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  • 1
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    Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 12 ( 2021-12-01), p. 3028-3047
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 12 ( 2021-12-01), p. 3028-3047
    Abstract: Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer. Significance: The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung. See related commentary by Meador and Lovly, p. 2962. This article is highlighted in the In This Issue feature, p. 2945
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1863
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Abstract 5598: Development and optimization of a comprehensive high-sensitivity NGS cancer assay and bioinformatics pipeline for plasma cfDNA profiling
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5598-5598
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5598-5598
    Abstract: The accessibility of tumor-derived cell-free DNA (cfDNA) in blood plasma provides a means to non-invasively profile somatic mutations in solid tumor patients. Clinical applications include longitudinal monitoring of disease burden and acquired drug resistance, identification of clinically relevant alterations and mutation signatures, and detection of minimal residual disease. However, the low fraction of tumor-derived cfDNA in plasma in many patients requires assays and bioinformatics methods that are much more sensitive than have been used for traditional tissue-based analysis. The design of our cfDNA NGS panel is based on prospectively-collected clinical sequencing data obtained from more than 20,000 patients at Memorial Sloan Kettering Cancer Center using MSK-IMPACT, a custom 468-gene sequencing test authorized by the FDA for somatic mutation profiling. Exons harboring hotspot mutations, clinically actionable mutations, and elevated somatic mutation rates were selected for inclusion in the cfDNA panel. Additional non-coding content was included to enable optimal detection of selected copy number alterations, regions of loss of heterozygosity, rearrangement breakpoints, and microsatellite instability. Altogether the panel contains 208 kilobases of sequence from 129 cancer genes. Ultra-deep sequencing and unique molecular indexing enable PCR-generated replicate sequences to be collapsed into error-free consensus sequences, thereby facilitating the high-confidence detection of mutations present at low allele fractions. We developed an open source bioinformatics tool, Marianas, for collapsing PCR replicates into consensus sequences and computing associated quality and performance metrics. Marianas incorporates many empirically derived features that lead to significant noise reduction. It efficiently processes a bam file with 20,000X coverage in 20 minutes on a single processor. We benchmarked the performance of Marianas against other available tools for collapsing and consensus base calling. The relative contributions of sources of error such as barcode contamination and sample cross-talk during PCR and sequencing were also quantified. We found that using unique dual sample indexes in multiplexed sequencing runs was essential to suppress these sources of noise. Applying these aggregated methods to analyze plasma cfDNA samples obtained from patients across a range of solid tumor types and disease stages, we were able to reliably detect clinically relevant mutations with variant allele fractions below 0.003, including subclonal mutations associated with acquired drug resistance. This approach, when applied prospectively on clinical specimens, has the potential to facilitate diagnosis, prognosis, and treatment selection in an era of precision oncology. Citation Format: Juber Patel, Maysun Hasan, Fanli Meng, Xiaohong Jing, Dilmi Perera, Jonathan Reichel, Erika Gedvilaite, Julie Yang, Maha Shady, Sandeep Raj, Preethi Srinivasan, Ian Johnson, Jiashi Wang, Mirna Jarosz, Aliaksandra Samoila, Agnes Viale, Bob Li, Pedram Razavi, Dana Tsui, Michael Berger. Development and optimization of a comprehensive high-sensitivity NGS cancer assay and bioinformatics pipeline for plasma cfDNA profiling [abstract]. In: Proceedings of the American Associatio n for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5598.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5598
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients
    Springer Science and Business Media LLC ; 2021
    In:  Genome Medicine Vol. 13, No. 1 ( 2021-12)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2021-12)
