Blood
Odronextamab Monotherapy in R/R DLBCL After Progression with CAR T-Cell Therapy: Primary Analysis of the ELM-1 Study
Crombie JL
Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post-CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ?3 events). No cases of immune effector cell-associated neurotoxicity syndrome were reported. Grade ?3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.
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Blood
ZUMA-8: A Phase 1 Study of Brexucabtagene Autoleucel in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Davids MS
ZUMA-8 (NCT03624036) is the first prospective trial to evaluate the safety of brexucabtagene autoleucel (previously KTE-X19), a CD19-directed autologous CAR T-cell immunotherapy, in patients with R/R CLL. Patients with ?2 prior lines of therapy (including a BTK inhibitor) underwent leukapheresis, followed by optional bridging therapy, then conditioning chemotherapy (fludarabine/cyclophosphamide) before infusing 1×106 (Cohort 1) or 2×106 (Cohort 2) anti-CD19 CAR T cells/kg. Patients in Cohort 3 (low tumor burden), and Cohort 4A (ibrutinib pre-treated closely to the apheresis) received 1×106 cells/kg. Fifteen patients, median age 63 years (52-79 years), were treated in Cohort 1 (n=6), Cohort 2 (n=3), Cohort 3 (n=3), and Cohort 4A (n=3). Median follow-up was 24.3 months. One DLT was observed in Cohort 3 (n=1 grade 4 cytokine release syndrome). Grade ?3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (ORR 47%, CR 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count (ALC) prior to the apheresis. Brexu-cel did not have any new safety signals in R/R CLL, and CAR T-cell expansion and responses occurred in patients with low tumor burden.
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Cancer Cell
Effective Targeting of PDGFRA-Altered High-Grade Glioma with Avapritinib
Mayr L, Neyazi S, Trissal M, Labelle J, Eder SK, Marques JG, de Biagi-Junior CAO, Lo Cascio C, Hack O, Nascimento A, Nguyen CM, Castellani S, Rozowsky JS, Groves A, Panditharatna E, Cruzeiro GAV, Haase RD, Tabatabai K, Supko J, Baumgartner A, Clark LM, Cameron A, Nguyen QD, Wakimoto H, Dubois F, Greenwald NF, Bandopadhayay P, Ligon K, Filbin MG
PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.
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Cancer Cell
New Horizons at the Interface of Artificial Intelligence and Translational Cancer Research
Yates J, Van Allen EM
Artificial intelligence (AI) is increasingly being utilized in cancer research as a computational strategy for analyzing multiomics datasets. Advances in single-cell and spatial profiling technologies have contributed significantly to our understanding of tumor biology, and AI methodologies are now being applied to accelerate translational efforts, including target discovery, biomarker identification, patient stratification, and therapeutic response prediction. Despite these advancements, the integration of AI into clinical workflows remains limited, presenting both challenges and opportunities. This review discusses AI applications in multiomics analysis and translational oncology, emphasizing their role in advancing biological discoveries and informing clinical decision-making. Key areas of focus include cellular heterogeneity, tumor microenvironment interactions, and AI-aided diagnostics. Challenges such as reproducibility, interpretability of AI models, and clinical integration are explored, with attention to strategies for addressing these hurdles. Together, these developments underscore the potential of AI and multiomics to enhance precision oncology and contribute to advancements in cancer care.
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Cancer Discovery
Antitumor Activity of Vebreltinib and Characterization of Clinicogenomic Features in Solid Tumors with MET Rearrangements
Nakazawa S, Pecci F, Odintsov I, Gazgalis D, Gottlieb FH, Ricciuti B, Alessi JV, Garbo E, Gandhi MM, Feng WW, Jiang J, Baldacci S, Facchinetti F, Makarem M, Locquet MA, Haratani K, Haradon D, Che J, Sholl LM, Janne PA, Awad MM
Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. Here, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ~0.04% of cancers. Preliminary analysis from a phase 2 clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion-positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types including lung adenocarcinoma, intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14-altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion-positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors.
