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B. Nagy
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ORAL 38 - Liquid Biopsies (ID 147)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M.S. Tsao, J. Wang
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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ORAL38.02 - Biopsy-Free Circulating Tumor DNA Assay Identifies Actionable Mutations in Lung Cancer (ID 2163)
16:56 - 17:07 | Author(s): B. Nagy
- Abstract
- Presentation
Background:
The National Comprehensive Cancer Network (NCCN) non-small cell lung cancer guidelines recommend testing for seven genomic targets amenable to matched therapies, including point mutations and insertions/deletions (indels) in EGFR and ERBB2 (HER2), point mutations in BRAF, fusions in ALK, RET and ROS1, and amplification of the MET gene. Novel digital sequencing technology allows assessment of these biomarkers without an invasive tissue biopsy.
Methods:
We prospectively tested cell free DNA from 43 advanced non-small cell lung cancer patients using a cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS) panel of 54 cancer genes (Guardant360). Single nucleotide variants (SNVs) in 54 genes and copy number variants (CNVs) in 3 genes (EGFR, ERBB2 and MET) were reported quantitatively as the mutant allele fraction (MAF) in cell-free DNA and the absolute copy numbers in plasma, respectively.
Results:
79% of patients had at least one ctDNA alteration detected. Five (11.6%) had sensitizing mutations in EGFR: EGFR L858R (n=1), EGFR exon 19 deletions (n=4), which may respond to first line tyrosine kinase inhibitors (TKIs) such as erlotinib and afatinib. Three patients with EGFR exon 19 deletions had concurrent T790M resistance mutations, which develop in over half of patients on early generation TKIs. MET amplification, which may respond to crizotinib, was identified in one patient. Clinical outcomes will be reported at the time of presentation. Of the 43 patients in our series, actionable findings were identified in 35 patients (81.4%), with an approved therapy in 5 (11.4%), off label therapies in 19 (44.2%), and clinical trials in 28 (65.1%).
Conclusion:
In our series of NSCLC patients with advanced disease, digital sequencing of cell-free circulating tumor DNA yielded results in approximately 80% of patients. Of these, over 80% had an actionable alteration, including 5 cases with EGFR alterations that could benefit from an approved therapy. Biopsy-free comprehensive sequencing of a patient’s cancer can empower informed treatment decisions from a simple blood draw, especially when repeat tissue biopsy is not feasible or tissue NGS is uninformative.
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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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P3.04-016 - EML4-ALK Fusion in a NSCLC Patient Detected by High Sensitivity Circulating Tumor DNA Assay Empowers Targeted Therapy Decisions (ID 2259)
09:30 - 09:30 | Author(s): B. Nagy
- Abstract
Background:
The National Comprehensive Cancer Network (NCCN) non-small cell lung cancer (NSCLC) guidelines recommend genomic testing of seven genes in order to determine appropriate targeted therapy, including fusions in the anaplastic lymphoma kinase (ALK) gene which may be highly responsive to matched therapies. Tissue-based approaches to determine the tumor’s genetic status are often hampered by patient intolerance to repeat biopsy or insufficient tissue. Novel digital sequencing technology of plasma cell free circulating tumor DNA (ctDNA) allows assessment of these biomarkers without an invasive tissue biopsy.
Methods:
A 58 year-old woman was diagnosed with metastatic lung adenocarcinoma with bone predominant metastatic disease in February 2013. Despite histologic confirmation of adenocarcinoma, tissue was insufficient for genotyping despite multiple attempts at biopsy. She was treated empirically with carboplatin/pemetrexed with initial response, suffered from symptomatic progression in bone and underwent cell free circulating tumor DNA testing. Assessment of ctDNA levels using a comprehensive 68-gene digital sequencing[TM ]panel (Guardant360) with high sensitivity (detection of single nucleotid variants, focal gene amplifications in 16 genes, EGFR indels and fusions in ALK, ROS1, RET and NTRK1) in 87%+ of advanced cancer patients) and ultra-high specificity (>99.9999%) was performed on a blood sample from the patient.
Results:
Analysis of the patient’s ctDNA revealed an EML4-ALK fusion at 0.06% mutant allele fraction, which is equivalent to a single mutant molecule in a 10 mL tube of blood. This result was repeated in a second tube of blood, and two DNA fragments with the EML4-ALK fusion breakpoint were found. The patient also had a single nucleotide variant (R386G) in the AR gene at 0.25% and JAK2 V617F variant at 0.93% concentration. Crizotinib therapy was initiated on the basis of the EML4-ALK fusion and clinical improvement has already been noted. Repeat ctDNA measurements are planned and will be correlated with clinical response parameters based on RECIST criteria and protein-based tumor marker levels. This information will be reported at the time of presentation.
Conclusion:
To our knowledge, this is the first case report of EML4-ALK fusion identified in the clinical setting via biopsy-free circulating tumor DNA analysis. With single molecule sensitivity, this simple blood test was able to identify a therapeutic option in a patient who was unable to undergo tissue-based NGS.
