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L.C. Heukamp
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ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:A. Katz, M.S. Tsao
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL21.03 - KEAP1-Mutations and NFE2L2-Mutations in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 2792)
11:07 - 11:18 | Author(s): L.C. Heukamp
- Abstract
- Presentation
Background:
Mutations in genes of the KEAP1-NFE2L2 pathway in patients with NSCLC are associated with an increased tumor growth, resistance towards cytostatic drugs and reduced survival rates. KEAP1 suppresses NFE2L2 under physiological conditions. Oxidative stress or electrophiles cause NFE2L2 to stabilize and translocate to the nucleus, resulting in transcription of various cytoprotective genes. Mutations in KEAP1 and NFE2L2 are described for diverse tumor entities and often cause an increased level of NFE2L2 leading to resistance of cancer cells against anti-cancer drugs and irradiation. This study was performed to characterize KEAP1-mutated and NFE2L2-mutated NSCLC clinically and genetically.
Methods:
Tumor tissue collected from 446 patients within a regional screening network was analysed for KEAP1 mutations and NFE2L2 mutations using next-generation sequencing (NGS). Clinical, pathological and genetic characteristics of these patients are described and compared with a control group of patients without KEAP1 mutation and without NFE2L2 mutation.
Results:
So far, we identified 33 patients with KEAP1 mutations. Among these we found 34 different mutations, of which the majority was not previously described. KEAP1 mutations were not restricted to a special exon. In 30 patients (90.9%), additional driver aberrations in KRAS, EGFR, FGFR1, FGFR3, STK11, ALK, DDR2, HRAS, BRAF, PIK3CA, PTEN, NFE2L2, EP300, TSC1, CREBBP, NRAS, MET and Her2 could be detected, as well as mutations and polymorphisms in TP53. KEAP1 mutations occurred in both genders (male/female ratio 3/1), in squamous-cell carcinoma (36.4%) and adenocarcinoma (60.6%) and were significantly associated with smoking. We also identified 26 patients with NFE2L2 mutations. Among these we found 15 different mutations, of which W24R and E79K were the most common. In 20 patients (76.9%) additional driver aberrations were detected. NFE2L2 mutations occurred in squamous-cell carcinoma (69.2%) and adenocarcinoma (23.1%) and were significantly associated with smoking as well. NFE2L2 mutations also occurred in both genders with 61.5% male and 38.5% female. Two patients had both a KEAP1 mutation and a NFE2L2 mutation.
Conclusion:
Our data suggest a role of KEAP1-mutations and NFE2L2-mutations as a cofactor in addition to classical driver mutations underlying the malignant phenotype of lung cancer cells. So far, this is the largest cohort of patients with KEAP1-mutations and NFE2L2-mutations analysed and described. Further survival and treatment analyses will reveal the role of these mutations for the outcome of these patients.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-005 - Discrepancies between ALK FISH and Capture Based NGS Test NEOplus and Clinical Outcome with ALK TKI Therapy (ID 2748)
09:30 - 09:30 | Author(s): L.C. Heukamp
- Abstract
Background:
Research in recent years has unraveled several gene fusions driving tumor development in lung cancer. Especially adenocarcinomas of the lung harboring ALK and ROS1 gene fusions exhibit striking sensitivity to ALK and ROS1 kinase inhibitors respectively, translating to dramatic responses in the clinic. Several different technologies are available to detect aberrant genomic structures. The most frequently used technologies include fluorescent in situ hybridization (FISH), currently considered as the “gold standard”, immunohistochemistry (IHC), RT-PCR based approaches and hybrid capture based NGS sequencing.
Methods:
Here, we describe a selection of tumor samples showing discrepant results between fluorescent in situ hybridization and hybrid capture based NGS sequencing. These included samples with positive FISH but negative NEOplus as well as negative FISH and positive NEOplus results. In addition, we used response data of targeted therapies to evaluate the true genetic phenotype of the tumor.
Results:
Overall, several lung adenocarcinomas showed discrepant results when FISH and NEOplus data were compared. First, one sample was tested positive for ALK rearrangement using FISH which was not confirmed using NEOplus. In line with this finding, the tumor did not respond to ALK TKI treatment. Second, a total of 4 cases were fusion negative by FISH but positive by NEOplus. Three out of 4 ALK positive cases showed clinical response to ALK kinase inhibition, the clinical results for case number 4 are pending. Interestingly, one of these responding tumors was also negative for ALK expression using IHC.
Conclusion:
In summary, we describe a selection of tumor samples with discrepant results for fusion detecting using FISH and NEOplus. Overall, in all of the cases for which clinical response data was available, tumor sensitivity was in line with the initial diagnosis generated by the NEOplus assay.
