David Kurtz

All Publications

• Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

  Abstract

  Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

  View details for DOI 10.1016/j.ccell.2022.12.005

  View details for PubMedID 36584673

• Disease Characterization and Response Prediction in Myeloma Patients Undergoing Conventional and Cellular Therapies from Circulating Tumor DNA Hosoya, H., Carleton, M., Tanaka, K. L., Sworder, B., Hovanky, V., Duran, G. E., Zhang, T. Y., Khodadoust, M. S., Miklos, D. B., Arai, S., Iberri, D., Liedtke, M., Sidana, S., Kurtz, D. M. AMER SOC HEMATOLOGY. 2022: 1546-1548

  View details for DOI 10.1182/blood-2022-160370

  View details for Web of Science ID 000893223201226

• Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nature biotechnology Kurtz, D. M., Soo, J., Co Ting Keh, L., Alig, S., Chabon, J. J., Sworder, B. J., Schultz, A., Jin, M. C., Scherer, F., Garofalo, A., Macaulay, C. W., Hamilton, E. G., Chen, B., Olsen, M., Schroers-Martin, J. G., Craig, A. F., Moding, E. J., Esfahani, M. S., Liu, C. L., Duhrsen, U., Huttmann, A., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2021

  Abstract

  Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

  View details for DOI 10.1038/s41587-021-00981-w

  View details for PubMedID 34294911

• The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer cell Steen, C. B., Luca, B. A., Esfahani, M. S., Azizi, A., Sworder, B. J., Nabet, B. Y., Kurtz, D. M., Liu, C. L., Khameneh, F., Advani, R. H., Natkunam, Y., Myklebust, J. H., Diehn, M., Gentles, A. J., Newman, A. M., Alizadeh, A. A. 2021

  Abstract

  Biological heterogeneity in diffuse large B cell lymphoma (DLBCL) is partly driven by cell-of-origin subtypes and associated genomic lesions, but also by diverse cell types and cell states in the tumor microenvironment (TME). However, dissecting these cell states and their clinical relevance at scale remains challenging. Here, we implemented EcoTyper, a machine-learning framework integrating transcriptome deconvolution and single-cell RNA sequencing, to characterize clinically relevant DLBCL cell states and ecosystems. Using this approach, we identified five cell states of malignant B cells that vary in prognostic associations and differentiation status. We also identified striking variation in cell states for 12 other lineages comprising the TME and forming cell state interactions in stereotyped ecosystems. While cell-of-origin subtypes have distinct TME composition, DLBCL ecosystems capture clinical heterogeneity within existing subtypes and extend beyond cell-of-origin and genotypic classes. These results resolve the DLBCL microenvironment at systems-level resolution and identify opportunities for therapeutic targeting (https://ecotyper.stanford.edu/lymphoma).

  View details for DOI 10.1016/j.ccell.2021.08.011

  View details for PubMedID 34597589

• A mathematical model of ctDNA shedding predicts tumor detection size. Science advances Avanzini, S., Kurtz, D. M., Chabon, J. J., Moding, E. J., Hori, S. S., Gambhir, S. S., Alizadeh, A. A., Diehn, M., Reiter, J. G. 2020; 6 (50)

  Abstract

  Early cancer detection aims to find tumors before they progress to an incurable stage. To determine the potential of circulating tumor DNA (ctDNA) for cancer detection, we developed a mathematical model of tumor evolution and ctDNA shedding to predict the size at which tumors become detectable. From 176 patients with stage I to III lung cancer, we inferred that, on average, 0.014% of a tumor cell's DNA is shed into the bloodstream per cell death. For annual screening, the model predicts median detection sizes of 2.0 to 2.3 cm representing a ~40% decrease from the current median detection size of 3.5 cm. For informed monthly cancer relapse testing, the model predicts a median detection size of 0.83 cm and suggests that treatment failure can be detected 140 days earlier than with imaging-based approaches. This mechanistic framework can help accelerate clinical trials by precomputing the most promising cancer early detection strategies.

  View details for DOI 10.1126/sciadv.abc4308

  View details for PubMedID 33310847

• Integrating genomic features for non-invasive early lung cancer detection. Nature Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y. J., Nesselbush, M. C., Co Ting Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020; 580 (7802): 245-251

  Abstract

  Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

  View details for DOI 10.1038/s41586-020-2140-0

  View details for PubMedID 32269342

• Dynamic Risk Profiling Using Serial Tumor Biomarkers for Personalized Outcome Prediction. Cell Kurtz, D. M., Esfahani, M. S., Scherer, F., Soo, J., Jin, M. C., Liu, C. L., Newman, A. M., Duhrsen, U., Huttmann, A., Casasnovas, O., Westin, J. R., Ritgen, M., Bottcher, S., Langerak, A. W., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Bahlo, J., Hallek, M., Tibshirani, R., Diehn, M., Alizadeh, A. A. 2019

  Abstract

  Accurate prediction of long-term outcomes remains a challenge in the care of cancer patients. Due to the difficulty of serial tumor sampling, previous prediction tools have focused on pretreatment factors. However, emerging non-invasive diagnostics have increased opportunities for serial tumor assessments. We describe the Continuous Individualized Risk Index (CIRI), a method to dynamically determine outcome probabilities for individual patients utilizing risk predictors acquired over time. Similar to "win probability" models in other fields, CIRI provides a real-time probability by integrating risk assessments throughout a patient's course. Applying CIRI to patients with diffuse large B cell lymphoma, we demonstrate improved outcome prediction compared to conventional risk models. We demonstrate CIRI's broader utility in analogous models of chronic lymphocytic leukemia and breast adenocarcinoma and perform a proof-of-concept analysis demonstrating how CIRI could be used to develop predictive biomarkers for therapy selection. We envision thatdynamic risk assessment will facilitate personalized medicine and enable innovative therapeutic paradigms.