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Cancer Discovery
Requirement for Cyclin D1 Underlies Cell Autonomous HIF2-Dependence in Kidney Cancer
Shirole NH, Kesar D, Lee Y, Goodale A, Syamala S, Kukreja S, Li R, Qiu X, Yu W, Goldman S, Long HW, Adelman K, Doench JG, Sellers WR, Kaelin WG
Inactivation of the VHL gene stabilizes HIF2a, which drives clear cell renal carcinoma (ccRCC). The HIF2a inhibitor belzutifan is approved for ccRCC treatment, but de novo and acquired resistance are common. HIF2a, bound to ARNT, transcriptionally activates many genes. We performed CRISPRa screens in HIF2a-dependent ccRCC lines treated with a belzutifan analog to identify HIF2a-responsive genes that confer cell-autonomous belzutifan resistance when not downregulated. Sustaining the expression of the HIF2a target gene CCND1, encoding Cyclin D1, promoted HIF2a-independence/belzutifan resistance. This activity requires Cdk4/6 activation by Cyclin D1, but is not solely due to phosphorylation of the canonical Cyclin D1 target, pRB. Indeed, ccRCC lines lacking all three pRB family members remained at least partially HIF2a-dependent. In this context, however, a kinase-defective Cyclin D1 variant partially overrode belzutifan's antiproliferative effects, suggesting that ccRCC promotion by Cyclin D1 requires the phosphorylation of pRB paralogs and one or more kinase-independent Cyclin D1 activities.
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Cell
HIF Regulates Multiple Translated Endogenous Retroviruses: Implications for Cancer Immunotherapy
Jiang Q, Braun DA, Clauser KR, Ramesh V, Shirole NH, Duke-Cohan JE, Kramer NJ, Forman C, Lippincott IE, Klaeger S, Phulphagar KM, Chea V, Kim N, Vanasse AP, Saad E, Parsons T, Carr-Reynolds M, Carulli I, Pinjusic K, Jiang Y, Li R, Syamala S, Rachimi S, Verzani EK, Stevens JD, Lane WJ, Camp SY, Meli K, Herbert ZT, Qiu X, Cejas P, Long HW, Van Allen EM, Choueiri TK, Churchman LS, Abelin JG, Gurer C, MacBeath G, Carr SA, Keskin DB, Wu CJ, Kaelin WG Jr
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
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Cell
Lysine Vitcylation is a Vitamin C-Derived Protein Modification that Enhances STAT1-Mediated Immune Response
He X, Wang Q, Cheng X, Wang W, Li Y, Nan Y, Xiu B, Jiang T, Bergholz JS, Gu H, Chen F, Xie S, Wei Y, Lee J, Asara JM, Cantley LC, Zhao JJ
Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
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Cell Stem Cell
Intestinal Secretory Differentiation Reflects Niche-Driven Phenotypic and Epigenetic Plasticity of a Common Signal-Responsive Terminal Cell
Bhattacharya S, Tie G, Singh PNP, He R, Kraiczy J, Perlov Y, Shivdasani RA
Enterocytes and four classic secretory cell types derive from intestinal epithelial stem cells. Based on morphology, location, and canonical markers, goblet and Paneth cells are considered distinct secretory types. Here, we report high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of their enteroendocrine or tuft cell siblings. Mouse and human goblet and Paneth cells express extraordinary fractions of few antimicrobial genes, which reflect specific responses to local niches. Wnt signaling retains some ATOH1+ secretory cells in crypt bottoms, where the absence of BMP signaling potently induces Paneth features. Cells that migrate away from crypt bottoms encounter BMPs and thereby acquire goblet properties. These phenotypes and underlying accessible cis-elements interconvert in post-mitotic cells. Thus, goblet and Paneth properties represent alternative phenotypic manifestations of a common signal-responsive terminal cell type. These findings reveal exquisite niche-dependent cell plasticity and cis-regulatory dynamics in likely response to antimicrobial needs.
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JAMA
Why Good Palliative Care Clinicians Get Fired
Rosenberg AR, Rabinowitz E
Even the most seasoned palliative care clinician gets fired. In the past year, one of us was fired after asking whether a patient endorsing suicidal ideation had access to a gun; the patient requested not to see the palliative care team because we asked intrusive questions and documented the encounter. One of us was fired after supporting a family’s decision to discontinue life-sustaining therapies for their loved one with multisystem organ failure; the primary intensivist suggested palliative care overstepped in discussing options for which the family (and clinical teams) was not ready. And one of us was fired after sharing the impression that a patient with cancer was dying; the family suggested they preferred the oncologist’s version of a more hopeful future.
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Journal of Clinical Oncology
Adjuvant Dose-Dense Chemotherapy in Hormone Receptor-Positive Breast Cancer
Metzger Filho O, Ligibel J, Partridge A, Winer EP
PURPOSE: In light of evolving evidence that some patients with node-positive estrogen receptor-positive (ER+) disease may receive less benefit from chemotherapy, this study reports 12-year outcomes of the C9741 trial overall, and by the sensitivity to endocrine therapy (SET2,3) test index, a biomarker measuring endocrine transcriptional activity, to identify patients most likely to benefit from dose-dense chemotherapy.
