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Adrian G. Sacher
Moderator of
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 8
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.01 - Detection of EGFR mutations from plasma ctDNA in the osimertinib Phase III trial (AURA3): comparison of three plasma assays (ID 8984)
11:00 - 12:30 | Presenting Author(s): Myung-Ju Ahn | Author(s): Ji-Youn Han, C. Tsai, A. Delmonte, T. Hsia, J. Laskin, S. Kim, Y. He, T. Hida, M. Maemondo, T. Kato, S. Jenkins, A. Markovets, K.S. Thress, T. Mok
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.
Method:
Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).
Result:
Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.
Conclusion:
Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.
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OA 10.02 - Unique Genetic Profiles from Circulating Cell-Free DNA of Cerebrospinal Fluid in Leptomeningeal Metastases of EGFR Mutant NSCLC (ID 8258)
11:00 - 12:30 | Presenting Author(s): Benyuan Jiang | Author(s): Y. Li, Jin -Ji Yang, X. Yang, Qing Zhou, W. Zhong, X. Zhang, Yi-Long Wu
- Abstract
- Presentation
Background:
Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.
Method:
Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available
Result:
Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.
Conclusion:
CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.
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OA 10.03 - Liquid Biopsy in the Lung Cancer Clinic: A Prospective Study of Plasma DNA next Generation Sequencing to Guide Matched Therapy (ID 8218)
11:00 - 12:30 | Presenting Author(s): Joshua K Sabari | Author(s): D. Stephens, A. Ni, A. Lee, Nick Pavlakis, S. Clarke, C.I. Diakos, M. Offin, S. Datta, N. Tandon, M. Duboff, J. Simpronio, A. Martinez, J. Isbell, Valerie W Rusch, D. Jones, Andreas Rimner, S. Henderson, C. Raymond, L. Lim, M. Li, Gregory J Riely, Charles M Rudin, Bob T. Li
- Abstract
- Presentation
Background:
Liquid biopsy for plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) is now commercially available and increasingly adopted in clinical practice with a paucity of evidence based guidance. We set out to prospectively determine the utility of plasma ctDNA NGS in the lung cancer clinic.
Method:
Patients (pts) with advanced NSCLC who were driver unknown or resistance mechanism unknown were eligible. Pts were enrolled prospectively at Memorial Sloan Kettering (NY, USA) and Northern Cancer Institute (Sydney, Australia). Peripheral blood was collected in Streck tubes (10-20mL) and sent to Resolution Bioscience (Bellevue, WA) for targeted NGS of extracted DNA using a bias corrected hybrid capture 21 gene assay in a CLIA laboratory with unique reads at 3000x and sensitive detection at variant allele frequency above 0.1%. Clinical endpoints included detection of oncogenic drivers, turnaround time, comparison to tissue NGS when available, and ability to match pts to targeted therapy along with their treatment outcomes.
Result:
Seventy-six pts were prospectively accrued. Plasma NGS detected an oncogenic driver in 36% (27/76) of pts, of whom 14% (11/76) were matched to targeted therapy; including pts matched to clinical trials for HER2 exon 20 insYVMA, BRAF L597Q and MET exon14. Of the 10 evaluable pts, 10 partial responses were observed. Mean turnaround time for plasma was 6 days (3-12) vs 21 days (16-30) for tissue (P <0.0001). Plasma ctDNA was detected in 60% (46/76) of pts; detection rate was 46% (16/35) if blood was drawn on active therapy and 73% (30/41) if drawn off therapy, either at diagnosis or progression (Odds ratio 0.31, 95% CI 0.12 – 0.81; P=0.02). Of the 25 concurrent tissue NGS performed to date, there was a 96% plasma concordance with tissue and a 60% tissue concordance with plasma for driver mutations.
Conclusion:
In pts who were driver or resistance mechanism unknown, plasma NGS identified a variety of oncogenic drivers with significantly shorter turnaround time compared to tissue NGS, and matched patients onto targeted therapy with clinical benefit. Plasma ctDNA is best detected at diagnosis of metastatic disease or at progression. A positive finding of an oncogenic driver in plasma is highly specific and can immediately guide treatment, but a negative finding may still require tissue biopsy. Our findings provide evidence to support the incorporation of plasma NGS into practice guidelines.