  View details for DOI 10.1016/j.cell.2019.06.011

  View details for PubMedID 31280963

• Prognostication with circulating tumor DNA: is it ready for prime time? Hematology. American Society of Hematology. Education Program Kurtz, D. M. 2019; 2019 (1): 47–52

  Abstract

  Emerging methods to detect tumor-derived DNA in the blood plasma of patients with lymphomas-so-called "circulating tumor DNA" (ctDNA)-have the potential to change the way in which lymphoma is diagnosed and managed in the clinic. The possible applications for ctDNA are numerous, including mutation genotyping, response monitoring, and detection of minimal residual disease during a time of radiographic remission. This article discusses the methodology for detecting ctDNA in aggressive B-cell lymphomas, including digital polymerase chain reaction, targeted sequencing of immunoglobulin receptors, and targeted next-generation sequencing. The advantages of each of these methods are also compared, with a focus on promising clinical applications. These include identification of molecular subtypes (eg, cell-of-origin and double-hit lymphomas) from pretreatment plasma, molecular response prediction after an initial course of therapy, and early detection of relapsing disease prior to clinical relapse. Finally, this article discusses the challenges in implementing ctDNA assays in the clinic today, including possible solutions to these challenges.

  View details for DOI 10.1182/hematology.2019000013

  View details for PubMedID 31808836

• Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018: JCO2018785246

  Abstract

  Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

  View details for PubMedID 30125215

• Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

  Abstract

  Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

  View details for DOI 10.1126/scitranslmed.aai8545

  View details for PubMedID 27831904

• Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

  Abstract

  High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

  View details for DOI 10.1038/nbt.3520

  View details for PubMedID 27018799

• Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood Kurtz, D. M., Green, M. R., Bratman, S. V., Scherer, F., Liu, C. L., Kunder, C. A., Takahashi, K., Glover, C., Keane, C., Kihira, S., Visser, B., Callahan, J., Kong, K. A., Faham, M., Corbelli, K. S., Miklos, D., Advani, R. H., Levy, R., Hicks, R. J., Hertzberg, M., Ohgami, R. S., Gandhi, M. K., Diehn, M., Alizadeh, A. A. 2015; 125 (24): 3679-3687

  Abstract

  Recent studies have shown limited utility of routine surveillance imaging for diffuse large B-cell lymphoma (DLBCL) patients achieving remission. Detection of molecular disease by immunoglobulin high-throughput sequencing (Ig-HTS) from peripheral blood provides an alternate strategy for surveillance. We prospectively evaluated the utility of Ig-HTS within 311 blood and 105 tumor samples from 75 patients with DLBCL, comparing Ig-HTS from the cellular (circulating leukocytes) and acellular (plasma cell-free DNA) compartments of peripheral blood to clinical outcomes and (18)fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET/CT; n = 173). Clonotypic immunoglobulin rearrangements were detected in 83% of patients with adequate tumor samples to enable subsequent monitoring in peripheral blood. Molecular disease measured from plasma, compared with circulating leukocytes, was more abundant and better correlated with radiographic disease burden. Before treatment, molecular disease was detected in the plasma of 82% of patients compared with 71% in circulating cells (P = .68). However, molecular disease was detected significantly more frequently in the plasma at time of relapse (100% vs 30%; P = .001). Detection of molecular disease in the plasma often preceded PET/CT detection of relapse in patients initially achieving remission. During surveillance time points before relapse, plasma Ig-HTS demonstrated improved specificity (100% vs 56%, P < .0001) and similar sensitivity (31% vs 55%, P = .4) compared with PET/CT. Given its high specificity, Ig-HTS from plasma has potential clinical utility for surveillance after complete remission.

  View details for DOI 10.1182/blood-2015-03-635169

  View details for PubMedID 25887775

• Specificity of Immunoglobulin High-Throughput Sequencing Minimal Residual Disease Monitoring in Non-Hodgkin Lymphomas. Blood advances Shukla, N., Schroers-Martin, J., Sworder, B., Kathuria, K. R., Alig, S., Frank, M. J., Miklos, D. B., Coutre, S. E., Diehn, M., Khodadoust, M. S., Roschewski, M. J., Kurtz, D. M., Alizadeh, A. A. 2023

  View details for DOI 10.1182/bloodadvances.2023011997

  View details for PubMedID 38147627

• Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature Alig, S. K., Esfahani, M. S., Garofalo, A., Li, M. Y., Rossi, C., Flerlage, T., Flerlage, J. E., Adams, R., Binkley, M. S., Shukla, N., Jin, M. C., Olsen, M., Telenius, A., Mutter, J. A., Schroers-Martin, J. G., Sworder, B. J., Rai, S., King, D. A., Schultz, A., Bögeholz, J., Su, S., Kathuria, K. R., Liu, C. L., Kang, X., Strohband, M. J., Langfitt, D., Pobre-Piza, K. F., Surman, S., Tian, F., Spina, V., Tousseyn, T., Buedts, L., Hoppe, R., Natkunam, Y., Fornecker, L. M., Castellino, S. M., Advani, R., Rossi, D., Lynch, R., Ghesquières, H., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., André, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. 2023

  Abstract

  The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels1-4. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq5 we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential.

  View details for DOI 10.1038/s41586-023-06903-x

  View details for PubMedID 38081297

• Genomic abnormalities involving class I HLA are common in advanced cutaneous T-cell lymphoma Kwang, A., Duran, G., Fernandez-Pol, S., Li, S., Najidh, S., Torres, A., Herrera, M., Wang, E., Kurtz, D., Kim, Y. H., Khodadoust, M. ELSEVIER SCI LTD. 2023: S14

  View details for DOI 10.1016/j.ejca.2023.113019

  View details for Web of Science ID 001077487800032

• Cell-of-Origin Subtypes and Therapeutic Benefit from Polatuzumab Vedotin. The New England journal of medicine Palmer, A. C., Kurtz, D. M., Alizadeh, A. A. 2023; 389 (8): 764-766

  View details for DOI 10.1056/NEJMc2306105

  View details for PubMedID 37611128

• Cell-free DNA in large B-cell lymphoma: MRD and beyond. Seminars in hematology Sworder, B. J., Kurtz, D. M. 2023

  Abstract

  Large B-cell lymphomas (LBCLs) are a strikingly diverse set of diseases, including clinical, biological, and molecular heterogeneity. Despite a wealth of information resolving this heterogeneity in the research setting, applying molecular features routinely in the clinic remains challenging. The advent of circulating tumor DNA (ctDNA) liquid biopsies promises to unlock additional molecular information in the clinic, including mutational genotyping, molecular classification, and minimal residual disease detection. Here, we examine the technologies, applications, and studies exploring the utility of ctDNA in LBCLs.