METHODS: In all, 1,973 patients were randomly assigned to dose-dense versus conventional chemotherapy. Hazard ratios (HRs) for prognosis and for predictive interaction with chemotherapy schedule were estimated from Cox models of long-term disease-free survival (DFS) and overall survival (OS). SET2,3 was tested on the 682 banked RNA samples from ER+ cancers.
RESULTS: Dose-dense chemotherapy improved DFS in the overall study population by 23% (HR, 0.77 [95% CI, 0.66 to 0.90]) and OS by 20% (HR, 0.80 [95% CI, 0.67 to 0.95]); the benefits of dose-dense therapy were seen for ER+ and ER-negative subsets, without significant interaction between treatment arm and ER status. Low SET2,3 status was highly prognostic, but also predicted improved outcomes from dose-dense chemotherapy (interaction P = .0998 for DFS; 0.027 for OS), independent of menopausal status. Specifically, low endocrine transcriptional activity predicted benefit from dose-dense chemotherapy, whereas tumor burden and proliferation-driven signatures for molecular subtype classification did not.
CONCLUSION: At 12-year follow-up, C9741 confirmed the sustained long-term benefit of adjuvant dose-dense chemotherapy for node-positive breast cancer. SET2,3 identified patients with ER+ breast cancer who benefited from dose-dense chemotherapy, and specifically, this benefit was predicted by low endocrine activity in the cancer, rather than tumor burden, molecular subtype, or menopausal status.
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Journal of Clinical Oncology
Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer with Actionable Genomic Alterations: Results from the Phase II TROPION-Lung05 Study
Sands J, Ahn MJ, Lisberg A, Cho BC, Blumenschein G Jr, Shum E, Pons Tostivint E, Goto Y, Heist R, Baas P, Planchard D, Pérol M, Felip E, Su WC, Paz-Ares L
PURPOSE: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy.
PATIENTS AND METHODS: Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival.
RESULTS: Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ?3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ?3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event.
CONCLUSION: Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ?3 toxicities was comparable with previous observations, and no new safety signals were observed.
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Journal of Clinical Oncology
Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma: A Pooled Analysis of Individual Patient Data from Multiple Randomized Trials
Anderson KC, Munshi N
PURPOSE: Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.
PATIENTS AND METHODS: Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.
RESULTS: The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.
CONCLUSION: Our findings provided the support for use of MRD-CR classified at a 10-5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.
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Journal of Clinical Oncology
Timely Reporting of Patient-Reported Outcomes in Cancer Clinical Trials: An Ethical Imperative
Blackstone EC, Meyerhardt JA, Abel GA
Cancer treatment often involves significant toxicity and interruptions to daily life. As a result, patient-reported outcomes (PROs) such as health-related quality of life (HRQoL) are an essential component of cancer research as they provide critical insights into the effects of therapies for patients beyond disease response and survival outcomes. Many clinical trials measure symptoms only (eg, pain) more so than a full suite of HRQoL domains. By contrast, HRQoL encompasses physical, psychological, and social impacts of treatment,1 augmenting symptoms and adverse events recovered by study teams and amplifying patient voices in cancer research. The hope is that patients' sacrifices in HRQoL are worthwhile to maximize chance of cure or disease control, but weighing these considerations is impossible without treatment-aligned HRQoL data available to inform decision making. Incorporating PROs is particularly important in the context of increasing reliance on surrogate outcomes such as progression-free survival (PFS) in cancer trials. If a new treatment is approved on the basis of surrogate measures alone, there is no way of knowing what those outcomes mean for the day-to-day lived experiences of patients. For these reasons, collection and timely publication of PROs are necessary—and indeed an ethical imperative—for holistic evaluation of new cancer therapies in clinical trials. Although valuable progress has been made in incorporating PRO collection into cancer trials, inadequate reporting of results combined with increasing use of surrogates threatens both scientific validity and ethical conduct of cancer trials. Recommendations are provided to researchers, journal editors, and regulators to ensure that PRO data are available for new cancer therapies going forward.
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Journal of the National Cancer Institute
Childhood, Adolescent, and Young Adulthood Cancer Risk in BRCA1 or BRCA2 Pathogenic Variant Carriers
Rebbeck TR, Diller LR
BACKGROUND: Whether carriers of BRCA1 or BRCA2 pathogenic variants have increased risks of childhood, adolescent, and young adult cancers is controversial. We aimed to evaluate this risk and to inform clinical care of young BRCA1 and BRCA2 pathogenic variant carriers and genetic testing for childhood, adolescent, and young adult cancer patients.