    Abstract: Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Methods Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z -score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES). Results cfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction ( z -score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction ( z -score 〈 5), 29 had sufficient material to be re-analyzed using a less comprehensive but more sensitive assay, MSK-ACCESS, which revealed somatic mutations in 14/29 (48%). Conversely, 5 patients without alterations detected by cf-IMPACT and with high tumor fraction ( z -score≥5) were analyzed by WES, which identified mutational signatures and alterations in potential oncogenic drivers not covered by the cf-IMPACT panel. Overall, we identified mutations in 90/118 (76%) patients in the entire cohort using the three complementary plasma profiling approaches. Conclusions cfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-021-00898-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 4
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    Sequenced circulating tumor (ct) DNA to detect the molecular landscape in advanced GIST.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 11036-11036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 11036-11036
    Abstract: 11036 Background: Molecular (mol) characteristics-guided precision therapy has well-established utility in GIST management. The GIST mol landscape is poorly represented by selective tumor biopsy (bx) material, especially in metastatic and treatment-refractory GIST. ctDNA can overcome some of the limitations of selective tissue bx specimens and provide comparable or greater mol information. ctDNA represents an emerging mol biomarker in advanced (adv) GIST. Methods: Next generation sequencing analyses (MSK-IMPACT or custom-capture GIST specific panel) were performed on ctDNA prospectively collected from patients (pts) with adv GIST. MSK-IMPACT was performed on tumor material (archival tissue or paired tissue bx specimens taken in parallel with ctDNA collection from clinical trial participants). The primary objective was to determine the concordance between the mol landscape of GIST identified by sequenced tumor tissue versus ctDNA. Secondary objective was to correlate characteristics of sequenced ctDNA with standard measurements of response assessment. Results: 47 ctDNA samples collected from 25 pts with adv GIST were sequenced using MSK-IMPACT ( 〉 400 genes). MSK-IMPACT was performed on archival tumor material. Sequenced ctDNA detected the mutational spectrum of tumor tissue in 48% of cases. In 50% of these cases, ctDNA identified novel treatment-resistance mutations not previously identified in the archival tissues. To optimize sensitivity of detection, a custom-designed GIST specific ctDNA sequencing panel was developed incorporating 19 of the most commonly altered genes observed from MSK-IMPACT analysis performed on 〉 75 imatinib-refractory adv GIST tumor samples. 52 ctDNA samples collected from 30 pts with paired tumor bx samples have been sequenced using the custom-capture GIST panel. The tumor bx samples have been sequenced using MSK-IMPACT. Results are pending and will be presented. A separate cohort of ctDNA samples serially collected in the setting of a prospective clinical trial are being sequenced. The mol results with correlated treatment response by RECIST will also be presented. Conclusions: ctDNA could detect a broad spectrum of mol heterogeneity and potentially be used as a biomarker to guide precision therapy in adv GIST. Further research is necessary to determine the optimal ctDNA sequencing assay and the appropriate clinical setting to utilize in GIST.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.11036
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 5
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    Abstract 2516: A bioinformatics framework for high-sensitivity detection and monitoring of oncogenic gene fusions in plasma cfDNA
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2516-2516
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2516-2516