  View details for DOI 10.1053/j.seminhematol.2023.06.004

  View details for PubMedID 37474409

• Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors. Cancer discovery Schroers-Martin, J. G., Soo, J., Brisou, G., Scherer, F., Kurtz, D. M., Sworder, B. J., Khodadoust, M. S., Jin, M. C., Bru, A., Liu, C. L., Stehr, H., Vineis, P., Natkunam, Y., Teras, L. R., Song, J. Y., Nadel, B., Diehn, M., Roulland, S., Alizadeh, A. A. 2023

  Abstract

  Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultra-deep sequencing of pre-diagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, p=0.03 and 0/20, p=0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with potential for discriminating subjects at risk of developing FL or monitoring residual disease.

  View details for DOI 10.1158/2159-8290.CD-23-0111

  View details for PubMedID 36939219

• Circulating Tumor DNA Profiling for Detection, Risk Stratification, and Classification of Brain Lymphomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mutter, J. A., Alig, S. K., Esfahani, M. S., Lauer, E. M., Mitschke, J., Kurtz, D. M., Kühn, J., Bleul, S., Olsen, M., Liu, C. L., Jin, M. C., Macaulay, C. W., Neidert, N., Volk, T., Eisenblaetter, M., Rauer, S., Heiland, D. H., Finke, J., Duyster, J., Wehrle, J., Prinz, M., Illerhaus, G., Reinacher, P. C., Schorb, E., Diehn, M., Alizadeh, A. A., Scherer, F. 2022: JCO2200826

  Abstract

  Clinical outcomes of patients with CNS lymphomas (CNSLs) are remarkably heterogeneous, yet identification of patients at high risk for treatment failure is challenging. Furthermore, CNSL diagnosis often remains unconfirmed because of contraindications for invasive stereotactic biopsies. Therefore, improved biomarkers are needed to better stratify patients into risk groups, predict treatment response, and noninvasively identify CNSL.We explored the value of circulating tumor DNA (ctDNA) for early outcome prediction, measurable residual disease monitoring, and surgery-free CNSL identification by applying ultrasensitive targeted next-generation sequencing to a total of 306 tumor, plasma, and CSF specimens from 136 patients with brain cancers, including 92 patients with CNSL.Before therapy, ctDNA was detectable in 78% of plasma and 100% of CSF samples. Patients with positive ctDNA in pretreatment plasma had significantly shorter progression-free survival (PFS, P < .0001, log-rank test) and overall survival (OS, P = .0001, log-rank test). In multivariate analyses including established clinical and radiographic risk factors, pretreatment plasma ctDNA concentrations were independently prognostic of clinical outcomes (PFS HR, 1.4; 95% CI, 1.0 to 1.9; P = .03; OS HR, 1.6; 95% CI, 1.1 to 2.2; P = .006). Moreover, measurable residual disease detection by plasma ctDNA monitoring during treatment identified patients with particularly poor prognosis following curative-intent immunochemotherapy (PFS, P = .0002; OS, P = .004, log-rank test). Finally, we developed a proof-of-principle machine learning approach for biopsy-free CNSL identification from ctDNA, showing sensitivities of 59% (CSF) and 25% (plasma) with high positive predictive value.We demonstrate robust and ultrasensitive detection of ctDNA at various disease milestones in CNSL. Our findings highlight the role of ctDNA as a noninvasive biomarker and its potential value for personalized risk stratification and treatment guidance in patients with CNSL.

  View details for DOI 10.1200/JCO.22.00826

  View details for PubMedID 36542815

• Polatuzumab vedotin with infusional chemotherapy (Pola-DA-EPCH-R) for untreated aggressive B-cell non-Hodgkin lymphomas. Blood advances Lynch, R. C., Poh, C., Ujjani, C. S., Warren, E. H., Smith, S. D., Shadman, M., Morris, K., Lee, S., Rasmussen, H., Ottemiller, S., Shelby, M., Keo, S., Verni, K., Kurtz, D. M., Alizadeh, A. A., Chabon, J. J., Hogan, G. J., Schulz, A., Gooley, T. A., Voutsinas, J. M., Gopal, A. K. 2022

  Abstract

  The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas, but it is unknown if Pola can be safely incorporated into intensified regimens (eg. DA-EPOCH-R) typically utilized for the highest risk histologies. This was a single-center, open label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R in aggressive large B-cell lymphomas. The primary endpoint was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with pre-specified suspension rules. Secondary and exploratory endpoints included efficacy and correlation with ctDNA levels. We enrolled 18 patients on study, and with only three DLTs observed, the study met its primary endpoint for safety. There were five serious adverse events including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis (1, 6%), and grade 5 sepsis/typhlitis (1, 6%). Among 17 evaluable patients, the best overall response rate was 100% and complete response rate of 76%. With median follow up of 12.9 months, 12-month EFS was 72% (95% CI 54-96%) and 12-month OS was 94% (95% CI 84-100%). No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety endpoint. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired.

