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C. Lydon
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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
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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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 - 14:30 | Author(s): C. Lydon
- Abstract
Background:
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:
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:
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).
Conclusion:
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.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-006 - Immune Recognition of ALK Fusion Proteins in Patients with ALK-Rearranged Non-Small Cell Lung Cancer (ID 6091)
14:30 - 14:30 | Author(s): C. Lydon
- Abstract
Background:
Although several tyrosine kinase inhibitors have potent antitumor activity against ALK-rearranged non-small cell lung cancers (NSCLC), resistance to these small molecules emerges through a number of mechanisms. Preclinical evidence suggests that ALK-positive NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. Immunologic responses against the ALK protein have been reported in ALK-positive anaplastic large cell lymphoma, and we sought to determine whether ALK could be recognized by the immune systems of patients with ALK-positive NSCLC.
Methods:
Serum was collected from 32 ALK-positive and 29 ALK-negative NSCLC patients over the course of routine clinical care who had consented to an institutional review board approved translational research protocol. We developed a novel enzyme-linked immunosorbent assay (ELISA) to detect autoantibodies against the ALK cytoplasmic domain in patients with ALK-rearranged NSCLC, and the specificity of these autoantibodies was validated using Western blot analysis. Short peptides spanning the length of the ALK cytoplasmic domain were synthesized to more narrowly define the precise immunogenic peptide sequences.
Results:
Among 32 ALK-positive NSCLC patients, very high ALK autoantibody titers were detected in the serum of 3 patients (9%), and ALK autoantibodies were not detected in any of the 29 patients with ALK-negative NSCLC. These autoantibodies specifically recognized only the ALK cytoplasmic domain and not the ALK extracellular domain. Epitope mapping demonstrated that the autoantibodies from each of the 3 patients with high autoantibody titers recognized distinct ALK peptide sequnces within the ALK cytoplasmic domain.
Conclusion:
ALK is capable of being recognized by the immune systems in some patients with ALK-positive NSCLC. Further investigation is needed to determine whether the presence of anti-ALK antibodies impacts prognosis in NSCLC. The naturally immunogenic properties of ALK in NSCLC may be able to be exploited using therapeutic ALK vaccines in patients.