METHODS: Using data from 47?117 individuals from 3086 BRCA1 or BRCA2 families, we conducted pedigree analysis to estimate relative risks (RRs) for cancers diagnosed before age 30 years.
RESULTS: Our data included 274 cancers diagnosed before age 30 years: 139 breast cancers, 10 ovarian cancers, and 125 nonbreast nonovarian cancers. Associations for breast cancer in young adulthood (aged 20-29?years) were found with relative risks of 11.4 (95% confidence interval [CI] = 5.5 to 23.7) and 5.2 (95% CI = 1.6 to 17.7) for BRCA1 and BRCA2 pathogenic variant carriers, respectively. No association was found for any other investigated childhood, adolescent, and young adult cancer or for all nonbreast nonovarian cancers combined; the relative risks were 0.4 (95% CI = 0.1 to 1.4) and 1.4 (95% CI = 0.7 to 3.0) in BRCA1 and BRCA2 pathogenic variant carriers, respectively.
CONCLUSION: We found no evidence that BRCA1 and BRCA2 pathogenic variant carriers have an increased childhood, adolescent, and young adult cancer risk aside from breast cancer in women aged between 20 and 30 years. Our results, along with a critical evaluation of previous germline sequencing studies, suggest that the childhood and adolescent cancer risk conferred by BRCA1 and BRCA2 pathogenic variant would be low (ie, RR?<?2) if it existed. Our findings do not support pathogenic variant testing for offspring of BRCA1 and BRCA2 pathogenic variant carriers at ages younger than 18?years or for conducting BRCA1 and BRCA2 pathogenic variant testing for childhood and adolescent cancer patients.
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JAMA Oncology
National Cancer System Characteristics and Global Pan-Cancer Outcomes
Nguyen PL
IMPORTANCE: Approximately 29.9 million cancer cases and 15.3 million deaths are anticipated by 2040 globally, necessitating cancer system strengthening. A greater understanding of health system factors that can be leveraged to improve cancer control may guide health system planning.
OBJECTIVE: To evaluate predictors of improved cancer outcomes globally.
DESIGN, SETTING, AND PARTICIPANTS: This pan-cancer ecological study used the most recent available national health system metrics and cancer statistics, spanning the breadth of global income levels across 185 countries. Estimates of age-standardized mortality to incidence ratios were derived from GLOBOCAN 2022 for patients with cancer of all ages. The analysis took place on November 27, 2024.
MAIN OUTCOMES AND MEASURES: Health spending as a percent of gross domestic product (GDP), physicians per 1000 population, nurses and midwives per 1000 population, surgical workforce per 1000 population, GDP per capita, Universal Health Coverage (UHC) service coverage index, availability of pathology services, human development index, gender inequality index (GII), radiotherapy centers per 1000 population, and out-of-pocket expenditure as percentage of current health expenditure were collected. The association between the mortality to incidence ratio (MIR) and each metric was evaluated using univariable linear regressions (??=?.0045), which were used to construct multivariable models (??=?.05). Variation inflation factor allowed exclusion of variables with significant multicollinearity. R2 measured goodness of fit.
RESULTS: On univariable analysis, all metrics were significantly associated with MIR of cancer (P?<?.001 for all), including UHC index (?, -0.0076 [95% CI, -0.0083 to -0.0068]), GDP per capita (?, -5.10?×?10-6 [95% CI, -5.75?×?10-6 to -4.46?×?10-6]), clinical and workforce capacity, radiotherapy capacity (?, -88.25 [95% CI, -100.43 to -76.06]), and gender inequality index (?, 0.63 [95% CI, 0.57-0.70]). After including metrics significant on univariable analysis and correcting for multicollinearity, on multivariable analysis, greater UHC index and GDP per capita were independently associated with lower (improved) MIR for cancer. The multivariable model had R2 of 0.87. On multivariable analysis stratified by sex, greater UHC index and greater GDP per capita were independently associated with improved MIR for all cancers. R2 for the multivariable models was 0.87 for females and 0.85 for males.
CONCLUSIONS: This study found that global health system metrics related to progress toward universal health care, greater health care spending and GDP per capita, strengthened clinical workforce and capacity, and increased gender equity were associated with improved pan-cancer outcomes at a population level on univariable analysis. The degree of UHC and GDP per capita were independently associated with improved cancer outcomes in multivariable models with good explanatory power. These exploratory findings merit further validation and may guide health system planning and prioritization.
