Blood
DLBclass: A Probabilistic Molecular Classifier to Guide Clinical Investigation and Practice in Diffuse Large B-Cell Lymphoma
Chapuy B, Wood T, Stewart C, Dunford A, Wienand K, Khan SJ, Calabretta E, Van Seters S, Wisemann S, Belkin S, Heimann D, Redd R, Shipp MA, Getz G
Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease. The increasing recognition and targeting of genetically defined DLBCLs highlight the need for robust classification algorithms. We previously characterized recurrent genetic alterations in DLBCL and identified 5 discrete subtypes, clusters 1 to 5 (C1-C5), with unique mechanisms of transformation, immune evasion, candidate treatment targets, and different outcomes after standard first-line therapy. Herein, we validate the C1 to C5 DLBCL taxonomy in an independent data set and use the expanded series of 699 primary DLBCLs to develop a probabilistic molecular classifier and confirm its performance in an independent test set. Using our previously assigned cluster labels as a reference, we systematically compared multiple machine learning models and strategies for input feature dimensionality reduction with a newly developed performance metric that captured the relationship between accuracy and confidence of class assignments. The winning neural network model, DLBclass, assigned all cases in the training/validation and independent test sets with 91% and 89% accuracies, respectively. In the 75% of cases with confidence >0.7, DLBclass assignments were accurate in 97% of the training/validation set and 98% of the test set. DLBclass enables robust prospective classification of single cases for inclusion in genetically guided clinical trials or practice and represents a framework for the development of genomics-based classification methods in other cancers
|
Blood
Donor Regulatory/Conventional T-Cell Grafts for the GVHD Win?
Koreth J
In this issue of Blood, Meyer et al report the promising outcomes of a phase 2 trial of 7 to 8 of 8 HLA-matched peripheral blood grafts that were manufactured to contain purified CD34+ cells plus T regulatory (Treg) and conventional (Tcon) cells in a ?1:1 ratio. In the 44-patient (33 matched, 11 mismatched) single-center myeloablative transplant study, infusion of >2 × 106 CD34+ cells per kilogram plus 2 to 3 × 106 Treg cells per kilogram on day 0, with a target of 3 × 106 Tcon cells per kilogram on day +2 to 3, followed by limited pharmacologic immune suppression with tacrolimus (Tac) ± short-course mycophenolate mofetil (MMF), resulted in low rates of acute and chronic graft-versus-host disease (GVHD) and low nonrelapse mortality (NRM), with promising GVHD and relapse-free survival (GRFS) compared with a contemporaneous cohort receiving calcineurin inhibitor (CNI) and methotrexate (MTX) prophylaxis.
|
Blood
How I Treat AML Relapse After Allogeneic HSCT
Gooptu M, Murdock HM, Soiffer RJ
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse after transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last 3 decades despite an evolving understanding of the immunobiology of the graft-versus-leukemia effect and the immune escape mechanisms that lead to post-HSCT relapse. The approach to posttransplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of 3 illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and nontargeted chemotherapeutic agents, and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse, including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse after transplantation.
|
Cancer Cell
A Circular RNA in Neuroendocrine Carcinomas
Li Y, Oser MG
In this issue of Cancer Cell, Teng et al. discover that small cell lung cancer and neuroendocrine prostate cancer highly express a circular RNA known as circRMST. They show that circRMST is necessary for these neuroendocrine cancers to promote their ASCL1-positive neuroendocrine phenotype through binding lineage transcription factors that promote ASCL1 expression.
|
Cancer Cell
Easing Cisplatin's Toll in Nasopharyngeal Carcinoma
Dennis MJ, Uppaluri R
Anti-PD-1 immune checkpoint inhibitors improve outcomes in relapsed/metastatic nasopharyngeal carcinoma (NPC). In this issue of Cancer Cell, Xu et al. achieved favorable outcomes by incorporating nivolumab into standard therapy for locally advanced NPC while removing chemotherapy from the radiation phase. This regimen offers a promising approach to reducing treatment-related toxicities
|
Cell
Unlocking LAG3: Ubiquitin’s Unexpected Role
Zhao Y, Wucherpfennig KW
The inhibitory receptor LAG3 is the target of the FDA-approved mAb relatlimab, but its mechanism of signaling is not well understood. In this issue of Cell, Jiang et al. demonstrate that ubiquitination of its cytoplasmic domain is essential for the inhibitory function of LAG3. Co-expression of LAG3 and the CBL E3 ligases represents a biomarker of clinical response to LAG3 inhibition in human melanoma.
|
JAMA
Atezolizumab in High-Risk Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial
Haddad R
IMPORTANCE: Treating locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) involves any combination of surgery, radiation, and chemotherapy, followed by routine monitoring for local recurrence or distant metastases. Given the poor patient outcomes, a significant unmet clinical need for improved treatment options remains.
