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Now showing items 1 - 16 of 91

  • Clinicopathologic Characteristics of BRG1-De fi cient NSCLC

    Dagogo-Jack, Ibiayi   Schrock, Alexa B.   Kem, Marina   Jessop, Nicholas   Lee, Jessica   Ali, Siraj M.   Ross, Jeffrey S.   Lennerz, Jochen K.   Shaw, Alice T.   Mino-Kenudson, Mari  

    Introduction: Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. Methods: Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. Results: We detected SMARCA4 genomic alterations in 9% (n =3D 117 of 1422) and 11% (n =3D 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n =3D 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n =3D 11) or chemotherapy plus immunotherapy (n =3D 5), median progression-free survival was 38 days and 35 days, respectively. Conclusions: BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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  • Molecular Analysis of Plasma From Patients With ROS1-Positive NSCLC

    Dagogo-Jack, Ibiayi   Rooney, Marguerite   Nagy, Rebecca J.   Lin, Jessica J.   Chin, Emily   Ferris, Lorin A.   Ackil, Jennifer   Lennerz, Jochen K.   Lanman, Richard B.   Gainor, Justin F.   Shaw, Alice T.  

    Introduction: Circulating tumor DNA analysis is an emerging genotyping strategy that can identify tumor-specific genetic alterations in plasma including mutations and rearrangements. Detection of ROS1 fusions in plasma requires genotyping approaches that cover multiple breakpoints and target a variety of fusion partners. Compared to other molecular subsets of NSCLC, experience with detecting ROS1 genetic alterations in plasma is limited. Methods: To describe the spectrum of ROS1 fusions in NSCLC and determine sensitivity for detecting ROS1 fusions in plasma, we queried the Guardant Health plasma dataset and an institutional tissue database and compared plasma findings to tissue results. In addition, we used the Guardant360 NGS assay to detect potential genetic mediators of resistance in plasma from patients with ROS1-positive NSCLC who were relapsing on crizotinib. Results: We detected seven distinct fusion partners in plasma, most of which (n =3D 6 of 7) were also represented in the tissue dataset. Fusions pairing CD74 with ROS1 predominated in both cohorts (plasma: n =3D 35 of 56, 63%; tissue: n =3D 26 of 52, 50%). There was 100% concordance between the specific tissue- and plasma-detected ROS1 fusion for seven patients genotyped with both methods. Sensitivity for detecting ROS1 fusions in plasma at relapse on ROS1-directed therapy was 50%. Six (33%) of 18 post-crizotinib plasma specimens harbored ROS1 kinase domain mutations, five of which were ROS1 G2032R. Two (11%) post-crizotinib plasma specimens had genetic alterations (n =3D 1 each BRAF V600E and PIK3CA E545K) potentially associated with ROS1-independent signaling. Conclusions: Plasma genotyping captures the spectrum of ROS1 fusions observed in tissue. Plasma genotyping is a promising approach to detecting mutations that drive resistance to ROS1-directed therapies. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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  • Ultra-rapid drug delivery in the oral cavity using ultrasound

    France, Marion M.   del Rio, Tony   Travers, Hannah   Raftery, Erin   Xu, Katherine   Langer, Robert   Traverso, Giovanni   Lennerz, Jochen K.   Schoellhammer, Carl M.  

    The delivery of therapeutics to the gastrointestinal (GI) mucosa remains primarily a function of diffusion and rapid delivery is a significant goal in drug delivery science. However, delivery is hindered by the molecular barrier properties of the mucosa, as well as environmental factors. We hypothesized that low-frequency ultrasound can overcome these barriers, achieving rapid delivery in an engineered, clinically-relevant system for buccal administration. The hand-held system enabled delivery of macromolecules in short, 60-s treatment times ex vivo. Tolerability of the prototype was demonstrated in awake, (unsedated) dogs. Finally, this technology enhanced the efficacy of the anti-inflammatory agent, budesonide, allowing for prophylactic treatment in a hamster model of oral inflammatory lesions in vivo. The capacity to deliver therapeutics in a targeted and rapid manner in a clinically-relevant form-factor presents an intriguing capability to expand the repertoire of therapeutics that can be applied topically in the mouth and beyond.
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  • Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

    Thierauf, Julia   Ramamurthy, Nisha   Jo, Vickie Y.   Robinson, Hayley   Frazier, Ryan P.   Gonzalez, Jonathan   Pacula, Maciej   Dominguez Meneses, Enrique   Nose, Vania   Nardi, Valentina   Dias-Santagata, Dora   Le, Long P.   Lin, Derrick T.   Faquin, William C.   Wirth, Lori J.   Hess, Jochen   Iafrate, A. John   Lennerz, Jochen K.  

