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A.A. Talasaz
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.04 - Dynamic Changes in Cell-Free Circulating Tumor DNA to Track Tumor Response and Risk of Recurrence in Stage III Non-Small Cell Lung Cancer (ID 2499)
16:45 - 18:15 | Author(s): A.A. Talasaz
- Abstract
- Presentation
Background:
While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.
Methods:
Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.
Results:
Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.
Conclusion:
In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-038 - Comparing Next-Generation Sequencing (NGS) Platforms in Patients with Thoracic Tumors: Tumor Tissue vs. Circulating Cell-Free DNA from Blood (ID 1732)
09:30 - 17:00 | Author(s): A.A. Talasaz
- Abstract
Background:
Next-generation sequencing (NGS) from tumor tissue is used to acquire comprehensive genomic information to aid clinical decision-making for cancer patients. In order to obtain sufficient tissue for tumor-based NGS, patients must often undergo repeat biopsies after diagnosis which are invasive, associated with risk and expense, and sometimes unsuccessful because of tumor size or location. Genomic information may also be obtained by analyzing cell-free DNA (cfDNA) from plasma samples, which affords the potential for NGS testing to a greater number of patients, and offers a wide variety of cancer diagnostic and surveillance applications. We sought to compare the results of tumor based-NGS with an analysis of circulating tumor cfDNA from matched plasma samples in patients with thoracic tumors (non-small cell lung cancer, small cell lung cancer and thymic malignancies) to determine concordance between the tests.
Methods:
We compared NGS results obtained from tumor tissue analyzed by Foundation One with plasma-based analysis of cfDNA using Guardant360, a 54-gene panel covering 80,000 base pairs with high sensitivity (75-85% in most solid tumors) and ultra-high specificity (>99.9999%). Guardant360 detects single nucleotide variants (SNVs), including synonymous alterations, variants of uncertain significance, and somatic point mutations, gene amplifications (CNVs), select insertions/deletions (indels) and genomic rearrangements. Because Foundation One is a 316-gene panel, concordance was defined based on the genes covered by both panels. Only patients with cancers originating in the chest were included.
Results:
Of 56 patients with Guardant360 testing performed between 6/2014 and 2/2015, 100% were successfully assayed. Eleven had matched NGS from tumor and concordance was noted in 5/11 (45%) of patients. TP53 and KRAS were commonly found in both tumor tissue and plasma cfDNA. A total of 34 patients (61%) with successful plasma-based cfDNA analysis were unable to undergo tissue-based NGS for various reasons; fourteen patients had tumor tissue sent for NGS analysis that was deemed “insufficient”, 16 had exhausted prior tumor biopsy specimen, and 4 patients were too ill to undergo a repeat biopsy. In 19 of these 34 cases where tissue NGS results were not available (56%), a genomic alternation was identified by plasma cfDNA analysis, which corresponded to targeted therapies available on clinical trials that otherwise would not have been known.
Conclusion:
Plasma-based NGS testing identified actionable genomic alternations in 23 of 56 (41%) patients tested. In most cases, this information was supplementary to that obtained from tumor-based NGS and partially concordant in matched cases. These findings support continued efforts to establish the value of cfDNA in those cases where repeat tissue biopsy is contraindicated or may pose undesirable risk of complications, or when tissue-biopsy based NGS is inadequate or 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 - 17:00 | Author(s): A.A. Talasaz
- 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.
