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R.B. Lanman
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-035 - Circulating Cell-Free Tumor DNA (cfDNA) Testing in Small Cell Lung Cancer (ID 6193)
14:30 - 14:30 | Author(s): R.B. Lanman
- Abstract
Background:
The diagnosis of small cell lung cancer (SCLC) is often made using fine needle aspiration or small biopsy of tumor specimens that are typically insufficient for next generation sequencing (NGS) analysis. Guardant360 (G360), a blood-based liquid biopsy that analyzes circulating free tumor DNA, may allow the detection of potentially targetable gene abnormalities without the need for repeated tissue biopsies.
Methods:
Peripheral blood samples from patients with SCLC were collected in two 10 mL tubes. Cell-free DNA was extracted and analyzed by digital sequencing for the detection of single nucleotide variants (SNVs), small Insertions and Deletions (INDELs), Copy Number Alterations (CNAs), and gene fusions. The Tumor Alterations Relevant for Genomics-Driven Therapy (TARGET) curated database (http://www.broadinstitute.org/cancer/cga/target) was queried for potentially actionable alterations.
Results:
240 samples from 227 de-identified patients were collected between June 2014 and June 2016. 7 patients had more than one sample analyzed. During this time period, the number of genes in the panel increased from 54 (10 samples) to 68 (87 samples) and finally to 70 (143 samples). The median time from sample collection to reporting was 13 days (range 8-28 days). Alterations in at least one gene were found in 222 (92.5%) of samples and 210 (92.5%) patients. SNVs in TP53 and RB1 were seen in 72.4% (152/210) and 25.7% (35/136) of patients with detectable alterations respectively. The most common potentially actionable alterations were amplifications of FGFR1 (11.8%) and ERBB2 (7.1%). MYC amplification, which was not considered an actionable alteration by TARGET but has been associated with sensitivity to Aurora kinase inhibitors in pre-clinical studies, was observed in 15.8% of patients. Eight patients had EGFR activating mutations (exon 21 L858R mutation or exon 19 deletion), of which 2 patients also had EGFR T790M mutation, likely representing transformation from NSCLC following targeted therapy with EGFR Tyrosine kinase inhibitors. KIF5B-ALK and AFAP1-RET fusions were seen in 1 patient each.
Conclusion:
G360 is a rapid non-invasive NGS platform which may be particularly useful in patients with advanced stage SCLC where tissue samples may be suboptimal for NGS. Due to the limited treatment options in this patient population, the detection of potentially actionable genes through G360 may provide valuable information to guide treatment decisions.
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P3.02b - Poster Session with Presenters Present (ID 494)
- 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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P3.02b-103 - Identification of On-Target Mechanisms of Resistance to EGFR Inhibitors Using ctDNA Next-Generation Sequencing (ID 5645)
14:30 - 14:30 | Author(s): R.B. Lanman
- Abstract
Background:
Osimertinib (OSM) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for use in EGFR T790M-positive non-small cell lung cancer (NSCLC) with a 65-70% response rate. However, patients invariably develop resistance to OSM, in ~30% of cases due to an acquired EGFR C797S mutation. Understanding additional, non-C797S resistance mechanisms will be critical to developing new therapeutic approaches. Here, we describe a case of T790M-positive NSCLC with progression on OSM, genotyped using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS).
Methods:
A 68-year-old male with EGFR L858R-mutant metastatic NSCLC whose disease progressed despite multiple lines of EGFR inhibitors (erlotinib, afatinib, cetuximab/afatinib) and chemotherapy was found to be T790M-positive, and initiated on OSM. Initial restaging scans demonstrated response. On disease progression 7 months later, ctDNA testing was performed with a highly sensitive and ultra-specific 70-gene NGS panel (Guardant360™) that includes all EGFR exons and reports on all EGFR single nucleotide variants, indels, and amplification.
Results:
Twelve somatic alterations were identified, including 7 mutations in EGFR. The original L858R driver mutation was present at a mutant allele fraction (MAF) of 16.9%, and T790M at MAF of 8.4%. C797S was detected at MAF of 4.6%. Four additional subclonal TK domain mutations were identified: L792H (1.4%), L718Q (0.7%), F795C (0.4%) and L792F (0.1%). Mutations within sufficient genomic proximity were phased to determine allelic origin, and a presumptive evolutionary history was constructed. T790M and C797S were in cis, and the F795C mutation arose on that allele. L792H and L792F were in cis to T790M, but arose independently from each other and from C797S. Review of the Guardant Health database, which includes 5,609 NSCLC samples, identified 1,228 samples with EGFR activating mutations L858R and exon 19 deletion. Of these, 341 (28%) had T790M, of which 17 (5%) carried C797S. Sixteen of 17 C797S mutations were in cis with T790M, and 1 in trans. There were 3 additional cases with L718 mutation and 1 with L792.
Conclusion:
Deep sequencing of ctDNA can reveal the global landscape and evolution of resistance mutations within a patient’s tumor. The T790M and C797S mutations were predominantly in cis configuration, underscoring the importance of developing new EGFR TKIs. The role of mutations L792H, L792F, and F795C is currently unknown. These mutations impinge on the ATP-binding pocket, which could be a potential structural resistance mechanism. Further studies are needed to validate and functionally characterize these candidate resistance mutations.