    Abstract: Gene fusions represent key oncogenic driver alterations in many solid tumors that can be targeted therapeutically. Beyond FDA-approved drugs targeting ALK and ROS1 fusions in lung cancer, investigational agents targeting gene fusions involving RET, NTRK1/2/3, and FGFR2/3 have elicited significant and durable responses in a wide range of cancer types. Cell-free DNA (cfDNA) profiling provides a transformative opportunity to non-invasively and longitudinally monitor responses to these investigational therapies and identify acquired mutations that confer drug resistance. We have developed a pan-cancer, high-sensitivity NGS cancer assay (MSK-ACCESS, presented previously) to detect and monitor somatic mutations in plasma cfDNA. Here, we present an improved bioinformatics pipeline that detects gene fusions and achieves greater sensitivity and accuracy for detecting point mutations and indels. MSK-ACCESS uses ultra-high depth sequencing (~20,000x) coupled with duplex unique molecular indexing (UMI) and dual sample barcodes to achieve high sensitivity through background error suppression. The panel was designed to capture key exons and domains of 129 cancer genes as well as introns harboring recurrent breakpoints in 10 commonly rearranged genes. We have now developed a bioinformatics module for sensitive detection of structural variation from cfDNA, leveraging the high-depth sequencing data and intronic coverage. We have also added a statistical polishing method that assigns confidence to detected somatic mutations by building frequency distributions for those mutations from a large set of normal samples that has been processed with the same laboratory protocol and bioinformatics pipeline as the patient samples. In parallel, we have further improved the wet lab protocols to address challenges of capturing sufficient numbers of cfDNA molecules and removing noise, both required for detection of somatic mutations with high sensitivity and specificity. Using this method, we have successfully detected druggable fusions in plasma cfDNA from patients spanning a diverse set of cancer types. Through longitudinal cfDNA collection efforts embedded within early-phase clinical trials, we demonstrate that the levels of oncogenic driver fusions in cfDNA may scale with the burden of disease. Moreover, the ability to simultaneously call high-confidence mutations at low allele fractions has revealed novel acquired mutations indicative of polyclonal resistance to investigational targeted therapies. Citation Format: Juber Patel, Maysun Hasan, Fanli Meng, Xiaohong Jing, Grittney Tam, Ian Johnson, Youyun Zheng, Chaitanya Bandlamudi, Caitlin Stewart, Helen Won, Oliver Hampton, Alison Schram, Ezra Rosen, Alexander Drilon, Anna Varghese, David Hyman, Dana Tsui, Brian Houck-Loomis, Michael Berger. A bioinformatics framework for high-sensitivity detection and monitoring of oncogenic gene fusions in plasma cfDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2516.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2516
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract 3656: Detecting MSI in plasma: Implications for early detection of lynch associated tumors
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3656-3656
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3656-3656
    Abstract: Lynch Syndrome (LS) is characterized by germline mutations in mismatch repair pathway genes. The increased cancer susceptibility risk in these patients and the association of these tumors with microsatellite instability (MSI) provides a transformative opportunity for early detection of cancer in these patients. The presence of microsatellite unstable DNA fragments or zygosity changes of the MMR mutations in the plasma of LS patients is predictive of the presence of cancer. Here we describe an approach to detect MSI from plasma cell-free DNA (cfDNA) of LS associated cancer patients. First, to determine the background rate of MSI in cfDNA of microsatellite stable patients, we screened plasma samples collected from a large number of advanced cancer patients using MSK-IMPACT, a custom sequencing assay targeting 468 cancer genes encompassing ~1.5 megabases. MSK-IMPACT is approved by the NYS Department of Health and authorized by the FDA for clinical testing, including MSI assessment based on more than 1,000 microsatellite regions covered by the assay, and has been used to profile more than 20,000 patients at our institution. We were also able to confirm the ability to detect MSI in cfDNA in a small cohort of plasma samples collected from patients with MSI High tumors, and determine thresholds to delineate MSI from MSS cases from plasma. Using MSK-IMPACT, we detected MSI in the plasma of four patients with advanced MSI-H cancer, including one with confirmed LS. Three of these were patients with confirmed MSI signature from tumor tissue (one prostate cancer and two colorectal cancers. The fourth patient with prostate cancer had no tissue available for sequencing, though MSI was independently confirmed. To improve the sensitivity to detect MSI in patients with earlier stage disease where the fraction of tumor-derived cfDNA is lower, we have