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  • 1
    Online Resource
    Online Resource
    Early Assessment of Chemotherapy Response in Advanced Non-Small Cell Lung Cancer with Circulating Tumor DNA
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 10 ( 2022-05-18), p. 2479-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 10 ( 2022-05-18), p. 2479-
    Abstract: Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p 〈 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14102479
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 2
    Online Resource
    Online Resource
    Abstract 728: Early assessment of treatment effect in small cell lung cancer (SCLC) via ctDNA analysis
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 728-728
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 728-728
    Abstract: INTRODUCTION: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. A ctDNA-based method for disease monitoring for small cell lung cancer (SCLC) would be beneficial to disease management. By employing plasma taken during early treatment cycles and NGS, we tested whether early response assessed by ctDNA level could predict treatment effect. METHODS: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (for Research Use Only, not for use in diagnostic procedures), ctDNA levels were assessed in post-treatment plasma samples based on variants identified at baseline. Mutant allele concentration or mutant molecules per milliliter-of-plasma (MMPM) was utilized to quantify ctDNA over all variants of all sequenced genomic regions. Samples collected from an observational German Lung Cancer Multi-Marker Study were analyzed retrospectively. In a cohort of 69 stage IV SCLC subjects, the association of survival with ctDNA-based monitoring classifier was evaluated in the first available post-treatment plasma sample after starting chemotherapy (median number of days after start of treatment = 25) by Kaplan-Meier methods and Cox proportional hazards model. RESULTS: The analysis demonstrated that subjects with mean MMPM less than the lower quartile (14.3) had longer progression free survival (PFS) compared to that of subjects with mean MMPM greater than or equal to the lower quartile (log-rank P = 0.0095; HR [95% CI] = 0.48 [0.27, 0.84] ). The same classifier was applied for overall survival analysis, and subjects with mean MMPM less than the lower quartile had longer overall survival (OS) compared to that of subjects with mean MMPM greater than or equal to the lower quartile (log-rank P = 0.0095; HR [95% CI] = 0.46 [0.26, 0.84] ). CONCLUSIONS: Changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects that either respond or fail to respond to therapy earlier than current standard of care methods such as computed tomography (CT) scan. Hypotheses will be validated in a separate cohort. Future prospective studies to confirm these results are needed. Citation Format: John Jiang, Christine Ju, Corinna Woestmann, Aarthi Balasubramanyam, Liu Xi, Stephanie J. Yaung, Sandeep Gattam, Bernd Hinzmann, Michael Thomas, Felix Lasitschka, Michael Meister, Marc Schneider, Felix Herth, Thomas Muley, Birgit Wehnl, John Palma. Early assessment of treatment effect in small cell lung cancer (SCLC) via ctDNA analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 728.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-728
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Assessment of a Highly Curated Somatic Oncology Database to Aid in the Interpretation of Clinically Important Variants in Next-Generation Sequencing Results
    Elsevier BV ; 2020
    In:  The Journal of Molecular Diagnostics Vol. 22, No. 11 ( 2020-11), p. 1356-1366
    Details
    In: The Journal of Molecular Diagnostics, Elsevier BV, Vol. 22, No. 11 ( 2020-11), p. 1356-1366
    Type of Medium: Online Resource
    ISSN: 1525-1578
    URL: Article
    DOI: 10.1016/j.jmoldx.2020.08.004
    RVK:
    XA 55072
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2032654-3
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  • 4
    Online Resource
    Online Resource
    Assessment of a highly curated somatic oncology mutation database to facilitate identification of clinically important variants in NGS results.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e18086-e18086
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e18086-e18086
    Abstract: e18086 Background: The increasing adoption of Next Generation Sequencing (NGS) in molecular profiling of cancer presents a growing need for streamlined interpretation of NGS results in clinical labs. This can be achieved through bioinformatics tools equipped with a highly-curated database on clinically important variants. Methods: We performed an initial assessment of an NGS result interpretation tool called NAVIFY Mutation Profiler (NMP), which enabled us to process a Variant Call Format (VCF) file and generate a report with consensus recommendations of NCCN, ASCO, CAP and ACMG. This annotation tool identifies pathogenic variants and variants of unknown clinical significance (VUS), and groups variants by AMP Tiers. At the time of this assessment, NMP contained curation for ~4,000 variants. In this study, we used NGS results from 38 anonymized clinical cases with known treatment regimens to retrospectively assess NMP as the variant interpretation tool. Our cohort contained lung cancer subjects treated with EGFR tyrosine kinase inhibitor (TKI) (5 cases), as well as subjects relapsed against EGFR