    Background Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy without effective systemic therapies. Delineation of molecular profiles in ACC has led to an increased number of biomarker-stratified clinical trials; however, the clinical utility and U.S.-centric financial sustainability of integrated next-generation sequencing (NGS) in routine practice has, to our knowledge, not been assessed. Materials and Methods In our practice, NGS genotyping was implemented at the discretion of the primary clinician. We combined NGS-based mutation and fusion detection, with MYB break-apart fluorescent in situ hybridization (FISH) and MYB immunohistochemistry. Utility was defined as the fraction of patients with tumors harboring alterations that are potentially amenable to targeted therapies. Financial sustainability was assessed using the fraction of global reimbursement. Results Among 181 consecutive ACC cases (2011-2018), prospective genotyping was performed in 11% (n =3D 20/181; n =3D 8 nonresectable). Testing identified 5/20 (25%) NOTCH1 aberrations, 6/20 (30%) MYB-NFIB fusions (all confirmed by FISH), and 2/20 (10%) MYBL1-NFIB fusions. Overall, these three alterations (MYB/MYBL1/NOTCH1) made up 65% of patients, and this subset had a more aggressive course with significantly shorter progression-free survival. In 75% (n =3D 6/8) of nonresectable patients, we detected potentially actionable alterations. Financial analysis of the global charges, including NGS codes, indicated 63% reimbursement, which is in line with national (U.S.-based) and international levels of reimbursement. Conclusion Prospective routine clinical genotyping in ACC can identify clinically relevant subsets of patients and is approaching financial sustainability. Demonstrating clinical utility and financial sustainability in an orphan disease (ACC) requires a multiyear and multidimensional program. Implications for Practice Delineation of molecular profiles in adenoid cystic carcinoma (ACC) has been accomplished in the research setting; however, the ability to identify relevant patient subsets in clinical practice has not been assessed. This work presents an approach to perform integrated molecular genotyping of patients with ACC with nonresectable, recurrent, or systemic disease. It was determined that 75% of nonresectable patients harbor potentially actionable alterations and that 63% of charges are reimbursed. This report outlines that orphan diseases such as ACC require a multiyear, multidimensional program to demonstrate utility in clinical practice.
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  • Highly Multiplexed FISH for in Situ Genomics

    Onozato, Maristela L.   Yapp, Clarence   Richardson, Douglas   Sundaresan, Tilak   Chahal, Varun   Lee, Jesse   Sullivan, James P.   Madden, Marisa W.   Shim, Hyo Sup   Liebers, Mathew   Ho, Quan   Maheswaran, Shyamala   Haber, Daniel A.   Zheng, Zongli   Clancy, Brian   Elliott, Hunter L.   Lennerz, Jochen K.   Iafrate, A. John  

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  • PAX8-positive Biphasic Synovial Sarcoma Expressing Hormonal Receptors

    Bur, Martin E.   Oliva, Esther   Lennerz, Jochen K.  

    PAX8, estrogen receptor-alpha (ER alpha) and progesterone receptor (PR) are markers usually expressed in neoplasms of mullerian origin. We report a subdiaphragmal mass in a 41-year-old woman corresponding to a malignant biphasic tumor with nests of epithelial-like cells forming variably sized cyst-like spaces alternating with spindle cells forming intersecting fascicles. The later were juxtaposed to coalescent densely cellular nodules of spindle cells with appreciable cytologic atypia and mitotic counts up to 30/10 high-power fields. The tumor cells were AE1/AE3, EMA, ERG, ER alpha, PR, and PAX8 positive whereas spindle cells showed reduced immunopositivity for these markers, especially marked in coalescent nodular areas, with notable exception of PAX8, which was diffuse and strongly positive. The possibility of an endometrioid carcinoma with spindle cells was considered by the referring pathologist, but fluorescent in situ hybridization showed rearrangement of SS18 gene in 48 of 50 tumor nuclei, rendering a diagnosis of biphasic synovial sarcoma, the first reported in the English literature to the best of our knowledge expressing PAX8, ER alpha, and PR. Further studies evaluating the expression of these markers in synovial sarcoma and other sarcomas are needed, as sometimes the findings may lead to misdiagnosis as other neoplasms including those of the female genital tract. Additional molecular tests may be helpful to determine the molecular mechanism of this aberrant immunoprofile, which could be directly or indirectly related to t(X:18).
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  • Ultra-rapid drug delivery in the oral cavity using ultrasound

    France, Marion M.   del Rio, Tony   Travers, Hannah   Raftery, Erin   Xu, Katherine   Langer, Robert   Traverso, Giovanni   Lennerz, Jochen K.   Schoellhammer, Carl M.  

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  • Molecular Analysis of Plasma From Patients With ROS1-Positive NSCLC

    Dagogo-Jack, Ibiayi   Rooney, Marguerite   Nagy, Rebecca J.   Lin, Jessica J.   Chin, Emily   Ferris, Lorin A.   Ackil, Jennifer   Lennerz, Jochen K.   Lanman, Richard B.   Gainor, Justin F.   Shaw, Alice T.  