developed a novel targeted panel with optimized sequencing process and informatics, incorporating a set of highly informative microsatellite regions as well as SNPs to assess tumor-specific zygosity changes in mismatch repairs pathway genes. Through this work, we demonstrate the ability of our assay to detect MSI in plasma cfDNA with high sensitivity. Citation Format: Preethi Srinivasan, Christina Tran, Jonathan Reichel, Juber Ahamad Patel, Maysun Hasan, Fanli Meng, Xiaohong Jing, Sumit Middha, Ahmet Zehir, Rona D. Yaeger, Diane Reidy, Dana Tsui, Zsofia Stadler, Michael F. Berger. Detecting MSI in plasma: Implications for early detection of lynch associated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3656.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3656
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    Abstract PR07: MSI detection in plasma cfDNA: MSI as a marker of disease burden
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 11_Supplement ( 2020-06-01), p. PR07-PR07
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 11_Supplement ( 2020-06-01), p. PR07-PR07
    Abstract: Lynch syndrome (LS), an inherited predisposition syndrome associated with an increased risk of colorectal, endometrial, and other cancers, is characterized by germline mutations in mismatch repair pathway genes, which typically lead to microsatellite instability (MSI) in the resulting tumors. The FDA approval of pembrolizumab for all advanced MSI-H solid tumors has led to increasing MSI assessment. The presence of MSI in LS-associated tumors provides a unique and transformative opportunity for early detection and disease monitoring in these patients. Here we describe an approach to detect MSI from plasma cfDNA using MSK-ACCESS, a custom capture “liquid biopsy” approved for clinical use by the NY State Department of Health. In addition to frequently mutated exons of 129 genes, MSK-ACCESS also includes 165 highly informative microsatellite loci, selected from over 1,000 microsatellite regions based on & gt;25,000 tumors sequenced using MSK-IMPACT, an FDA-authorized tumor sequencing panel. A key challenge in detecting MSI from cfDNA is the lack of ground truth in these samples, as cfDNA obtained from patients with MSI-high tumors may not always exhibit sufficient tumor-derived DNA fragments. To address this, we developed a machine learning approach for cfDNA analysis trained on orthogonally validated tumors sequenced via MSK-IMPACT. We present Allelic Distance-based Microsatellite Instability Estimator (ADMIE), an approach to translate deviation in tumor/cfDNA from normal/buffy coat DNA at individual microsatellite loci to a binary MSI call. ADMIE achieved a cross-validation precision of 1.00 +/- 0.02 and recall of 0.99 +/- 0.07. We ran this on 44 plasma samples collected from over 30 patients with MSI tumors including colorectal, prostate, and gastric cancers across multiple time points. We also evaluated plasma from 70 patients with known MSS tumors and 46 healthy controls. None of the cfDNA from healthy controls or patients with MSS tumors were found to be MSI positive, indicating high specificity. To establish our limit of detection, we performed in silico dilution experiments leveraging patient samples and MSI signal of biologic origin to simulate different tumor fractions, establishing our limit of detection at 1%. Among patients with MSI-high tumors, we found the presence and magnitude of MSI in the cfDNA to be correlated with measurable response to treatment with immunotherapy. In these patients, we detected MSI in the cfDNA of 6/8 samples where at least one mutation was detectable in plasma above 0.2% at baseline. Among the 4/6 patients for whom we had additional time points post treatment, we did not detect any mutations or evidence of MSI. In one patient, MSK-ACCESS indicated the presence of a second primary tumor based on the detection of MSI and mutations in cfDNA completely independent from those identified in the previously sequenced tumor. Our results suggest that MSI can be reliably detected in cfDNA using MSK-ACCESS and the MSI signature can represent a marker of occult metastatic disease in LS. This abstract is also being presented as Poster A54. Citation Format: Preethi Srinivasan, Alicia Latham, Zalak Patel, John Ziegler, Maysun Hasan, Juber A. Patel, Ian Johnson, Ronak Shah, Fanli Meng, Xiaohong Jing, Grittney Tam, Rose Brannon, Andrea Cercek, Ahmet Zehir, Brian Houck-Loomis, Dana Tsui, Zsofia Stadler, Michael F. Berger. MSI detection in plasma cfDNA: MSI as a marker of disease burden [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR07.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.LiqBiop20-PR07
