucleotide variants resembled the KRAS NS cohort (median=6.5) but the total copy number variants were more similar to the KRAS HS cohort (median=25). Compared to KRAS NS tumors, KRAS HS tumors were also more likely to have: a) concurrent mutation in TP53 (43/104 v 8/41, p=.012) and b) concurrent mutations/2-copy deletions in >1 tumor suppressor (TS)/tumor (panel of TP53, STK11, APC, CDKN2A/B, RB) (26/104 v 4/41, p=.042). Although the total number of nucleotide variants in the EGFR cohort was most similar to the KRAS NS cohort, TS distribution in these EGFR tumors was closer to the KRAS HS cohort (TP53 variants in 31/48 and multiple TS variants in 14/48). Finally, median OS for KRAS HS patients with Stage IV disease was 9.7m v 28.7m in KRAS NS patients (HR=0.56).
Conclusions: The genomic landscape of KRAS+ NSCLC from HS patients is distinct from NS patients and includes increased total mutations and frequency of TS loss. EGFR mutant tumors share some similarities with KRAS tumors from both NS and HS patients. Overall, NS KRAS+ tumors may be a genetically distinct cohort within the broader context of KRAS+ NSCLC.