![Joseph Schroers-Martin](https://profiles.stanford.edu/proxy/api/cap/profiles/181963/resources/profilephoto/350x350.1582250291564.jpg)
Joseph Schroers-Martin
Assistant Professor of Medicine (Oncology)
Medicine - Oncology
Bio
I am an assistant professor in medical oncology in the lymphoma group at Stanford. After a career in software development, I pursued training first in computational genomics and then in clinical hematology & oncology. My primary clinical interest is the detection, treatment, and surveillance of lymphomas. As a faculty member in the lymphoma group, I treat all lymphoma subtypes with a special emphasis on Hodgkin lymphoma and follicular lymphoma.
Clinical Focus
- Medical Oncology
Honors & Awards
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2017 Cancer Fellow, Stanford Cancer Institute (2017)
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Abstract Achievement Award, American Society of Hematology (2018)
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ACP Award for Excellence in Internal Medicine, University of Hawaii John A. Burns School of Medicine (2015)
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Alpha Omega Alpha, University of Hawaii John A. Burns School of Medicine (2014)
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Gold Humanism Honor Society, University of Hawaii John A. Burns School of Medicine (2013)
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Merit Achievement Scholarship, University of Hawaii John A. Burns School of Medicine (2012)
Professional Education
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Board Certification: American Board of Internal Medicine, Medical Oncology (2022)
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Fellowship: Stanford University Hematology and Oncology Fellowship (2022) CA
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Board Certification: American Board of Internal Medicine, Internal Medicine (2020)
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Residency: Stanford University Internal Medicine Residency (2017) CA
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Medical Education: University of Hawaii at Manoa John A Burns School of Medicine (2015) HI
Current Research and Scholarly Interests
I am an assistant professor in medical oncology in the lymphoma group at Stanford. After a career in software development, I pursued training first in computational genomics and then in clinical hematology & oncology. My primary clinical interest is the detection, treatment, and surveillance of lymphomas. As a faculty member in the lymphoma group, I treat all lymphoma subtypes with a special emphasis on Hodgkin lymphoma and follicular lymphoma.
Graduate and Fellowship Programs
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Hematology (Fellowship Program)
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Oncology (Fellowship Program)
All Publications
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Cell-Free DNA in Hematologic Malignancies.
JCO oncology practice
2024; 20 (11): 1491-1499
Abstract
Liquid biopsy techniques using cell-free DNA (cfDNA) play an increasingly important role in the characterization and surveillance of solid tumors. For blood cancers, molecular response assessment techniques using circulating malignant cells or bone marrow aspirates are well established in clinical care. However, cfDNA has an emerging role in hematology as well, with the opportunity for disease assessment and quantification independent of circulating disease burden or invasive biopsies. In this review, we discuss key technologies and clinical data for the utilization of cfDNA in lymphomas, myeloma, and leukemias.
View details for DOI 10.1200/OP-24-00648
View details for PubMedID 39531844
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Integrating Novel Agents Into the Clinical Management of Classic Hodgkin Lymphoma.
JCO oncology practice
2024: OP2400277
Abstract
Classic Hodgkin lymphoma (cHL) is highly curable at all stages. Research efforts over the past few decades have largely focused on interim PET-adapted strategies for therapy de-escalation or intensification. The overarching goals have been to increase cure rates, minimize potential therapy-related effects, and optimize survivorship. Better understanding of the biology of cHL has led to the development and approval of effective novel agents including the antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitor immunotherapies. In this review, we discuss recent trial results and how these agents are integrated into clinical practice with the goal of further optimizing outcomes.
View details for DOI 10.1200/OP.24.00277
View details for PubMedID 39265129
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The role of response adapted therapy in the era of novel agents.
Seminars in hematology
2024
Abstract
The optimal treatment of classic Hodgkin Lymphoma (cHL) requires an individualized approach, with therapy guided by pretreatment clinical risk stratification and interim response assessment with positron emission tomography (PET). The overall goal is to achieve high cure rates while minimizing acute toxicity and late therapy-related effects. Interim PET-adapted strategies (iPET) were initially developed with traditional chemotherapy, reducing intensity after interim complete response and escalating treatment for patients with iPET+ disease. Recently, novel agents including brentuximab vedotin and the checkpoint inhibitor immunotherapies (CPIs) pembrolizumab and nivolumab have been adopted into the front-line treatment of cHL, and PET-adapted approaches may be relevant for these drugs as well. In this review we discuss response-adapted strategies utilizing novel agents, consider challenges including indeterminate radiographic findings with CPIs, and address emerging techniques for response assessment including new PET-based imaging metrics and the role of circulating tumor DNA.
View details for DOI 10.1053/j.seminhematol.2024.06.002
View details for PubMedID 39004520
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ULTRASENSITIVE URINARY LIQUID BIOPSY ANALYSIS FOR BCG RESPONSE ASSESSMENT IN HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER
LIPPINCOTT WILLIAMS & WILKINS. 2024: E1169
View details for Web of Science ID 001263885304019
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Long-term outcome of peripheral T-cell lymphomas: Ten-year follow-up of the International Prospective T-cell Project.