  View details for DOI 10.1182/bloodadvances.2022009145

  View details for PubMedID 36521030

• Viral cfDNA Profiling Reveals Distinct EBV Subtypes and Stratifies Risk in Hodgkin Lymphomas Garofalo, A., Alig, S. K., Schroers-Martin, J., Shyam, R., Olsen, M., Kurtz, D. M., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1318-1319

  View details for DOI 10.1182/blood-2022-159230

  View details for Web of Science ID 000893223201135

• Clonal Hematopoiesis Driven By Recurrent Somatic Mutations but Not with Recurrent Copy Number Alterations Is Associated with Inferior Outcomes in DLBCL after Induction Chemotherapy, but Not CAR19 Therapy Boegeholz, J., Alig, S. K., Sworder, B., Schroers-Martin, J., Macaulay, C., Craig, A. M., Duehrsen, U., Huettmann, A., Westin, J., Cherng, H. J., Miklos, D. B., Frank, M. J., Diehn, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 8609-8610

  View details for DOI 10.1182/blood-2022-170087

  View details for Web of Science ID 000893230301297

• Accurate Detection of Clinically Actionable Copy Number Variants in Diverse Hematological Neoplasms By Routine Targeted Sequencing: A Comparative Performance Study Mosquera, A., Hosoya, H., Jin, M. C., Esfahani, M., Schroers-Martin, J., Sworder, B., Liu, C., Spiteri, E., Natkunam, Y., Zehnder, J. L., Stehr, H., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 10712-10713

  View details for DOI 10.1182/blood-2022-167900

  View details for Web of Science ID 000893230303319

• Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547

  View details for DOI 10.1182/blood-2022-165600

  View details for Web of Science ID 000893230300247

• Ultrasensitive Circulating Tumor DNA (ctDNA) Dynamics after Autologous CD30.CAR-T Cell Therapy for Relapsed or Refractory (r/r) Classical Hodgkin Lymphoma (CHARIOT Trial) Kurtz, D. M., Ahmed, S., Tong, C., Mei, M., Ding, C., Flinn, I. W., Riedell, P. A., Hogan, G. J., Schultz, A., Chabon, J. J., Heslop, H. E., Myo, A., Alizadeh, A. A., Horak, I. D. AMER SOC HEMATOLOGY. 2022: 2378-2380

  View details for DOI 10.1182/blood-2022-162150

  View details for Web of Science ID 000893223202159

• MRD-Negativity As a Potential Surrogate Endpoint after Frontline DLBCL Therapy: Pooled Analysis of Trials & Implications for Clinical Trial Design Roschewski, M., Kurtz, D. M., Westin, J., Lynch, R. C., Macaulay, C., Kuffer, C., Hogan, G. J., Close, S., Chabon, J. J., Rossi, D., Diehn, M., Alizadeh, A. A., Schultz, A. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-167936

  View details for Web of Science ID 000893223200322

• Ultrasensitive MRD Profiling Predicts Outcomes in DLBCL after Frontline Therapy with Tafasitamab in Combination with Lenalidomide and R-CHOP Kurtz, D. M., Hogan, G. J., Schultz, A., Kopeckova, K., Kuffer, C., Blair, D., Wagner, S., Close, S., Diehn, M., Chabon, J. J., Alizadeh, A. A., Westin, J. AMER SOC HEMATOLOGY. 2022: 3498-3499

  View details for DOI 10.1182/blood-2022-168378

  View details for Web of Science ID 000893223203237

• Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas Sworder, B., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N. D., Garofalo, A., Macaulay, C., Esfahani, M., Olsen, M., Hamilton, J., Hosoya, H., Hamilton, M. P., Spiegel, J. Y., Baird, J. H., Carleton, M., Craig, A. M., Younes, S. F., Sahaf, B., Sheybani, N., Schroers-Martin, J., Liu, C., Oak, J. S., Jin, M. C., Beygi, S., Huttmann, A., Hanoun, C., Duhrsen, U., Westin, J., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1301-1303

  View details for DOI 10.1182/blood-2022-165545

  View details for Web of Science ID 000893223201129

• Specificity & Precision of Minimal Residual Disease Monitoring in DLBCL Using Ig-HTS Shukla, N. D., Schroers-Martin, J., Kathuria, K. R., Sworder, B., Alig, S. K., Frank, M. J., Miklos, D. B., Coutre, S., Diehn, M., Khodadoust, M. S., Roschewski, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 6403-6404

  View details for DOI 10.1182/blood-2022-165656

  View details for Web of Science ID 000893223206185

• Tumor Microenvironment Determinants of Immunotherapy Response Identified By Integrated Host & Viral Analysis of Post-Transplant Lymphoproliferative Disorders Schroers-Martin, J., Garofalo, A., Soo, J., Boegeholz, J., Alig, S. K., Sworder, B., Liu, C., Luikart, H., Gamino, G., Morales, D., Freystaetter, K., Hamilton, J., Kurtz, D. M., Hollander, S., Rosenthal, D., Dhillon, G., Raikhelkar, J., Verleden, S., Nijland, M., Agbor-Enoh, S., Andreas, M., Kfoury, A., Ross, H., Zaffiri, L., Natkunam, Y., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022

  View details for DOI 10.1182/blood-2022-158647

  View details for Web of Science ID 000893223200073

• Distinct Molecular Subtypes of Classic Hodgkin Lymphoma Identified By Comprehensive Noninvasive Profiling Alig, S. K., Esfahani, M., Li, M. Y., Adams, R., Garofalo, A., Jin, M. C., Olsen, M., Telenius, A., Sworder, B., Schroers-Martin, J., King, D. A., Rossi, C., Schultz, A., Kathuria, K. R., Liu, C., Spina, V., Buedts, L., Flerlage, J. E., Castellino, S. M., Advani, R. H., Rossi, D., Lynch, R. C., Casasnovas, O., Kurtz, D. M., Marks, L. J., Link, M. P., Andre, M., Vandenberghe, P., Steidl, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1295-1296

  View details for DOI 10.1182/blood-2022-164744

  View details for Web of Science ID 000893223201127

• A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL. Blood advances Cherng, H. J., Alig, S., Oki, Y., Nastoupil, L. J., Fayad, L. E., Neelapu, S. S., Turturro, F., Hagemeister, F. B., Craig, A., Macaulay, C., Rodriguez, M. A., Lee, H. J., McDonnell, T., Flowers, C. R., Vega, F., Green, M. R., Feng, L., Kurtz, D. M., Alizadeh, A. A., Davis, R. E., Westin, J. R. 2022