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  • Clinically Integrated Molecular Diagnostics in Adenoid Cystic Carcinoma

    Thierauf, Julia   Ramamurthy, Nisha   Jo, Vickie Y.   Robinson, Hayley   Frazier, Ryan P.   Gonzalez, Jonathan   Pacula, Maciej   Dominguez Meneses, Enrique   Nose, Vania   Nardi, Valentina   Dias‐Santagata, Dora   Le, Long P.   Lin, Derrick T.   Faquin, William C.   Wirth, Lori J.   Hess, Jochen   Iafrate, A. John   Lennerz, Jochen K.  

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  • Artificial Intelligence Approach for Variant Reporting

    Zomnir, Michael G.   Lipkin, Lev   Pacula, Maciej   Meneses, Enrique Dominguez   MacLeay, Allison   Duraisarny, Sekhar   Nadhamuni, Nishchal   Al Turki, Saeed H.   Zheng, Zongli   Rivera, Miguel   Nardi, Valentina   Dias-Santagata, Dora   Le, Long P.   Lennerz, Jochen K.  

    Purpose Next-generation sequencing technologies are actively applied in clinical oncology. Bioinformatics pipeline analysis is an integral part of this process; however, humans cannot yet realize the full potential of the highly complex pipeline output. As a result, the decision to include a variant in the final report during routine clinical sign-out remains challenging. Methods We used an artificial intelligence approach to capture the collective clinical sign-out experience of six board-certified molecular pathologists to build and validate a decision support tool for variant reporting. We extracted all reviewed and reported variants from our clinical database and tested several machine learning models. We used 10-fold cross-validation for our variant call prediction model, which derives a contiguous prediction score from 0 to 1 (no to yes) for clinical reporting. Results For each of the 19,594 initial training variants, our pipeline generates approximately 500 features, which results in a matrix of > 9 million data points. From a comparison of naive Bayes, decision trees, random forests, and logistic regression models, we selected models that allow human interpretability of the prediction score. The logistic regression model demonstrated 1% false negativity and 2% false positivity. The final models' Youden indices were 0.87 and 0.77 for screening and confirmatory cutoffs, respectively. Retraining on a new assay and performance assessment in 16,123 independent variants validated our approach (Youden index, 0.93). We also derived individual pathologist-centric models (virtual consensus conference function), and a visual drill-down functionality allows assessment of how underlying features contributed to a particular score or decision branch for clinical implementation. Conclusion Our decision support tool for variant reporting is a practically relevant artificial intelligence approach to harness the next-generation sequencing bioinformatics pipeline output when the complexity of data interpretation exceeds human capabilities. (C) 2018 by American Society of Clinical Oncology
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  • Clinical Utility of Rapid EGFR Genotyping in Advanced Lung Cancer

    Dagogo-Jack, Ibiayi   Azzolli, Christopher G.   Fintelmann, Florian   Mino-Kenudson, Mad   Farago, Anna F.   Gainor, Justin F.   Jiang, Ginger   Piotrowska, Zofia   Heist, Rebecca S.   Lennes, Inga T.   Temel, Jennifer S.   Mooradian, Meghan J.   Lin, Jessica J.   Digumarthy, Subba R.   Batten, Julie M.   Robinson, Hayley   Nose, Vania   Rivera, Miguel   Nardi, Valentina   Dias-Santagata, Dora   Le, Long P.   Sequist, Lecia, V   Pitman, Martha   Shepard, Jo-Anne O.   Shaw, Alice T.   Iafrate, A. John   Lennerz, Jochen K.  

    Purpose Targeted therapy is the cornerstone of treatment of advanced EGFR-mutant non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS), the preferred method for genotyping, typically requires several weeks. Here, we assessed workflows designed to rapidly identify patients with actionable EGFR mutations and reduce time to initiation (TTI) of epidermal growth factor receptor (EGFR)-directed therapy. Patients and Methods We performed rapid testing for EGFR L858R mutations and exon 19 deletions on paraffin-embedded or frozen section biopsy specimens from newly diagnosed patients with metastatic NSCLC by using an EGFR-specific assay (rapid test). To determine clinical utility, we assessed concordance with NGS results, turnaround time, and TTI of EGFR therapy, and we evaluated reimbursement data. Results Between January 2015 and September 2017, we performed 243 rapid EGFR tests and identified EGFR mutations in 43 patients (18%). With NGS results as a reference, sensitivity and specificity of the rapid EGFR polymerase chain reaction assay were 98% and 100%, respectively. The median turnaround time for NGS was 14 days, compared with 7 days for rapid testing (P < .001). In the rapid group, 95% of patients received an EGFR inhibitor in the first-line setting. The median TTI of EGFR therapy was significantly shorter in the rapid cohort when compared with 121 historical cases (22 v 37 days; P =3D .01). Escalation of the initiative into an interdisciplinary ultra-rapid next-day frozen-section workflow for highly symptomatic patients (n =3D 8) resulted in a reduction in the median (+/- standard deviation) turnaround time to 1 +/- 0.4 days and allowed several patients to initiate therapy within 1 week of biopsy. An extended 9-month clinical evaluation phase confirmed operational sustainability (turnaround times: ultra-rapid, 0.81 +/- 0.4 days; rapid, 3 +/- 1.5 days), and a 63% reimbursement rate indicated financial sustainability. Conclusion Rapid genotyping facilitates earlier initiation of EGFR-directed therapies without compromising NGS workflows. (C) 2018 by American Society of Clinical Oncology
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  • Artificial Intelligence Approach for Variant Reporting