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OA 10.04 - Discussant - OA 10.01, OA 10.02, OA 10.03 (ID 10806)
11:00 - 12:30 | Presenting Author(s): R. Hui
- Abstract
- Presentation
Abstract not provided
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OA 10.05 - Non-Invasive Molecular Profiling in NSCLC by Targeted and Whole Exome Analysis of Plasma cfDNA (ID 10422)
11:00 - 12:30 | Presenting Author(s): Dana W.Y. Tsui | Author(s): M.L. Cheng, J.L. Yang, M. Shady, P. Ulz, E. Heitzer, N.D. Socci, V. Seshan, M. Offin, D. Stephens, A. Makhnin, N. Tandon, S. Datta, D.S. Selcuklu, K. Huberman, K. Vanness, E. Gedvilaite, A. Viale, Maria E Arcila, Marc Ladanyi, J.E. Chaft, Charles M Rudin, M.F. Berger, D.B. Solit, Bob T. Li
- Abstract
- Presentation
Background:
Molecular characterization of tumor can guide the choice of therapy for NSCLC patients. However, tumors are complicated by spatial heterogeneity and sometimes may not be of sufficient quality and quantity for analysis. NGS using plasma cell-free DNA (cfDNA) input may capture temporal and spatial heterogeneity, and enable genomic profiling in patients without adequate available tumor tissue. Targeted gene panels allow for robust detection of known oncogenic drivers, but may not be comprehensive enough to screen for novel biomarkers or mechanisms of acquired resistance. Whole exome sequencing (WES) allows for hypothesis-free biomarker discovery, but may be technically challenging in the setting of limited tumor-derived DNA content in plasma cfDNA. In this study, we aim to develop a workflow to guide the selection of samples for targeted and whole exome sequencing for noninvasive molecular profiling.
Method:
Plasma samples were collected from 20 NSCLC patients receiving a variety of treatment (chemotherapy, targeted therapy, or immunotherapy). Most patients (>70%) had stage III or IV disease at the time of plasma collection. CfDNA was extracted from 3 mL of plasma, and analyzed using low-pass shallow whole genome sequencing (sWGS) and MSK-IMPACT, a hybridization capture-based assay targeting over 400 cancer-related genes. Analysis of matched normal was performed for somatic variant calling.
Result:
Median cfDNA yield per plasma sample was 28ng (range 7 - 236ng). We applied z-score statistics to estimate the levels of tumor-derived mutant allele fractions in cfDNA based on sWGS data. We trained the algorithm using a separate cohort of cfDNA data from >100 patients with metastatic solid tumors to classify samples by mutant allele fraction (MAF) as either low (<5% MAF) or high (>5% MAF) tumor-derived DNA. In the subset of 10 patients with unknown drivers, two were estimated to have MAF >5% in cfDNA, and WES recapture was performed. MSK-IMPACT targeted sequencing identified actionable alterations in a subset of patients who did not have sufficient materials for tissue profiling. WES in cases with high tumor-derived DNA content by sWGS identified alterations in genes outside of the MSK-IMPACT panel.
Conclusion:
Molecular profiling using cfDNA is feasible in lung cancer and may identify actionable alterations to inform treatment decisions in patients without sufficient tissue for molecular characterization. The application of sWGS to estimate the levels of tumor-derived mutant allele fractions in plasma cfDNA samples may help guide selection of the optimal downstream sequencing strategy.
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OA 10.06 - Longitudinal Mutation Monitoring in Plasma by Deep Sequencing as a Potential Predictor of Disease Progression in NSCLC (ID 9595)
11:00 - 12:30 | Presenting Author(s): John Jiang | Author(s): H. Adams, M. Lange, S. Siemann, M. Feldkamp, S. Schulze, S. Froehler, S. Yaung, L. Yao, A. Balasubramanyam, N. Tikoo, H..J. Achenbach, R. Krügel, J.F. Palma, André Rosenthal
- Abstract
- Presentation
Background:
Circulating tumor DNA (ctDNA) sequencing and analysis has the potential to transform clinical management of patients with advanced NSCLC. Non-invasive sampling of blood draws at different time points during treatment could potentially be used for routine monitoring of disease progression and detection of therapy resistant mutations by using next generation sequencing (NGS).