OBJECTIVE: To evaluate efficacy and safety of maintenance atezolizumab in patients with LA SCCHN at high risk of disease progression after multimodal definitive treatment.
DESIGN, SETTING, AND PARTICIPANTS: IMvoke010 was a phase 3, global, double-blind, randomized clinical trial. Patients were recruited at 128 sites in 23 countries between April 3, 2018, and February 14, 2020 (clinical cutoff date: September 27, 2023). Eligible patients had LA SCCHN (stage IVa/IVb involving the oral cavity, larynx, hypopharynx, or human papillomavirus-negative oropharynx, or stage III human papillomavirus-positive oropharynx [AJCC Cancer Staging Manual, eighth edition]) without disease progression after multimodal definitive treatment.
INTERVENTION: Patients were randomized (1:1) to receive atezolizumab 1200 mg or placebo every 3 weeks for 1 year or until disease recurrence, disease progression, unacceptable toxicity, or consent withdrawal.
MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed event-free survival. Other end points included overall survival and safety.
RESULTS: Overall, 406 patients were randomized to receive atezolizumab (n?=?203) or placebo (n?=?203); baseline demographics were balanced between both treatment groups (<65 years, 142 [70.0%] vs 155 [76.4%]; male, 168 [82.8%] vs 174 [85.7%]; Asian, 68 [35.6%] vs 61 [31.0%]; Black, 1 [0.5%] vs 1 [0.5%]; and White, 121 [63.4%] vs 135 [68.5%], respectively). At clinical cutoff (median follow-up, 46.5 months), median investigator-assessed event-free survival was 59.5 months (95% CI, 46.8 to not estimable) with atezolizumab vs 52.7 months (95% CI, 41.4 to not estimable) with placebo (hazard ratio, 0.94; 95% CI, 0.70-1.26; P?=?.68). There was no difference in overall survival between atezolizumab and placebo (24-month overall survival, 82.0% vs 79.2%, respectively). No new or unexpected safety signals were identified.
CONCLUSIONS AND RELEVANCE: In this study, atezolizumab did not improve clinical outcomes in patients with LA SCCHN at high risk of disease progression after multimodal definitive treatment. These data contribute to evidence on the limited activity of checkpoint inhibitors in the global population of this disease setting. Overall, the role of immunotherapy for patients with LA SCCHN remains to be determined.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03452137.
|
JAMA
Bridging Medicine and Society – A Call to Expand the Pipeline of Physician-Social Scientists
Walensky LD, Mather RV, Meng EX
Health care crises, whether sparked by natural disaster or human action, have underscored the urgent need for leaders who can navigate the social dimensions of modern medicine. From inequities in delivery to barriers in public trust, today’s health care challenges require more than medical or scientific expertise – they demand a deeper understanding of societal forces to achieve transformative interventions. Physician-scientists trained in the social sciences and humanities (SSH) are positioned to tackle these issues, combining clinical insight with unique perspectives from a broad range of disciplines, including health policy, economics, anthropology, history, epidemiology, and bioethics. Despite their critical contributions – from founding nongovernmental organizations to leading national and international institutions – SSH physician-scientists remain a minority in the physician-scientist workforce. Traditional training pathways and funding mechanisms have prioritized basic and translational science, leaving SSH MD-PhD students to navigate fewer training sites, limited funding opportunities, and numerous logistical barriers. Expanding the pipeline of SSH physician-scientists is essential to meeting the growing demand for leaders who can fully integrate medicine and society.
|
JAMA
The Role of Affirming Language
Rosenberg AR
Fourteen countries explicitly criminalize the gender identity and/or expression of transgender people, and the national state of emergency for LGBTQIA+ US residents declared by the Human Rights Campaign in 2023 is intensifying. As of April 2025, 851 antitransgender bills have been introduced across 49 states, 64 have passed in 21 states with 51 signed into law, and another 742 are currently under deliberation. Since 2021, this is a 495% increase in the number of antitransgender bills being considered, making 2025 the sixth consecutive record-breaking year for antitransgender legislation introduced in the US. This Viewpoint provides clinicians with tools to support transgender patients given the evolving antitransgender policies
|
JAMA Oncology
Persistent Prostate-Specific Antigen Following Radical Prostatectomy for Prostate Cancer and Mortality Risk
D'Amico AV
IMPORTANCE: Whether the conventional 1.5-month to 2.0-month time interval following radical prostatectomy (RP) for prostate cancer (PC) is sufficient to accurately document a persistent prostate-specific antigen (PSA) remains unanswered.