British journal of haematology
2024
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of haematological cancers with generally poor clinical outcomes. However, a subset of patients experience durable disease control, and little is known regarding long-term outcomes. The International T-cell Lymphoma Project (ITCLP) is the largest prospectively collected cohort of patients with PTCLs, providing insight into clinical outcomes at academic medical centres globally. We performed a long-term outcome analysis on patients from the ITCLP with available 10-year follow-up data (n = 735). The overall response rate to first-line therapy was 68%, while 5- and 10-year overall survival estimates were 49% and 40% respectively. Most deaths occurred prior to 5 years, and for patients alive at 5 years, the chance of surviving to 10 years was 84%. However, lymphoma remained the leading cause of death in the 5- to 10-year period (67%). Low-risk International Prognostic Index and Prognostic Index for T-cell lymphoma scores both identified patients with improved survival, while in multivariate analysis, age >60 years and Eastern Cooperative Oncology Group performance status 2-4 were associated with inferior outcomes. The favourable survival seen in patients achieving durable initial disease control emphasizes the unmet need for optimal front-line therapeutic approaches in PTCLs.
View details for DOI 10.1111/bjh.19433
View details for PubMedID 38532575
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CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity.
Blood advances
2024
Abstract
Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.
View details for DOI 10.1182/bloodadvances.2024012637
View details for PubMedID 38498731
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A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment.
Cell stem cell
2024
Abstract
Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.
View details for DOI 10.1016/j.stem.2024.01.012
View details for PubMedID 38402619
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Specificity of Immunoglobulin High-Throughput Sequencing Minimal Residual Disease Monitoring in Non-Hodgkin Lymphomas.
Blood advances
2023
View details for DOI 10.1182/bloodadvances.2023011997
View details for PubMedID 38147627
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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.
Nature
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
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CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-182522
View details for Web of Science ID 001159306701117
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Longitudinal Noninvasive Surveillance & Fragmentomic Characterization of Follicular Lymphoma
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-187116
View details for Web of Science ID 001159306702041
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Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-178257
View details for Web of Science ID 001159740307115
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Inferred Gene Expression By Cell-Free DNA Profiling Allows Noninvasive Lymphoma Classification
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-186853
View details for Web of Science ID 001159306701002
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An Integrated Multimodal Framework for Noninvasive TCL Disease Detection and Monitoring
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-180492
View details for Web of Science ID 001159306706091
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Genomic, Transcriptional, and Immunological Validation of Distinct Molecular Subtypes of Classic Hodgkin Lymphoma through Tissue-Based and Noninvasive Methods
AMER SOC HEMATOLOGY. 2023
View details for DOI 10.1182/blood-2023-186810
View details for Web of Science ID 001159306700178
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Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors.
Cancer discovery
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
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Investigating and modeling positron emission tomography factors associated with large cell transformation from low-grade lymphomas.
EJHaem
2023; 4 (1): 90-99
Abstract
Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma.
View details for DOI 10.1002/jha2.615
View details for PubMedID 36819184
View details for PubMedCentralID PMC9928791
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Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
Cancer cell
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
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Specificity & Precision of Minimal Residual Disease Monitoring in DLBCL Using Ig-HTS
AMER SOC HEMATOLOGY. 2022: 6403-6404
View details for DOI 10.1182/blood-2022-165656
View details for Web of Science ID 000893223206185
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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
AMER SOC HEMATOLOGY. 2022: 8609-8610
View details for DOI 10.1182/blood-2022-170087
View details for Web of Science ID 000893230301297
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Accurate Detection of Clinically Actionable Copy Number Variants in Diverse Hematological Neoplasms By Routine Targeted Sequencing: A Comparative Performance Study
AMER SOC HEMATOLOGY. 2022: 10712-10713
View details for DOI 10.1182/blood-2022-167900
View details for Web of Science ID 000893230303319
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Tumor Microenvironment Determinants of Immunotherapy Response Identified By Integrated Host & Viral Analysis of Post-Transplant Lymphoproliferative Disorders
AMER SOC HEMATOLOGY. 2022
View details for DOI 10.1182/blood-2022-158647
View details for Web of Science ID 000893223200073
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Distinct Molecular Subtypes of Classic Hodgkin Lymphoma Identified By Comprehensive Noninvasive Profiling
AMER SOC HEMATOLOGY. 2022: 1295-1296
View details for DOI 10.1182/blood-2022-164744
View details for Web of Science ID 000893223201127
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Viral cfDNA Profiling Reveals Distinct EBV Subtypes and Stratifies Risk in Hodgkin Lymphomas
AMER SOC HEMATOLOGY. 2022: 1318-1319
View details for DOI 10.1182/blood-2022-159230
View details for Web of Science ID 000893223201135
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Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects
AMER SOC HEMATOLOGY. 2022: 7545-7547
View details for DOI 10.1182/blood-2022-165600
View details for Web of Science ID 000893230300247
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Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas
AMER SOC HEMATOLOGY. 2022: 1301-1303
View details for DOI 10.1182/blood-2022-165545
View details for Web of Science ID 000893223201129
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Molecular Monitoring of Lymphomas.
