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E. Pazarentzos
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MINI 10 - ALK and EGFR (ID 105)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T. Yap, T. Li
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI10.03 - Evolution of Concurrent Driver Mutations in Lung Adenocarcinoma Patients on EGFR TKI Therapy Uncovered by Comprehensive Molecular Profiling (ID 2848)
16:55 - 17:00 | Author(s): E. Pazarentzos
- Abstract
Background:
Lung adenocarcinoma (LAC) patients (p) with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, NF-kB, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. We hypothesized that tumor cell populations present pre-treatment harbor mechanisms of EGFR TKI resistance that are subsequently selected for by EGFR TKI therapy.
Methods:
We performed longitudinal comprehensive molecular tumor profiling on 10 p with metastatic EGFR-mutant LAC throughout the course of their disease. Exome sequencing to a mean depth of coverage of 100 X, was performed on FFPE or frozen patient tumor specimens as well as matched normal control specimens collected from patients prior to initiating standard erlotinib (erl) treatment, upon the development of erl resistance, and upon resistance to subsequent 2[nd] line therapy when available. One case of a patient with acquired resistance to the 3[rd] generation EGFR TKI Rociletinib was analyzed. We performed functional analysis of select mutations identified using established cellular models of EGFR-mutant LAC.
Results:
We constructed phylogenetic trees based on somatic mutations and copy number alterations identified by exome sequencing of longitudinally acquired patient specimens. Activating mutations (L858R or exon 19 deletion) were present in all tumor specimens analyzed, indicating that this is a ‘truncal’ event. We identified on-target mutation in EGFR (T790M) in ~ 50% of erl resistant specimens as expected. However, in three patients we identified concurrent low frequency oncogenic driver events pre-EGFR TKI treatment that subsequently increased in frequency upon erlotinib resistance. This included: 1) a BRAF V600E mutation that was detected pre-treatment at a low frequency that expanded in the erlotinib resistant tumor specimen; 2) a PIK3CA G106V mutation that was not present in a patient’s primary tumor, but developed in a lymph node metastasis at a low frequency and subsequently expanded in the erlotinib resistant tumor, and 3) a pre-treatment KRAS amplification that was found in a patient with de novo resistance to erlotinib. The functional significance of these mutations in driving tumor growth and EGFR TKI resistance will be discussed. We will also present exome sequencing analysis from multiple tumors (including a CNS and spinal metastasis) collected from the autopsy of a patient with initial response, but rapid development of acquired resistance to Rociletinib.
Conclusion:
These results indicate that EGFR-mutant LAC can harbor additional oncogenic driver mutations at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of these subclonal populations likely contributing to EGFR TKI resistance in patients with or without the EGFR T790M resistance mutation. These data demonstrate the utility of comprehensive molecular profiling of LAC p on targeted therapy beyond assessing EGFR T790M mutational status, and suggest that pre-treatment tumor analyses can in some cases predict mechanisms of EGFR TKI resistance before they become clinically significant.