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Abstract 1387: Tracking minimal residual disease in post-operative cell-free DNA using MSK-ACCESS
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1387-1387
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1387-1387
    Abstract: A noted clinical application for liquid biopsy is as a non-invasive method of detecting and monitoring of minimal residual disease (MRD) in patients with cancer. The low concentration of circulating tumor DNA in blood, especially in early stage cancers, however, complicates the detection of tumor-derived cell-free DNA. To address this challenge, we have developed MSK-ACCESS (Analysis of Circulating cfDNA to Examine Somatic Status), a custom NGS assay covering selected exons from 129 cancer related genes for high-sensitivity detection of somatic mutations from plasma. Using ultra-high depth sequencing, with duplex unique molecular indexing (UMI), unique dual sample barcodes, and background error suppression, MSK-ACCESS is able to detect low-frequency (0.1%) variants with high confidence. The design of MSK-ACCESS leverages our dataset of more than 30,000 tumors profiled by our institutional tumor sequencing assay, MSK-IMPACT, ensuring that the majority of patients harbor multiple mutations that can be tracked in plasma. We have validated MSK-ACCESS using plasma samples collected from 40 healthy individuals and 70 cancer patients harboring a range of somatic mutations in 11 genes. Greater than 95% of mutations at allele fractions & gt;0.1% were empirically detected, and we established the performance characteristics of the assay through intra- and inter-assay reproducibility tests and dilution experiments. We have initiated clinical trials in multiple tumor types to evaluate the benefit of early therapeutic intervention in patients where MSK-ACCESS can detect circulating tumor DNA following surgery. Tumor mutations revealed by MSK-IMPACT in surgically resected specimens will be monitored at regular intervals as evidence of MRD. As a proof of concept, we have applied MSK-ACCESS to monitor variants known from tissue tumor sequencing in pre- and post-surgical cfDNA samples from 9 colon adenocarcinoma patients. All samples were sequenced to an average total depth of approximately 20,000X coverage and subsequently collapsed to consensus sequences exhibiting an average noise level less than 0.0006%. Circulating tumor DNA was detected in 66%(6/9) of the pre-surgical samples. Of these samples, ctDNA was also detected in 50% (3/6) of the post-surgical samples. Overall, this study shows that MSK-ACCESS can be used to successfully detect MRD. Citation Format: Maysun M. Hasan, Juber Patel, Ian Johnson, Fanli Meng, Grittney K. Tam, Xiaohong Jing, Julie L. Yang, A. Rose Brannon, Jayakumaran Gowtham, Dennis P. Stephens, Monica Diosdado, Ryma Benayed, Ahmet Zehir, Chin-Tung Chen, Martin R. Weiser, Dana Tsui, Brian Houck-Loomis, Michael Berger. Tracking minimal residual disease in post-operative cell-free DNA using MSK-ACCESS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1387.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1387
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Cell‐free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience
    Wiley ; 2020
    In:  Cancer Medicine Vol. 9, No. 17 ( 2020-09), p. 6093-6101
    Details
    In: Cancer Medicine, Wiley, Vol. 9, No. 17 ( 2020-09), p. 6093-6101
    Abstract: The enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell‐free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblastoma has not been shown. We analyzed cfDNA collected from 10 patients with available tumor tissue to determine whether sufficient tumorderived cfDNA is shed in plasma from retinoblastoma tumors to enable noninvasive RB1 mutation detection. Methods Tumor tissue was collected from eye enucleations in 10 patients diagnosed with advanced intra‐ocular unilateral retinoblastoma, three of which went on to develop metastatic disease. Tumor RB1 mutation status was determined using an FDA‐cleared tumor sequencing assay, MSK‐IMPACT. Plasma samples were collected before eye enucleation and analyzed with a customized panel targeting all exons of RB1 . Results Tumor‐guided genotyping detected 10 of the 13 expected somatic RB1 mutations in plasma cfDNA in 8 of 10 patients (average variant allele frequency 3.78%). Without referring to RB1 status in the tumor, de novo mutation calling identified 7 of the 13 expected RB1 mutations (in 6 of 10 patients) with high confidence. Conclusion Plasma cfDNA can detect somatic RB1 mutations in patients with unilateral retinoblastoma. Since intraocular biopsies are avoided in these patients because of concern about spreading tumor, cfDNA can potentially offer a noninvasive platform to guide clinical decisions about treatment, follow‐up schemes, and risk of metastasis.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    URL: Article