  Abstract

  Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy (R-CHOP), but a third of patients experience refractory or relapsed disease after frontline R-CHOP. Randomized studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) to R-CHOP have not resulted in improved outcomes, but the combination of L and O may enhance NK-cell mediated antibody dependent cellular toxicity when paired with CHOP. Here, we report on long term outcomes of a phase Ib/II study (NCT02529852) where 53 patients with newly diagnosed DLBCL received 6 cycles of LO-CHOP. End of treatment overall and complete response rates in the 50 evaluable patients were 98% and 90%, respectively. After a median follow up of 4.5 years, 4-year progression free and overall survival rates were 87.4% and 91.3%. Grade 3-4 adverse events were experienced by 70% of patients and included neutropenia (38%), thrombocytopenia (17%), fatigue (13%), neutropenic fever (13%), and infection (9%). Of 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pre-treatment ctDNA with CAPP-Seq, 24/31 (77%) were classifiable by LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using PhasED-Seq, 16/18 evaluable patients (89%) had no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA by end of therapy. This trial is registered at www.clinicaltrials.gov as NCT02529852.

  View details for DOI 10.1182/bloodadvances.2022008174

  View details for PubMedID 36375046

• Inferring gene expression from cell-free DNA fragmentation profiles. Nature biotechnology Esfahani, M. S., Hamilton, E. G., Mehrmohamadi, M., Nabet, B. Y., Alig, S. K., King, D. A., Steen, C. B., Macaulay, C. W., Schultz, A., Nesselbush, M. C., Soo, J., Schroers-Martin, J. G., Chen, B., Binkley, M. S., Stehr, H., Chabon, J. J., Sworder, B. J., Hui, A. B., Frank, M. J., Moding, E. J., Liu, C. L., Newman, A. M., Isbell, J. M., Rudin, C. M., Li, B. T., Kurtz, D. M., Diehn, M., Alizadeh, A. A. 2022

  Abstract

  Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.

  View details for DOI 10.1038/s41587-022-01222-4

  View details for PubMedID 35361996

• The many facets of liquid biopsies in lymphoma. Blood Kurtz, D. M. 2022; 139 (12): 1780-1781

  View details for DOI 10.1182/blood.2021015022

  View details for PubMedID 35323879

• CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Pre-Established Immunity. Blood cancer discovery Shree, T., Shankar, V., Lohmeyer, J. J., Czerwinski, D. K., Schroers-Martin, J. G., Rodriguez, G. M., Beygi, S., Kanegai, A. M., Corbelli, K. S., Gabriel, E., Kurtz, D. M., Khodadoust, M. S., Gupta, N. K., Maeda, L. S., Advani, R. H., Alizadeh, A. A., Levy, R. 2022

  Abstract

  To obtain a deeper understanding of poor responses to COVID-19 vaccination in lymphoma patients, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies post-vaccination, compared to 100% of controls. Evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.

  View details for DOI 10.1158/2643-3230.BCD-21-0222

  View details for PubMedID 35015688

• Circulating Tumor DNA in Lymphoma: Principles and Future Directions. Blood cancer discovery Roschewski, M., Rossi, D., Kurtz, D. M., Alizadeh, A. A., Wilson, W. H. 1800; 3 (1): 5-15

  Abstract

  Lymphomas are heterogeneous tumors with striking genetic diversity and variable outcomes even within pathologic diagnoses. Treatment response assessment relies on radiologic and nuclear scans, which cannot detect disease at the molecular level. Molecular tumor analyses require invasive tissue biopsies that cannot accurately capture spatial tumor heterogeneity within each patient. Circulating tumor DNA (ctDNA) is a minimally invasive and highly versatile biomarker that overcomes fundamental limitations of imaging scans and tissue biopsies and may aid clinical decision-making in lymphoma. In this review, we highlight the key established principles regarding ctDNA in lymphoma and emphasize the important research questions and future directions. SIGNIFICANCE: ctDNA is an emerging biomarker for lymphomas that noninvasively provides genotypic information and can measure the effectiveness of treatment by detecting the presence of minimal residual disease. Key principles have emerged related to ctDNA for lymphoma, but further studies are needed to standardize its use and establish clinical utility.

  View details for DOI 10.1158/2643-3230.BCD-21-0029

  View details for PubMedID 35015693

• Time Since Last Anti-CD20 Treatment Is a Major Determinant of Sars-Cov-2 Vaccine Response in a Large Cohort of Patients with B-Cell Lymphoma Shree, T., Shankar, V., Czerwinski, D. K., Rodriguez, G., Beygi, S., Schroers-Martin, J. G., Advani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Kurtz, D. M., Corbelli, K. S., Gabriel, E., Kanegai, A. M., Alizadeh, A. A., Levy, R. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153901

  View details for Web of Science ID 000736413900065

• Phase 2 Study of Acalabrutinib Window Prior to Frontline Therapy in Untreated Aggressive B-Cell Lymphoma: Preliminary Results and Correlatives of Response to Acalabrutinib Roschewski, M., Phelan, J. D., Pittaluga, S., Melani, C., Lakhotia, R., Chabon, J. J., Muppidi, J. R., Lurain, K. A., Simard, J., Pradhan, A., Hillsman, A., Rilko, M., Steinberg, S. M., Wright, G. W., Huang, D., Yang, Y., Lionakis, M. S., Bagaev, A., Postovalova, E., Meerson, M., Kudryashova, O., Kotlov, N., Fowler, N. H., Kurtz, D. M., Alizadeh, A. A., Jaffe, E. S., Staudt, L. M., Wilson, W. H. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-145228