    Zomnir, Michael G.   Lipkin, Lev   Pacula, Maciej   Dominguez Meneses, Enrique   MacLeay, Allison   Duraisamy, Sekhar   Nadhamuni, Nishchal   Al Turki, Saeed H.   Zheng, Zongli   Rivera, Miguel   Nardi, Valentina   Dias-Santagata, Dora   Iafrate, A. John   Le, Long P.   Lennerz, Jochen K.  

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  • Highly Multiplexed Fluorescence in Situ Hybridization for in Situ Genomics

    Onozato, Maristela L.   Yapp, Clarence   Richardson, Douglas   Sundaresan, Tilak   Chahal, Varun   Lee, Jesse   Sullivan, James P.   Madden, Marisa W.   Shim, Hyo S.   Liebers, Matthew   Ho, Quan   Maheswaran, Shyamala   Haber, Daniel A.   Zheng, Zongli   Clancy, Brian   Elliott, Hunter L.   Lennerz, Jochen K.   Iafrate, A. John  

    The quantification of changes in gene copy number is critical to our understanding of tumor biology and for the clinical management of cancer patients. DNA fluorescence in situ hybridization is the gold standard method to detect copy number alterations, but it is limited by the number of genes one can quantify simultaneously. To increase the throughput of this informative technique, a fluorescent barcode system for the unique labeling of dozens of genes and an automated image analysis algorithm that enabled their simultaneous hybridization for the quantification of gene copy numbers were devised. We demonstrate the reliability of this multiplex approach on normal human Lymphocytes, metaphase spreads of transformed cell lines, and cultured circulating tumor cells. It also opens the door to the development of gene panels for more comprehensive analysis of copy number changes in tissue, including the study of heterogeneity and of high-throughput clinical assays that could provide rapid quantification of gene copy numbers in samples with limited cellularity, such as circulating tumor cells.
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  • Origins of lymphatic and distant metastases in human colorectal cancer

    Naxerova, Kamila   Reiter, Johannes G.   Brachtel, Elena   Lennerz, Jochen K.   van de Wetering, Marc   Rowan, Andrew   Cai, Tianxi   Clevers, Hans   Swanton, Charles   Nowak, Martin A.   Elledge, Stephen J.   Jain, Rakesh K.  

    The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.
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  • Health Care Infrastructure for Financially Sustainable Clinical Genomics

    Lennerz, Jochen K.   McLaughlin, Heather M.   Baron, Jason M.   Rasmussen, David   Shin, Meini Sumbada   Berners-Lee, Nancy   Batten, Julie Miller   Swoboda, Kathryn J.   Gala, Manish K.   Winter, Harland S.   Schmahmann, Jeremy D.   Sweetser, David A.   Boswell, Marianne   Pacula, Maciej   Stenzinger, Albrecht   Le, Long P.   Hynes, William   Rehm, Heidi   Klibanski, Anne   Black-Schaffer, Stephen W.   Golden, Jeffrey A.   Louis, David N.   Weiss, Scott T.   Iafrate, A. John  

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  • Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity

    Dagogo-Jack, Ibiayi   Rooney, Marguerite   Lin, Jessica J.   Nagy, Rebecca J.   Yeap, Beow Y.   Hubbeling, Harper   Chin, Emily   Ackil, Jennifer   Farago, Anna F.   Hata, Aaron N.   Lennerz, Jochen K.   Gainor, Justin F.   Lanman, Richard B.  

    Purpose: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma geno-typing for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.Experimental Design: We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.Results: By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor >=3D 2 ALK mutations (24% vs. 2%, P =3D 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with >=3D 2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of >=3D 2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P =3D 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired >=3D 1 new ALK mutations on lorlatinib.Conclusions: ALK resistance mutations increase with each successive generation of ALK TKI andmay be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.
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