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Molecular Cell
Amplified Dosage of the NKX2-1 Lineage Transcription Factor Controls its Oncogenic Role in Lung Adenocarcinoma
Pulice JL, Meyerson M
Amplification-mediated oncogene overexpression is a critical and widespread driver event in cancer, yet our understanding of how amplification and dosage mediate oncogene regulation is limited. Here, we find that the most significant focal amplification event in lung adenocarcinoma (LUAD) targets a lineage "super-enhancer" near the NKX2-1 lineage transcription factor. The NKX2-1 super-enhancer is targeted by focal and co-amplification with NKX2-1 and controls NKX2-1 expression and regulation. We find that NKX2-1 directly controls enhancer accessibility to drive a lineage-addicted state in LUAD. We precisely map the effects of NKX2-1 dosage modulation upon both overexpression and knockdown and identify both linear and non-linear regulation by NKX2-1 dosage. We find that NKX2-1 is a widespread dependency in LUAD cell lines and that NKX2-1 confers persistence to EGFR inhibitors. Our data suggest a defining role for dosage in the oncogenic regulation of amplified NKX2-1 and that amplified NKX2-1 lineage addiction defines LUAD tumors.
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Molecular Cell
Widespread Variation in Molecular Interactions and Regulatory Properties Among Transcription Factor Isoforms
Lambourne L, Mattioli K, Sheynkman G, Inukai S, Spirohn-Fitzgerald K, Rothman E, Laval F, Carroll BS, Yang Z, Prasad A, Phanor S, Balcha D, Gebbia M, Twizere JC, Hao T, Calderwood MA, Hill DE, Vidal M, Bulyk ML, Fuxman Bass JI
Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators," both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.
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Nature
Crypt Density and Recruited Enhancers Underlie Intestinal Tumour Initiation
Gaynor L, Singh H, Tie G, Badarinath K, Madha S, Bhattacharya S, Murata K, Jadhav U, Shivdasani RA
Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Apc, the most common initiating event in conventional adenomas3, activates Wnt signalling, thus conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arise by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear whether both generate tumours equally well in uninjured intestines. It is also unknown whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source, but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs that are not associated with adenomas. These cis elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumorigenesis.
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Nature Communications
Disrupting Bile Acid Metabolism by Suppressing Fxr Causes Hepatocellular Carcinoma Induced by YAP Activation
Liu Y, Zhu J, Jin Y, Yang Y
Disruption of bile acid (BA) metabolism causes various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains elusive. Here, we report that BA metabolism is directly controlled by a repressor function of YAP, which induces cholestasis by altering BA levels and composition via inhibiting the transcription activity of Fxr, a key physiological BA sensor. Elevated BA levels further activate hepatic YAP, resulting in a feedforward cycle leading to HCC. Mechanistically, Teads are found to bind Fxr in a DNA-binding-independent manner and recruit YAP to epigenetically suppress Fxr. Promoting BA excretion, or alleviating YAP repressor function by pharmacologically activating Fxr and inhibiting HDAC1, or overexpressing an Fxr target gene Bsep to promote BA exportation, alleviate cholestasis and HCC caused by YAP activation. Our results identify YAP's transcriptional repressor role in BA metabolism as a key driver of HCC and suggest its potential as a therapeutic target.
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New England Journal of Medicine
Application Overload — A Call to Reduce the Burden of Applying to Medical School
Walensky RP, Walensky LD
As physician-parents surrounded by colleagues and friends who are also doctors, we see many of our collective children following in their parents’ footsteps and applying to medical school. The view from our parental perch reveals a spiraling burden that is unfamiliar and disconcerting: the volume of medical school applications has become exasperating — far worse than what our children faced for college admission and much more demanding than our own medical school application process. Admittedly, children from a physician family are probably among the most resourced and privileged. Yet application overload burdens aspiring physicians across all socioeconomic strata, with far greater hurdles for those from disadvantaged backgrounds. Systemic barriers — such as limited access to mentors, uncertainty about the logistics of fee waivers, and fewer resources for navigating the process — can make an already herculean task even more daunting.
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Blood Advances
Characteristics and Outcomes of Patients with Double Refractory and Double Exposed Chronic Lymphocytic Leukemia
Yoon JT, Zhou Y, Mikhaleva M, Choi DS, Fernandes SM, Armand P, Bessnow AC, Crombie JL, Fisher DC, Jacobsen ED, Jacobson CA, Kim AI, LaCasce AS, Merryman RW, Odejide OO, Parry EM, Qualls DA, Ryan CE, Sekar A, Soumerai JD, Arnason JE, Tyekucheva S, Davids MS, Brown JR, Ahn IE
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