  View details for Web of Science ID 000736398802066

• Noninvasive Cell-of-Origin Classification of Diffuse Large B-Cell Lymphoma Using Inferred Gene Expression from Cell-Free DNA Sequencing Esfahani, M., Alig, S., Mehrmohamadi, M., Hamilton, E. G., King, D. A., Schultz, A., Steen, C. B., Macaulay, C., Sworder, B., Kurtz, D. M., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-150964

  View details for Web of Science ID 000736398800037

• A comprehensive circulating tumor DNA assay for detection of translocation and copy number changes in pediatric sarcomas. Molecular cancer therapeutics Shah, A. T., Azad, T. D., Breese, M. R., Chabon, J. J., Hamilton, E. G., Straessler, K., Kurtz, D. M., Leung, S. G., Spillinger, A., Liu, H., Behroozfard, I. H., Wittber, F. M., Hazard, F. K., Cho, S., Daldrup-Link, H. E., Vo, K. T., Rangaswami, A., Pribnow, A., Spunt, S. L., Lacayo, N. J., Diehn, M., Alizadeh, A. A., Sweet-Cordero, E. A. 2021

  Abstract

  Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy number changes. We applied CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy number alterations. We analyzed 64 prospectively collected plasma samples from 17 pediatric sarcoma patients. Translocations were detected in the pre-treatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy number changes in the pre-treatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and copy number alterations in the plasma of pediatric sarcoma patients. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

  View details for DOI 10.1158/1535-7163.MCT-20-0987

  View details for PubMedID 34353895

• Phased variants improve DLBCL minimal residual disease detection at the end of therapy. Kurtz, D., Chabon, J. J., Soo, J., Keh, L., Alig, S., Schultz, A., Jin, M. C., Scherer, F., Craig, A. M., Liu, C., Duehrsen, U., Huettmann, A., Casasnovas, R., Westin, J., Roschewski, M. J., Wilson, W., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.7565

  View details for Web of Science ID 000708120604161

• Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600087

• Short Diagnosis-to-Treatment Interval Is Associated With Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Alig, S. n., Macaulay, C. W., Kurtz, D. M., Dührsen, U. n., Hüttmann, A. n., Schmitz, C. n., Jin, M. C., Sworder, B. J., Garofalo, A. n., Shahrokh Esfahani, M. n., Nabet, B. Y., Soo, J. n., Scherer, F. n., Craig, A. F., Casasnovas, O. n., Westin, J. R., Gaidano, G. n., Rossi, D. n., Roschewski, M. n., Wilson, W. H., Meignan, M. n., Diehn, M. n., Alizadeh, A. A. 2021: JCO2002573

  Abstract

  Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias.We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome.Short DTI was associated with advanced-stage disease (P < .001) and higher IPI (P < .001). We also found an inverse correlation between DTI and TMTV (RS= -0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels (P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI (P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2]).Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.

  View details for DOI 10.1200/JCO.20.02573

  View details for PubMedID 33909455

• Bringing circulating tumor DNA to the clinic in Hodgkin lymphoma. Haematologica Kurtz, D. M. 2021; 106 (1): 5–6

  View details for DOI 10.3324/haematol.2020.265165

  View details for PubMedID 33386712

• Liquid biopsy in lymphoma: Molecular methods and clinical applications. Cancer treatment reviews Cirillo, M., Craig, A. F., Borchmann, S., Kurtz, D. M. 2020; 91: 102106

  Abstract

  In this article, we broadly review the application of cfDNA analysis to the diagnosis and management of lymphoma. We introduce the advantages of cfDNA measurement over conventional tissue biopsy and describe how cfDNA may be utilized for both genotyping and detection of minimal residual disease. First, we discuss genotyping, beginning with differences in identifying mutations from the blood plasma vs. from circulating cells. We review the technical distinctions between PCR- and NGS-based assays and describe two important applications of NGS-based cfDNA tests, namely the identification of resistance mutations and classification of disease subtype. We discuss difficulties in genotyping diseases with low burden of tumor cells and the application of cfDNA assays in these contexts. Second, we describe the utility of ctDNA measurement in assessing MRD. We cover recent advances in the assessment of pre-treatment disease burden as a prognostic biomarker, detection of molecular response to therapy, and early detection of relapsing disease. Third, we explore select emerging areas of research in ctDNA technologies that show promise in boosting the performance of existing ctDNA-based assays. These include cell-free DNA fragment structure analysis or 'fragmentomics', epigenetic modifications, and novel circulating analytes such as tumor-educated platelets and extracellular vesicular DNA. We also discuss alternative analytes to blood plasma for tumor detection, such as urine, saliva, and stool. Finally, we present a case that highlights potential applications of ctDNA approaches to the management of patients with lymphoma, while also defining important prerequisite advances before this can be fully realized. We close with a look to the future of cfDNA applications, outlining one potential timeline and path forward towards routine clinical application.

  View details for DOI 10.1016/j.ctrv.2020.102106

  View details for PubMedID 33049623

• Chromatin accessibility patterns in cell-free DNA reveal tumor heterogeneity Esfahani, M., Mehrmohamadi, M., Steen, C. B., Hamilton, E. G., King, D. A., Soo, J., Macaulay, C., Jin, M., Kurtz, D. M., Nabet, B., Moding, E., Chabon, J., Newman, A., Diehn, M., Alizadeh, A. A. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-3388

  View details for Web of Science ID 000590059301076

• ctDNA shedding dynamics dictate early lung cancer detection potential Avanzini, S., Kurtz, D. M., Chabon, J. J., Hori, S. S., Alizadeh, A. A., Diehn, M., Reiter, J. G. AMER ASSOC CANCER RESEARCH. 2020: 25

  View details for Web of Science ID 000537848000023

• KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D. S., Yoo, C., Kurtz, D., Owen, S., Backhus, L., Berry, M. F., Shrager, J. B., Ramchandran, K., Padda, S., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303348

• Integrating genomic features for non-invasive early lung cancer detection NATURE Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y., Nesselbush, M. C., Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020