Method:
448 longitudinal plasma samples (mean 6.3 per subject) collected from 71 subjects with advanced NSCLC during 1[st] line treatment were analyzed by NGS. Of these 71 subjects, 47 also had matched baseline tumor tissue samples. The AVENIO ctDNA Surveillance kit and AVENIO FFPET Analysis kit (RUO, Roche, Pleasanton, CA, USA) were used for sequencing analysis. The Surveillance kit contains 17 cancer driver genes and additional 180 frequently mutated genes mainly selected for NSCLC and colorectal cancer. This kit is capable of detecting four mutation classes: SNVs, fusions, CNVs and InDels. CT images were reviewed centrally using RECIST v1.1.
Result:
Somatic, disease-associated mutations were detected with allele frequency (AF) of >5% in 94% of baseline tumor samples (44/47), and in 100% of plasma samples with AF in ctDNA ranging from ≥0.5% to ≤30%. The most commonly mutated genes in tumors were TP53 (22/47 subjects), KRAS (14/47), BRAF (7/47), STK11 (5/47), and ERBB2 (5/47). Tracking the AF’s of key tumor mutations by the Surveillance panel in the paired longitudinal plasma samples allowed the monitoring of treatment response at the molecular level. We identified a number of subjects in which the AF of cfDNA mutations increased three to four months before clinical evidence of progression of disease detected by CT scans that were centrally reviewed according to RECIST v1.1. Cases were also observed where the AF’s of key mutations decreased in 1[st] line chemotherapy to nearly zero which correlated with clinical partial response and stable disease. . Additionally, first post treatment plasma samples collected during first line treatment showed a difference of 96 days in median survival times of ctDNA- vs ctDNA+ groups (logrank p value =0.0371).
Conclusion:
ctDNA testing with molecular bar coded duplex sequencing and digital background error suppression of a large 197 gene panel offers high sensitivity for tumor variant detection. The study demonstrated that the presence of tumor variants detected in blood at the beginning and end of 1[st] line treatment is a risk factor for early disease progression. Longitudinal mutation monitoring has the potential to predict disease progression earlier than regular CT imaging.
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- Abstract
- Presentation
Background:
The detection of driver gene mutation based on tumor tissue can instruct target therapy and conduct molecular monitoring after drug-resistance in advanced NSCLC, but many patients have no access to this kind of test because of inadequate tumor tissue or inability to tolerate the invasive test. Some studies have explored the value of EGFR mutation test in body fluids such as plasma，urine and sputum from NSCLC patients. But the sensitivity based on individual liquid specimen is poor compared with gold standard---tissue. We detect multi-genes in multi-liquid samples in parallel to investigate the Consistency and complementarity of genetic profile in different liquid samples and it’s correlation with efficacy of the real world therapy in advanced NSCLC.
Method:
The patients newly diagnosed with NSCLC and first-generation EGFR-TKI acquired drug-resistance were enrolled into our research (NCT:02778854) prospectively, the pre-treatment samples including tumor tissue, plasma, urine and sputum were collected. We conducted capture-based NGS (next generation sequencing) on all of these samples from 50 patients with a ctDNA panel covering significant exons and introns from 400 human genes including EGFR, KRAS, ALK, ROS1, c-MET and other important genes in the tumor related singling pathways such as PI3K-AKT-mTOR, JAK-STAT, Notch, Wnt and so on. Patients recruited in our experiment have been given unique treatment such as targeted treatment or chemotherapy according to the clinical examination. The final molecular diagnostic results of all clinical liquid or tissue specimen are supposed to be correlated with clinical response data.
Result:
（Applied for Late-Breaking Abstract） This section is not applicable now because the sequencing and complex data analysis is in progress. Therefore, we will submit the final results as late-breaking abstract.
Conclusion:
Section not applicable. We expect to figure out the molecular diagnostic value of different body fluid compared with tumor tissue. we are able to analyze for correlation of the genomic profile derived from liquid samples and respective tissue results and clinical response of each patient.
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OA 10.08 - Discussant - OA 10.05, OA 10.06, OA 10.07 (ID 10807)
11:00 - 12:30 | Presenting Author(s): Naoko Aragane
- Abstract
- Presentation
Abstract not provided
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Author of
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MA 03 - Chemotherapy (ID 651)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Jin-Hyoung Kang, W. Su
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 502
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MA 03.04 - Discussant - MA 03.01, MA 03.02, MA 03.03 (ID 10808)
11:00 - 12:30 | Presenting Author(s): Adrian G. Sacher
- Abstract
- Presentation
Abstract not provided
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