OBJECTIVE: To evaluate the time necessary to accurately document a persistent PSA level after RP.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated whether a significant interaction existed between (1) a pre-RP PSA level greater than 20 ng/mL vs 20 ng/mL or less and (2) persistent PSA vs undetectable PSA after RP on PC-specific mortality (PCSM) risk and all-cause mortality (ACM) risk, adjusting for known PC prognostic factors, age at RP, year of RP, and the time-dependent use of post-RP radiation therapy (RT) and androgen deprivation therapy (ADT). Whether an increasing persistent PSA level was associated with a worse prognosis was also investigated. Patients with T1N0M0 to T3N0M0 PC treated with RP between 1992 and 2020 at 2 academic centers were included. Follow-up data were collected until November 2023. Data were analyzed from July 2024 to January 2025.
EXPOSURE: RP.
MAIN OUTCOMES AND MEASURES: Adjusted hazard ratio (aHR) of ACM and PCSM risk.
RESULTS: Of 30?461 patients included in the discovery cohort, the median (IQR) age was 64 (59-68) years; of 12?837 patients included in the validation cohort, the median (IQR) age was 59 (54-64) years. Compared with patients with undetectable PSA, among patients with persistent PSA, a pre-RP PSA level greater than 20 ng/mL vs 20 ng/mL or less was significantly associated with reduced ACM risk (aHR, 0.69; 95% CI, 0.51-0.91; P?=?.01; P for interaction?<?.001) and PCSM risk (aHR, 0.41; 95% CI, 0.25-0.66; P?<?.001; P for interaction?=?.02). This result remained after adjustment for prostate volume and was confirmed in the validation cohort for PCSM risk and may represent a higher proportion of patients with a pre-RP PSA greater than 20 ng/mL vs 20 ng/mL or less who could have reached an undetectable PSA level if additional time for PSA assessment occurred before initiating post-RP therapy for presumed persistent PSA. Notably, there was more frequent and a shorter median time to post-RP RT plus ADT or ADT use in patients with a pre-RP PSA greater than 20 ng/mL (244 of 446 [54.7%] at a median [IQR] of 2.68 [1.51-4.40] months) vs 20 ng/mL or less (338 of 972 [34.8%] at a median [IQR] of 3.30 [2.00-5.39] months). These treatment times were shorter than the times to an undetectable PSA in observed patients (median [IQR] of 2.96 [1.84-3.29] months vs 3.37 [2.35-4.09] months, respectively). Increasing persistent PSA level was associated with an increased ACM risk (aHR, 1.14; 95% CI, 1.04-1.24; P?=?.004) and PCSM risk (aHR, 1.27; 95% CI, 1.12-1.45; P?<?.001).
CONCLUSIONS AND RELEVANCE: PSA level assessed for at least 3 months after RP may minimize overtreatment, and in this study, a higher persistent PSA level was associated with a worse prognosis.
|
Journal of Clinical Oncology
First-Line Mobocertinib Versus Platinum-Based Chemotherapy in Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer in the Phase III EXCLAIM-2 Trial
Jänne PA
PURPOSE: Mobocertinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets EGFR exon 20 insertion (ex20ins) mutations in non-small cell lung cancer (NSCLC). This open-label, phase III trial (EXCLAIM-2, ClinicalTrials.gov identifier: NCT04129502) compared mobocertinib versus platinum-based chemotherapy as first-line treatment of EGFR ex20ins+ advanced/metastatic NSCLC.
METHODS: Patients with treatment-naive EGFR ex20ins+ locally advanced/metastatic NSCLC were randomly assigned 1:1 to mobocertinib 160 mg once daily or pemetrexed plus cisplatin or carboplatin every 3 weeks for four cycles followed by maintenance pemetrexed. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR), with planned interim analysis (IA) after approximately 70% of 227 expected PFS events.
RESULTS: A total of 354 patients were randomly assigned (mobocertinib: n = 179; chemotherapy: n = 175). Baseline characteristics were balanced between arms. At IA (cutoff: April 4, 2023), the median PFS per BICR was 9.6 months in each treatment arm (hazard ratio [HR], 1.04 [95% CI, 0.77 to 1.39]; P = .803). The primary end point crossed the prespecified futility boundary (HR > 1). The confirmed objective response rate (95% CI) per BICR was 32% (26 to 40) with mobocertinib versus 30% (24 to 38) with chemotherapy; the median duration of response was 12.0 versus 8.4 months. Quality-of-life assessments indicated clinically meaningful delays in time to deterioration of lung cancer symptoms, cognitive function, and constipation with mobocertinib versus chemotherapy. Grade ?3 adverse events in >5% of patients (mobocertinib, chemotherapy) were diarrhea (20%, 1%), anemia (6%, 10%), increased lipase (6%, 0%), and decreased neutrophil count (1%, 7%).