  View details for DOI 10.1038/s41586-020-2140-0

  View details for Web of Science ID 000521531000011

• KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

  Abstract

  Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

  View details for DOI 10.1158/2159-8290.CD-20-0282

  View details for PubMedID 33071215

• Prognostication with circulating tumor DNA: is it ready for prime time? Kurtz, D. M. AMER SOC HEMATOLOGY. 2019: 47–52

  View details for Web of Science ID 000538564000007

• Changes in circulating tumor DNA levels are associated with treatment response and progression-free survival in relapse/refractory DLBCL subjects. Lovejoy, A. F., Lin, H., Tabari, E., Saelee, S., Kurtz, D., Vitazka, P., Morschhauser, F., Chu, Y., Szafer-Glusman, E., Venstrom, J., Luong, K., Klass, D. M. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806308

• Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

  View details for PubMedID 30753108

• Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer. Gastroenterology Azad, T. D., Chaudhuri, A. A., Fang, P. n., Qiao, Y. n., Esfahani, M. S., Chabon, J. J., Hamilton, E. G., Yang, Y. D., Lovejoy, A. n., Newman, A. M., Kurtz, D. M., Jin, M. n., Schroers-Martin, J. n., Stehr, H. n., Liu, C. L., Bik-Yu Hui, A. n., Patel, V. n., Maru, D. n., Lin, S. H., Alizadeh, A. A., Diehn, M. n. 2019

  Abstract

  Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy.We performed deep sequencing (CAPP-Seq) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes, and fixed esophageal tumor biopsies collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy individuals (controls). We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6-8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) following chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy).The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA following chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P<.0001), formation of distant metastases (hazard ratio, 32.1; P<.0001), and shorter disease-specific survival times (hazard ratio, 23.1; P<.0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P=.03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P<.001 for comparison of either technique to combined analysis).In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

  View details for DOI 10.1053/j.gastro.2019.10.039

  View details for PubMedID 31711920

• The Development of Liquid Biopsy for Research and Clinical Practice in Lymphomas: Report of the 15-ICML Workshop on ctDNA. Hematological oncology Rossi, D. n., Kurtz, D. M., Roschewski, M. n., Cavalli, F. n., Zucca, E. n., Wilson, W. H. 2019

  Abstract

  This report summarizes a closed workshop co-sponsored by the American Association for Cancer Research, the European School of Oncology and the 15th-International Conference on Malignant Lymphoma to discuss critical open questions on liquid biopsy in lymphoid malignancies, develops a roadmap for their analytical and clinical validation, and prioritizes research areas. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/hon.2704

  View details for PubMedID 31872890

• Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing Schroers-Martin, J. G., Garofalo, A., Soo, J., Jin, M. C., Kurtz, D. M., Buedts, L., Duehrsen, U., Huettmann, A., Cottereau, A., Meignan, M., Casasnovas, O., Westin, J. R., Gaidano, G., Rossi, D., Roschewski, M., Wilson, W. H., Advani, R. H., Vandenberghe, P., Diehn, M., Khush, K., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119905

  View details for Web of Science ID 000454842800062

• Distinct Chromatin Accessibility Profiles of Lymphoma Subtypes Revealed By Targeted Cell Free DNA Profiling Mehrmohamadi, M., Esfahani, M. S., Soo, J., Scherer, F., Schroers-Martin, J. G., Chen, B., Kurtz, D. M., Hamilton, E., Liu, C., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119361

  View details for Web of Science ID 000454837602050

• Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma Jin, M. C., Schroers-Martin, J. G., Kurtz, D. M., Buedts, L., Esfahani, M. S., Macaulay, C., Sworder, B., Soo, J., Glover, C., Roschewski, M., Wilson, W. H., Duhrsen, U., Huettmann, A., Rossi, D., Gaidano, G., Westin, J. R., Maeda, L. S., Advani, R. H., Vandenberghe, P., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119140

  View details for Web of Science ID 000454842800039

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• High-throughput sequencing for noninvasive disease detection in hematologic malignancies. Blood Scherer, F. n., Kurtz, D. M., Diehn, M. n., Alizadeh, A. A. 2017; 130 (4): 440–52

  Abstract

  Noninvasive monitoring of minimal residual disease (MRD) has led to significant advances in personalized management of patients with hematologic malignancies. Improved therapeutic options and prolonged survival have further increased the need for sensitive tumor assessment that can inform treatment decisions and patient outcomes. At diagnosis or relapse of most hematologic neoplasms, malignant cells are often easily accessible in the blood as circulating tumor cells (CTCs), making them ideal targets to noninvasively profile the molecular features of each patient. In other cancer types, CTCs are generally rare and noninvasive molecular detection relies on circulating tumor DNA (ctDNA) shed from tumor deposits into circulation. The ability to precisely detect and quantify CTCs and ctDNA could minimize invasive procedures and improve prediction of clinical outcomes. Technical advances in MRD detection methods in recent years have led to reduced costs and increased sensitivity, specificity, and applicability. Among currently available tests, high-throughput sequencing (HTS)-based approaches are increasingly attractive for noninvasive molecular testing. HTS-based methods can simultaneously identify multiple genetic markers with high sensitivity and specificity without individual optimization. In this review, we present an overview of techniques used for noninvasive molecular disease detection in selected myeloid and lymphoid neoplasms, with a focus on the current and future role of HTS-based assays.