    DOI: 10.1002/cam4.v9.17
    DOI: 10.1002/cam4.3144
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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    Abstract PR08: Validation and clinical implementation of MSK-ACCESS, an ultra-deep sequencing assay for noninvasive somatic mutation profiling
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 11_Supplement ( 2020-06-01), p. PR08-PR08
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 11_Supplement ( 2020-06-01), p. PR08-PR08
    Abstract: Introduction: Circulating cell-free DNA (cfDNA) is a source of tumor-derived DNA to interrogate somatic alterations when tissue is not available or of insufficient quantity for analysis. At MSKCC, we have developed and validated MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), a targeted next-generation sequencing assay that can detect ultra-low frequency somatic variants in select exons and introns of 129 genes. MSK-ACCESS can identify mutations, copy number alterations, gene fusions, and MSI status in plasma and was recently approved by the NYS-DOH for clinical testing. Here, we present the results of the validation study and our clinical experience with MSK-ACCESS since June 2019. Methods: Target regions from 129 genes were selected to maximize coverage of actionable, oncogenic, and hotspot mutations based on the first 25,000 tumors sequenced using MSK-IMPACT, our institutional clinical sequencing assay. Plasma cfDNA and buffy-coat DNA were extracted from whole blood collected in cell-stabilizing tubes (STRECK BCT cell-free DNA tube). Unique molecular indexes were introduced during DNA library construction, allowing for error suppression from consensus reads collapsed by Marianas, an in-house-developed algorithm. These consensus reads enable variant calling at low allelic frequency (AF) based on a 10−6 background error rate. Results: Analytical validation of MSK-ACCESS demonstrated 93% accuracy (n=100 variants), 99% precision (n=153 variants), and 100% sensitivity based on an assay limit of detection of 0.5% AF (n=19 variants). Variants were detected down to 0.1% AF. To date, 240 clinical cfDNA and matched normal DNA pairs have been sequenced, analyzed for somatic alterations, and clinically reported to guide patient management. Most clinical cases were from lung (55%) or prostate (13%) cancers and submitted for diagnostic purposes (71%). Median raw coverage was 18,367X, and median consensus coverage was 1411X. Mutations were detected in 180 (75%) samples with a median variant AF of 1.8% (0.02% - 95%). Comparison of concurrent commercial plasma testing results to MSK-ACCESS revealed multiple variants that were of clonal hematopoiesis or germline origin incorrectly reported as somatic variants. In the lung cohort, 48 patients had tissue testing with MSK-IMPACT; among 32 patients with a driver alteration detected by MSK-ACCESS, 91% had the identical driver alteration reported by MSK-IMPACT. Additionally, MSK-ACCESS identified a MET exon 14 alteration in one lung cancer patient that led to protocol enrollment and partial response. Conclusions: Liquid biopsy testing using MSK-ACCESS reliably detected clinically actionable mutations, reducing the need for multiple biopsies. These results also illustrate the importance of analyzing a matched normal sample when interpreting cfDNA results and highlight the potential of using cfDNA analysis to guide treatment selection, assess for treatment response, and identify mechanisms of treatment resistance. This abstract is also being presented as Poster A20. Citation Format: A. Rose Brannon, Gowtham Jayakumaran, Monica Diosdado, Yu Hu, Anna Razumova, Fanli Meng, Emily Lebow, Juber Patel, Ian Johnson, Preethi Srinivasan, Maysun Hasan, Jenna-marie Dix, Aijazuddin Syed, Brian Houck-Loomis, Bob T. Li, Charles Rudin, David Solit, Marc Ladanyi, Maria Arcila, Dana Tsui, Ahmet Zehir, Michael Berger, Ryma Benayed. Validation and clinical implementation of MSK-ACCESS, an ultra-deep sequencing assay for noninvasive somatic mutation profiling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR08.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.LiqBiop20-PR08
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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