Annual review of pathology
2022
Abstract
Molecular monitoring of tumor-derived alterations has an established role in the surveillance of leukemias, and emerging nucleic acid sequencing technologies are likely to similarly transform the clinical management of lymphomas. Lymphomas are well suited for molecular surveillance due to relatively high cell-free DNA and circulating tumor DNA concentrations, high somatic mutational burden, and the existence of stereotyped variants enabling focused interrogation of recurrently altered regions. Here, we review the clinical scenarios and key technologies applicable for the molecular monitoring of lymphomas, summarizing current evidence in the literature regarding molecular subtyping and classification, evaluation of treatment response, the surveillance of active cellular therapies, and emerging clinical trial strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
View details for DOI 10.1146/annurev-pathol-050520-044652
View details for PubMedID 36130071
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Cellular and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients: An observational cohort study.
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
2022; 153: 105217
Abstract
BACKGROUND: Humoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.METHODS: We performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naive individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.RESULTS: 496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P<0.001), sphingosine 1-phsophate (S1P) receptor modulators (P<0.001), mycophenolate (P=0.002), and B cell lymphoma (P=0.004); those associated with low cellular response rates included S1P receptor modulators (P<0.001) and mycophenolate (P<0.001). Of patients who had poor humoral response to primary vaccination, 35% (18/52) developed a significantly higher response after the booster. Only 5% (2/42) of patients developed a significantly higher cellular response to the booster dose compared to primary vaccination.CONCLUSIONS: Humoral and cellular response rates to primary and booster SARS-CoV-2 vaccination differ among immunosuppressed patient groups. Clinical testing of cellular immunity is important in monitoring vaccine response in vulnerable populations.
View details for DOI 10.1016/j.jcv.2022.105217
View details for PubMedID 35714462
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Inferring gene expression from cell-free DNA fragmentation profiles.
Nature biotechnology
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
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CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Pre-Established Immunity.
Blood cancer discovery
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
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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
AMER SOC HEMATOLOGY. 2021
View details for DOI 10.1182/blood-2021-153901
View details for Web of Science ID 000736413900065
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Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA.
Nature biotechnology
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
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Integrating genomic features for non-invasive early lung cancer detection.
Nature
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
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Integrating genomic features for non-invasive early lung cancer detection
NATURE
2020
View details for DOI 10.1038/s41586-020-2140-0
View details for Web of Science ID 000521531000011
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Deep Sequencing of Viral Cell-Free DNA for Noninvasive Detection of Immunosuppression-Related Lymphoid Malignancies
AMER SOC HEMATOLOGY. 2019
View details for DOI 10.1182/blood-2019-131602
View details for Web of Science ID 000518218500906
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Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA
CANCER DISCOVERY
2019; 9 (4): 500–509
View details for DOI 10.1158/2159-8290.CD-18-0825
View details for Web of Science ID 000462990400024
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Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer.
Gastroenterology
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
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Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing
AMER SOC HEMATOLOGY. 2018
View details for DOI 10.1182/blood-2018-99-119905
View details for Web of Science ID 000454842800062
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Distinct Chromatin Accessibility Profiles of Lymphoma Subtypes Revealed By Targeted Cell Free DNA Profiling
AMER SOC HEMATOLOGY. 2018
View details for DOI 10.1182/blood-2018-99-119361
View details for Web of Science ID 000454837602050
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Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma
AMER SOC HEMATOLOGY. 2018
View details for DOI 10.1182/blood-2018-99-119140
View details for Web of Science ID 000454842800039
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Early detection of post-transplant lymphoproliferative disorder using circulating tumor DNA.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.7572
View details for Web of Science ID 000442916003038
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Post-transplant head and neck cancers: A prospective analysis of clinical factors for risk stratification.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.e18051
View details for Web of Science ID 000442916005614
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Detection and surveillance of bladder cancer using urine tumor DNA.
Cancer discovery
2018
Abstract
Current regimens for the detection and surveillance of bladder cancer (BLCA) are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage BLCA who either had urine collected prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per BLCA patient and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of BLCA. We detected utDNA pre-treatment in 93% of cases using a tumor mutation-informed approach and in 84% when blinded to tumor mutation status, with 96-100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, p=0.02) and cytology and cystoscopy combined (p is less than or equal to 0.006), detecting 100% of BLCA cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of BLCA.
View details for PubMedID 30578357
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Circulating tumor DNA analysis for outcome prediction in localized esophageal cancer.
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.4055
View details for Web of Science ID 000411895708139
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Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma.
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.7507
View details for Web of Science ID 000411931708176