  View details for PubMedID 28600337

  View details for PubMedCentralID PMC5881609

• Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 2016; 113 (52): E8379-E8386

  Abstract

  Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

  View details for DOI 10.1073/pnas.1608461113

  View details for PubMedID 27956614

• Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7

  Abstract

  Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

  View details for DOI 10.1038/ncomms11815

  View details for PubMedID 27283993

• Organocatalytic removal of formaldehyde adducts from RNA and DNA bases NATURE CHEMISTRY Karmakar, S., Harcourt, E. M., Hewings, D. S., Lovejoy, A. F., Kurtz, D. M., Ehrenschwender, T., Barandun, L. J., Roost, C., Alizadeh, A. A., Kool, E. T. 2015; 7 (9): 752-758

  Abstract

  Formaldehyde is universally used to fix tissue specimens, where it forms hemiaminal and aminal adducts with biomolecules, hindering the ability to retrieve molecular information. Common methods for removing these adducts involve extended heating, which can cause extensive degradation of nucleic acids, particularly RNA. Here, we show that water-soluble bifunctional catalysts (anthranilates and phosphanilates) speed the reversal of formaldehyde adducts of mononucleotides over standard buffers. Studies with formaldehyde-treated RNA oligonucleotides show that the catalysts enhance adduct removal, restoring unmodified RNA at 37 °C even when extensively modified, while avoiding the high temperatures that promote RNA degradation. Experiments with formalin-fixed, paraffin-embedded cell samples show that the catalysis is compatible with common RNA extraction protocols, with detectable RNA yields increased by 1.5-2.4-fold using a catalyst under optimized conditions and by 7-25-fold compared with a commercial kit. Such catalytic strategies show promise for general use in reversing formaldehyde adducts in clinical specimens.

  View details for DOI 10.1038/NCHEM.2307

  View details for Web of Science ID 000360191800014

  View details for PubMedCentralID PMC4545578

• Organocatalytic removal of formaldehyde adducts from RNA and DNA bases. Nature chemistry Karmakar, S., Harcourt, E. M., Hewings, D. S., Scherer, F., Lovejoy, A. F., Kurtz, D. M., Ehrenschwender, T., Barandun, L. J., Roost, C., Alizadeh, A. A., Kool, E. T. 2015; 7 (9): 752-758

  Abstract

  Formaldehyde is universally used to fix tissue specimens, where it forms hemiaminal and aminal adducts with biomolecules, hindering the ability to retrieve molecular information. Common methods for removing these adducts involve extended heating, which can cause extensive degradation of nucleic acids, particularly RNA. Here, we show that water-soluble bifunctional catalysts (anthranilates and phosphanilates) speed the reversal of formaldehyde adducts of mononucleotides over standard buffers. Studies with formaldehyde-treated RNA oligonucleotides show that the catalysts enhance adduct removal, restoring unmodified RNA at 37 °C even when extensively modified, while avoiding the high temperatures that promote RNA degradation. Experiments with formalin-fixed, paraffin-embedded cell samples show that the catalysis is compatible with common RNA extraction protocols, with detectable RNA yields increased by 1.5-2.4-fold using a catalyst under optimized conditions and by 7-25-fold compared with a commercial kit. Such catalytic strategies show promise for general use in reversing formaldehyde adducts in clinical specimens.

  View details for DOI 10.1038/nchem.2307

  View details for PubMedID 26291948

• Next-generation surveillance strategies for patients with lymphoma. Future oncology Cohen, J. B., Kurtz, D. M., Staton, A. D., Flowers, C. R. 2015; 11 (13): 1977-1991

  Abstract

  While remission and cure rates for Hodgkin and non-Hodgkin lymphoma continue to improve, surveillance approaches remain controversial, especially in light of recent reports suggesting limited benefit for routine radiologic assessment. Routine cross-sectional imaging results in considerable patient expense and anxiety, and this approach does not clearly improve patient outcomes. Next-generation approaches including minimal residual disease detection may provide an opportunity to identify relapse early and intervene prior to progression of clinical disease. This review discusses the role of surveillance imaging in Hodgkin and non-Hodgkin lymphoma and provides an introduction to serologic assessment of minimal residual disease. Future studies will need to focus on the clinical application of minimal residual disease surveillance and its ability to predict relapse, treatment response and survival.

  View details for DOI 10.2217/fon.15.92

  View details for PubMedID 26161931

  View details for PubMedCentralID PMC4519355

• Tracking Cellular and Immune Therapies in Cancer EMERGING APPLICATIONS OF MOLECULAR IMAGING TO ONCOLOGY Kurtz, D. M., Gambhir, S. S. 2014; 124: 257-296

  Abstract

  The field of tumor immunology has seen an explosion of renewed interest over the last decade. With the FDA approval of new immunotherapies for prostate cancer and melanoma, as well as several exciting new drugs in clinical trials, tumor immunology is becoming an increasingly important topic in preclinical studies and patient care. However, the current methods for assessing the immune status of a patient and tumor are limited, which has led to the development of novel molecular imaging methods for assessing tumor immunology. From cell tracking for cellular therapeutics to assessing the tumor immune microenvironment, these imaging methods have the potential to further preclinical understanding of immunotherapies and potentially translate into clinically useful tests to predict and assess therapeutic response of these exciting new agents. In this review, we first discuss the recent advances in cancer immunotherapy, followed by a detailed review of the current state of molecular imaging for tumor immunology. Finally, we discuss opportunities for further development and innovation in this rapidly growing field.

  View details for DOI 10.1016/B978-0-12-411638-2.00008-2

  View details for Web of Science ID 000344511500008

• Tracking cellular and immune therapies in cancer. Advances in cancer research Kurtz, D. M., Gambhir, S. S. 2014; 124: 257-296

  Abstract

  The field of tumor immunology has seen an explosion of renewed interest over the last decade. With the FDA approval of new immunotherapies for prostate cancer and melanoma, as well as several exciting new drugs in clinical trials, tumor immunology is becoming an increasingly important topic in preclinical studies and patient care. However, the current methods for assessing the immune status of a patient and tumor are limited, which has led to the development of novel molecular imaging methods for assessing tumor immunology. From cell tracking for cellular therapeutics to assessing the tumor immune microenvironment, these imaging methods have the potential to further preclinical understanding of immunotherapies and potentially translate into clinically useful tests to predict and assess therapeutic response of these exciting new agents. In this review, we first discuss the recent advances in cancer immunotherapy, followed by a detailed review of the current state of molecular imaging for tumor immunology. Finally, we discuss opportunities for further development and innovation in this rapidly growing field.

  View details for DOI 10.1016/B978-0-12-411638-2.00008-2

  View details for PubMedID 25287692