TKI (1 case) or ALK TKI crizotinib (22 cases). We also included 10 control cases where standard of care chemo was used because initial diagnostic methods did not reveal any actionable targets. Results: NMP annotated NGS VCF data and generated a report within 10 minutes per case although some cases contained 〉 100 variants. NMP correctly associated EGFR TKI therapies options with the corresponding 5 cases. As expected, NMP did not recommend targeted therapies for the 10 chemo-treated control cases. For the subject relapsed against EGFR TKI, NMP correctly interpreted the complex EGFR mutation profile containing both activating (L858R) and drug-resistance (T790M) variants. In addition, out of 22 cases relapsed against ALK TKI crizotinib, NMP correctly marked 14 with crizotinib resistance when a known ALK variant conferring crizotinib resistance was detected. There was limited or no published clinical evidence to interpret the remaining 8 cases of ALK TKI resistance. Conclusions: NMP correctly interpreted cases containing EGFR and ALK variants in this study. With a highly-curated knowledge base, this tool simplifies NGS clinical reporting by identifying clinically actionable mutations and associating treatment options qualified by supporting clinical evidence.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e18086
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Early assessment of therapy response in non-small cell lung cancer (NSCLC) via longitudinal ctDNA analysis.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e20701-e20701
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e20701-e20701
    Abstract: e20701 Background: Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect. Methods: Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline. We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm, and applied it to an independent set of 22 late stage lung squamous cell carcinoma (SCC) that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes. Results: We divided the 83 adenocarcinoma cohort into training (n = 53) and test (n = 30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) 〈 1% in the training set. We applied the classifier to our validation set and found that subjects with mean AF 〈 1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P = 0.021). Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the SCC cohort. Subjects with mean AF 〈 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P = 0.001). Conclusions: Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, which is earlier than current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e20701
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 6
    Online Resource
    Online Resource
    Assessing the impact of clonal hematopoiesis in disease monitoring using targeted cell-free DNA (cfDNA) sequencing technology.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14530-e14530
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14530-e14530
    Abstract: e14530 Background: Somatic variants found in plasma cell-free DNA (cfDNA) may derive from either solid tumors or clonal hematopoiesis (CH). Little is known about how this may impact plasma-based longitudinal disease monitoring using targeted sequencing of circulating tumor DNA (ctDNA). Methods: To assess the potential impact of CH in disease monitoring, we evaluated monitoring algorithms by targeted sequencing with and without matched peripheral blood mononuclear cells (PBMC). Samples were collected from a prospective observational study, where 62 late stage lung adenocarcinoma subjects were treated with first-line chemo or chemoradiation therapy. Pre-treatment plasma cfDNA and matched PBMC were analyzed with the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a sequencing panel of 198 kilobases targeting cancer genes. Median input amounts of 25 ng cfDNA and 50 ng PBMC DNA were sequenced to median deduplicated depths of 4582 and 6134, respectively. Results: A median of 120 single nucleotide variants were detected per cfDNA sample, with 93.1% of these identified in matched PBMC. Most PBMC-matched cfDNA variants were germline SNPs, with allele frequency (AF) ~ 50% or 100%. A median of 1 (range 0-5) PBMC-matched cfDNA variants per sample were detected with an AF 〈 10%, consistent with CH. The number of these variants was positively associated with age (p-value = 0.0039) and the most frequently mutated gene was TP53. The remaining somatic variants (i.e., in cfDNA and not PBMC) had an AF range 0.03-40.9%. These PBMC-informed variants (median of 7 per sample) were used in longitudinal monitoring in the first post-treatment plasma sample to assess early response to therapy. Association between ctDNA level and progression-free survival using the same monitoring algorithm yielded nearly identical results on somatic variants derived from filtering approaches independent of matched PBMC (HR 0.32; 95% CI 0.16 - 0.65; log-rank P = 0.0009) and the PBMC-informed method (HR 0.31; 95% CI 0.14 - 0.66; log-rank P = 0.0013). Conclusions: A targeted panel focused on solid tumors by design has limited impact from CH. For disease monitoring applications in a non-MRD setting, measuring multiple variants instead of a single variant further enables robust classifiers that can moderate the impact of variants, if any, from CH.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14530
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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