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E. Kay
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.10 - Co-Occurrence of Driver Mutations of MAPK and PI3K Pathways in Non Small Cell Lung Cancer: A Report from Lung Cancer Genomics Ireland (LCGI) Study (ID 2627)
17:45 - 17:50 | Author(s): E. Kay
- Abstract
- Presentation
Background:
The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are frequently altered in human cancers. Targeting these pathways is an attractive therapeutic strategy in malignant disease. The frequency of single and dual pathway alterations varies substantially across various cancers. Co-occurrence of the MAPK and PI3K pathway aberrations is reported in 5-7% of melanomas, gastric and colorectal cancers, and is associated with a worse clinical outcome. In this report we aim to determine the co-occurrence of the MAPK and PI3K pathway mutations in a large cohort of surgically resected NSCLC tumors.
Methods:
We used the platform of Sequenom’s MassArray to perform genotyping for 548 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways in surgically resected NSCLC tumors. MAPK pathway genes that were screened include: KRAS, HRAS, BRAF, RAF1, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP2K1, MAP2K2, MAP2K3, and PTPN11. PI3K pathway genes that were screened include: PIK3CA, PIK3R1, PIK3R2, PTEN, PDPK1, AKT1, AKT2, and MTOR. Fisher’s exact test was used to determine the statistical significance of association between the MAPK and PI3K pathway mutations. The strength of association was determined in the form of odds ratio.
Results:
NSCLC tumors from 356 patients (258 squamous cell, 98 adenocarcinomas) were tested using Sequenom’s MassArray. The frequency of mutations in the MAPK and PI3K pathways was 22.5% (n=80) and 22.8% (n=81) respectively. Among these patients, 38 patients had mutations in both pathways (i.e: 47.5% of patients with a MAPK pathway mutation also had a mutation in the PI3K pathway, and 46.9% of patients with a PI3K pathway mutation also had a mutation in the MAPK pathway, see table 1). Fisher’s exact test revealed that mutations in the MAPK and the PI3K pathways are mutually inclusive (p<0.0001, odds ratio=4.95, 95% CI 2.9-8.5) Table 1: The co-occurrence of MAPK and PI3K pathway mutations in NSCLCPathway/no of patients PI3K WT PI3K MT MAPK WT 235 43 MAPK MT 42 38
Conclusion:
38 (10.7%) of 356 NSCLC patients included in the LCGI study had hotspot somatic mutations in both the MAPK and PI3K pathways. Contrary to previous reports, we observed that activating mutations of the MAPK and PI3K pathways are mutually inclusive in NSCLC. These findings may have implications in designing clinical trials of targeted therapies in lung cancer.
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.08 - Targetable Genomic Aberrations in Squamous Cell Lung Cancer (SCC): A Report from the Lung Cancer Genomics Ireland (LCGI) Study (ID 766)
11:25 - 11:30 | Author(s): E. Kay
- Abstract
- Presentation
Background:
The prognosis of lung SCC continues to be poor with no molecularly targeted agents specifically developed for its treatment. LCGI aims to identify potential targetable oncogenes in lung SCC.
Methods:
The LCGI study is being carried out in 500 patients with surgically resected lung SCC, treated at St James’s University Hospital and Beaumont University Hospital, Dublin. We used the platform of Sequenom’s MassArray to perform genotyping for accustomed panel of 258 somatic hotspot mutations in 49 genes including genes in the MAPK and PI3K pathways. We also evaluated FGFR1 amplification by fluorescence in situ hybridization (FISH) and MET protein expression by immunohistochemistry (IHC).
Results:
Lung SCCs from 258 patients have been tested by Sequenom MassArray to date. Lung SCCs from 150 patients have been evaluated for MET protein expression and 89 for FGFR1 amplification. 163 (63.2%) patients were male. The median age of the cohort was 68. The majority of patients were either current (39.5%) or former (58.1%) smokers at the time of diagnosis. 138 (53.5%) were stage I, 87 (33.7%) were stage II, and 33 (12.8%) were stage III SCCs. At least one aberrant, potentially targetable oncogene was identified in the SCC of 101 (39.1%) patients (see Table). The presence of PIK3CA or KRAS mutations, or FGFR1 amplification did not have a statistically significant impact on median overall survival or recurrence-free survival. However, the presence of two or more aberrations in driver oncogenes in a tumor (patients, n=19) was associated with a worse median overall survival compared to patients with either a single driver aberration (p=0.04) or no aberrations (p<.01). Table: Frequency of driver mutations in LCGI compared to The Cancer Genome Atlas (TCGA) studyMutation LCGI (n=258) TCGA (n=178) FGFR1 amp (n=89) 13 % 16.8 % PIK3CA 15.1 % 10.1 % KRAS 6.5 % 0.6 % PTPN11 3.5 % 1.7 % STK11 3.1 % 1.7 % MYC 1.9 % 0.0 % NRAS 1.6 % 0.0 % BRAF 1.2 % 3.9 % HRAS 1.6 % 1.7 % CTNNB1 1.5 % 1.7 % FBXW7 1.5 % 3.4 % MET Overexpression (n=150) 1.3 % NA EGFR 0.9 % 2.8 % AKT1 0.4 % 0.6 % CDK4 0.4 % 0.0 % GNA11 0.4 % 0.6 % MAP2K1 0.4 % 0.6 % DDR2 0 % 1.1 %
Conclusion:
39.1% of lung SCC patients have an aberrant, potentially targetable driver oncogene in their tumor. The presence of two or more aberrant oncogenes is a poor prognostic factor in lung SCC. These findings can be used to guide clinical trials in lung SCC.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
