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D. Gale
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.12 - Circulating Tumor DNA for Noninvasive Monitoring of Non-Small Cell Lung Cancer Patients Receiving EGFR-Targeted Therapies (ID 372)
16:45 - 18:15 | Author(s): D. Gale
- Abstract
Background:
Analysis of circulating tumor DNA (ctDNA) in plasma offers an opportunity to noninvasively monitor tumor burden and identify alternative drivers of disease progression in real-time. However, cancer progression during targeted therapy, such as EGFR-targeted therapies in non-small cell lung cancer (NSCLC), is driven by clonal evolution, and how this impacts the levels of targeted mutations in circulating tumor DNA (ctDNA) for monitoring disease burden is unclear.
Methods:
We collected serial plasma samples from 47 NSCLC patients receiving EGFR-targeted therapy (gefitinib) and hydroxychloroquine, and analysed mutations in EGFR, TP53, PTEN and PIK3CA in plasma by digital PCR and tagged-amplicon deep sequencing (TAm-Seq) of ctDNA.
Results:
We identified the same EGFR mutations in tumor and plasma samples in over 97% of patients, and found that patients with high pre-treatment levels of ctDNA are associated with worse progression-free survival and overall survival. Serial plasma analysis of 32 patients reveals clonal dynamics in ctDNA in response to treatment. In >72% of patients (23/32), EGFR mutations levels increased preceding clinical progression, with the resistant mutation T790M detected in around 50% of these patients (13/23) a median of 6 months before progression became clinically evident. In the remaining 9 of the 32 patients, EGFR-mutant ctDNA levels became uninformative during treatment, and in two patients we identified alternative driver mutations in ctDNA that correlated with progression. In one patient we also showed that the analysis of relative representations of resistant and sensitizing mutations may provide insight to the response to sequential treatment.
Conclusion:
Our results demonstrate the potential of ctDNA for noninvasive stratification and monitoring disease progression in NSCLC patients, and highlight that targeted therapy may drive the selection of alterative mutations. This may impact the representation of the targeted mutations in plasma for assessing disease burden. We therefore propose that effective ctDNA-based monitoring of targeted therapies in oncogene-addicted cancers requires tracking of multiple mutations beyond the targeted genes.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-093 - Assessment of Clinical Applications of Circulating Tumor DNA in Lung Cancer Using an Enhanced TAm-Seq Platform (ID 2270)
09:30 - 17:00 | Author(s): D. Gale
- Abstract
Background:
Novel biomarkers are required to assess tumor burden and response in lung cancer as conventional biopsies are invasive, costly and only provide a snapshot of the mutational profile at a given time and location. A promising biomarker is the detection of genomic material released from tumors into the blood plasma of patients, known as circulating tumor DNA (ctDNA). ctDNA has been detected in plasma for a wide range of solid tumors and can be distinguished from other (germline) cell-free DNA by the presence of tumor-specific DNA alterations or known hotspot mutations. However, the potential of ctDNA as a biomarker in lung cancer has not yet been fully realized due to technical challenges associated with its detection and analysis, including the short fragment sizes (140-170 bp), small number of amplifiable copies and low/variable allele fractions of ctDNA. To further develop applications of ctDNA in lung cancer, we have developed a process to analyse ctDNA and utilise it in a range of clinical studies.
Methods:
We have developed an enhanced platform for tagged-amplicon deep sequencing (TAm-Seq). Using a combination of improved library preparation and bespoke data analysis methods, this platform can be used to sequence established cancer hotspots and the entire coding regions of selected genes, while preserving high levels of specificity and sensitivity.
Results:
Using this approach, we have developed an assay that analyzes ~20 kb of the genome (including regions of interest in more than 30 genes) with sensitivity down to a few mutant copies. Performance of this assay has been demonstrated using spike-in experiments, dilution series and clinical sample cohorts from lung cancer patients.
Conclusion:
Our proof of concept studies show the potential of ctDNA to be used to assess tumor mutation status, monitor tumor dynamics, assess response to treatment and identify mutations associated with acquired drug resistance and disease progression. This non-invasive approach - a “liquid biopsy” - offers a revolution in how cancer can be detected, monitored and treated. Further studies in lung cancer are being developed and will be presented.