CONCLUSION: The EXCLAIM-2 trial did not meet its primary end point. The efficacy of mobocertinib was not superior to platinum-based chemotherapy for first-line treatment of patients with EGFR ex20ins+ advanced/metastatic NSCLC.
|
Nature Communications
Nivolumab Plus Low-Dose Ipilimumab in Hypermutated HER2-Negative Metastatic Breast Cancer: A Phase II Trial (NIMBUS)
Zanudo JGT, Li T, Kuntz TM, AlDubayan SH, Chu H, Overmoyer B, Lange P, DiLullo MK, Kasparian J, Hughes ME, Attaya V, Basta A, Lin NU, Tayob N, Jeselsohn R, Mittendorf EA, Tolaney SM
In the phase II NIMBUS trial, patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and high tumor mutational burden (TMB???9 mut/Mb) received nivolumab (3?mg/kg biweekly) and low-dose ipilimumab (1?mg/kg every 6 weeks) for 2 years or until progression. The primary endpoint was objective response rate (ORR) per RECIST 1.1 criteria. Among 30 patients enrolled, the median TMB was 10.9 mut/Mb (range: 9-110) and the confirmed objective response rate was 20%. Secondary endpoints included progression-free survival, overall survival, clinical benefit rate, and safety and tolerability, including immune-related adverse events (irAEs). A prespecified correlative outcome was to evaluate the ORR in patients with a TMB???14 mut/Mb. Patients with TMB???14 mut/Mb (n?=?6) experienced higher response rates (60% vs 12%; p?=?0.041) and showed a trend towards improved progression-free survival and overall survival compared to patients with TMB?<?14 mut/Mb. Exploratory genomic analyses suggested that ESR1 and PTEN mutations may be associated with poor response, while clinical benefit was associated with a decrease or no change in tumor fraction by serial circulating tumor DNA during treatment. Stool microbiome analysis revealed that baseline blood TMB, PD-L1 positivity, and immune-related diarrhea are associated with distinct taxonomic profiles. In summary, some patients with hypermutated HER2-negative MBC experience extended clinical benefit with a dual immunotherapy regimen; a higher TMB, and additional genomic and microbiome biomarkers may optimize patient selection for therapy with nivolumab plus low-dose ipilimumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov identifier, NCT03789110).
|
Science
Pancreatic Cancer-Restricted Cryptic Antigens are Targets for T Cell Recognition
Kulstad ZJ, Gunaydin G, Addepalli S, Verzani EK, Casarrubios M, Clauser KR, Wang X, Lippincott IE, Louvet C, Kapner KS, Hennessey CJ, Cleary JM, Klaeger S, Wolpin BM, Raghavan S, Smith EL, Aguirre AJ, Abelin JG, Carr SA, Freed-Pastor WA
Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.
|
Annals of Surgical Oncology
ASO Visual Abstract: Impact of the American Society of Breast Surgeons' Guidelines on Genetic Testing and Contralateral Prophylactic Mastectomy Rates
Weiss A, Rosito MS, Braun D, Barton B, McGrath M, Stokes S, Laws A, Warren L, Morganti S, Lynce F, Bychkovsky B, Rana HQ, Davis D, Stopfer J, Garber JE, King TA
|
British Journal of Haematology
Forecasting Optimal Treatments in Relapsed/Refractory Mature T- and NK-Cell Lymphomas: A Global PETAL Consortium Study
Sorial MN, Li S, Duan R, Lu J, Lei MM, MacVicar CT, Freydman J, Malespini J, Aniagboso KN, McCabe SM, Singh S, Iwasaki M, Eche-Ugwu IJ, Gabler J, Fernandez Turizo MJ, Garg A, Disciullo A, Chopra K, Ford J, Lenart A, Nwodo E, Barnes J, Koh MJ, Merrill M, Jacobsen E, Kariya KM, Bhanushali F, Meharwal A, Mistry D, Kosovsky M, Jain S
|
Clinical Cancer Research
A Prospective Trial of Biomarker-Guided Surveillance for HPV-Positive Oropharynx Cancer Using Plasma Tumor Tissue-Modified Viral HPV DNA
Rettig EM, Schoenfeld JD, Miller J, Sargent B, Carey E, Margalit DN, Sehgal K, Sethi RKV, Uppaluri R, Tishler RB, Goguen LA, Annino DJ, Sim ES, Jo VY, Wong KS, Guenette JP, Haddad RI, Hanna GJ
|
|
|
