Blood
Loss of BCL7A Permits IRF4 Transcriptional Activity and Cellular Growth in Multiple Myeloma
Chakraborty C, Talluri S, Binder M, Mayoral JE, Derebail S, Aktas Samur A, Epstein CB, Anderson KC, Shammas MA, Samur MK, Fulciniti M, Munshi NC
Multiple myeloma (MM) is a complex hematological malignancy characterized by genomic changes and transcriptomic dysregulation. Initial exome sequencing approaches have failed to identify any single frequent (>25%) mutation in the coding genome. However, using whole-genome sequencing (WGS), we found that one of the genomic regions most frequently mutated (62% of the MM patients) was the 5' untranslated (UTR) region and/or intron 1 of the BCL7A gene. RNA-seq data from a large cohort suggests a loss of BCL7A expression in a large majority of MM patients as compared to normal plasma cells. BCL7A loss of function in a panel of MM cell lines led to a highly proliferative phenotype in vitro and in vivo, while its ectopic expression significantly reduced cell viability, suggesting a tumor suppressor function for BCL7A in MM. We studied the cellular and molecular effects of BCL7A loss and observed that it endows myeloma cells with proliferative potential in cooperation with the plasma cell-defining transcription factor IRF4. BCL7A is involved in a direct protein-protein interaction with IRF4, limiting its DNA binding activity. Loss of BCL7A thus enhances the expression of IRF4-associated cytokines and reduces mitochondrial metabolism and ROS levels. Our study therefore suggests that BCL7A loss provides the necessary molecular change to allow IRF4-mediated transcriptional activity and MM cell growth and survival.
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Blood
PI3K? in Leukemia: Class IB PI3 Kinase Reemerges as a Cancer-Intrinsic Target
Luo Q, Fortune AL, Lane AA
Phosphoinositide 3-kinase gamma (PI3K?), the only class IB PI3 kinase, is a cell-extrinsic immunotherapy target in solid tumors. PI3K? inhibition reprograms immunosuppressive myeloid cells to acquire immunostimulatory phenotypes, which promote antitumor cytotoxic T cell activity. Although PI3K? inhibition has no direct effect on solid tumor cells, several new studies have nominated PI3K? as a cell-intrinsic target in various leukemias, particularly acute myeloid leukemia (AML). Intrinsic dependency on PI3K? is present at baseline in leukemias with specific pathologic characteristics, is inducible by extrinsic inflammation in others, and may also be acquired with resistance to certain therapies. The discovery of leukemia PI3K? dependency has generated enthusiasm for immediate clinical trial evaluation of inhibitor monotherapy and combinations. Parallel laboratory evaluation is needed to develop an improved understanding of leukemia disease features associated with clinical inhibitor sensitivity that might suggest biomarker-directed patient enrichment strategies. In this review, we discuss recent progress credentialling PI3K? as a bona fide target in leukemia. We also highlight open questions, including a need to understand the mechanism of acquired resistance to PI3K? inhibition, how to optimally prioritize combination therapies to enhance PI3K? inhibitor utility, and how cell-extrinsic effects of PI3K? inhibition in the leukemia microenvironment might also contribute to clinical activity.
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JAMA
Active Monitoring with or without Endocrine Therapy for Low-Risk Ductal Carcinoma In Situ: The COMET Randomized Clinical Trial
Schnitt S, Partridge AH
IMPORTANCE: Active monitoring for low-risk ductal carcinoma in situ (DCIS) of the breast has been proposed as an alternative to guideline-concordant care, but the safety of this approach is unknown.
OBJECTIVE: To compare rates of invasive cancer in patients with low-risk DCIS receiving active monitoring vs guideline-concordant care.
DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized noninferiority trial enrolling 995 women aged 40 years or older with a new diagnosis of hormone receptor-positive grade 1 or grade 2 DCIS without invasive cancer at 100 US Alliance Cancer Cooperative Group clinical trial sites from 2017 to 2023.
INTERVENTIONS: Participants were randomized to receive active monitoring (follow-up every 6 months with breast imaging and physical examination; n?=?484) or guideline-concordant care (surgery with or without radiation therapy; n?=?473).
MAIN OUTCOMES AND MEASURES: The primary outcome was 2-year cumulative risk of ipsilateral invasive cancer diagnosis, according to planned intention-to-treat and per-protocol analyses, with a noninferiority bound of 5%.
RESULTS: The median age of the 957 participants analyzed was 63.6 (95% CI, 55.5-70.5) years in the guideline-concordant care group and 63.7 (95% CI, 60.0-71.6) years in the active monitoring group. Overall, 15.7% of participants were Black and 75.0% were White. In this prespecified primary analysis, median follow-up was 36.9 months; 346 patients had surgery for DCIS, 264 in the guideline-concordant care group and 82 in the active monitoring group. Forty-six women were diagnosed with invasive cancer, 19 in the active monitoring group and 27 in the guideline-concordant care group. The 2-year Kaplan-Meier cumulative rate of ipsilateral invasive cancer was 4.2% in the active monitoring group vs 5.9% in the guideline-concordant care group, a difference of -1.7% (upper limit of the 95% CI, 0.95%), indicating that active monitoring is not inferior to guideline-concordant care. Invasive tumor characteristics did not differ significantly between groups.
CONCLUSIONS AND RELEVANCE: Women with low-risk DCIS randomized to active monitoring did not have a higher rate of invasive cancer in the same breast at 2 years compared with those randomized to guideline-concordant care.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02926911.
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JAMA
US Science in Peril
Walensky LD
On January 22, 2025, the National Institutes of Health (NIH) came to a sudden standstill. Study sections were halted and agency communications muzzled, sparking alarm across the US scientific community. Study sections represent the steady flow of scientific progress and consist of panels of experts who convene 3 times yearly to critically review scientific proposals from the US’ budding and seasoned scientists alike. Its members review approximately 10 grants per session, with multiple experts assigned to each grant in an effort to maximize fairness and rigor. Preparing applications for submission takes months of painstaking work and the reviewers who study the applications, draft reviews, and complete a scoring rubric do so essentially pro bono (i.e., ~$600 for weeks of preparatory review and several days of meeting, often including travel). For most of these scientists, whether writer or reviewer, the ultimate reward is not what is printed in green or wired to an institutional account, but rather the thrill of discovery and the satisfaction that comes with contributing to potentially lifesaving research.
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Journal of Clinical Oncology
Targeting CD30 in Diffuse Large B-Cell Lymphoma: Where Does It Fit In?
Crombie JL, LaCasce AS
Over the past 5 years, the treatment landscape of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has evolved dramatically with the introduction of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and other novel agents. CAR T-cell therapy has become the preferred treatment choice for eligible patients in the second-line setting on the basis of the results of the ZUMA-7 and TRANSFORM trials, one of which included an overall survival (OS) benefit. Despite the promise of CAR T-cell therapy, patient eligibility, access to care, and treatment logistics continue to be barriers for many patients. In addition, a large subset of patients will ultimately relapse.
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Journal of the National Cancer Institute
Development of a Multi-Institutional Dataset to Validate a Novel Inflammatory Breast Cancer Diagnostic Score
Lynce F, Niman SM, Ma SR, Troll E, Overmoyer BA, Nakhlis F, Harrison BT, Yeh ED, Bellon JR, Warren LE, Regan MM
PURPOSE: Susan G. Komen, the Inflammatory Breast Cancer (IBC) Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to propose novel quantitative scoring rubrics for IBC diagnosis. In this study, we developed a multi-institutional clinical dataset to test and validate the proposed scoring system.
METHODS: IBC (N?=?988) and non-IBC (N?=?332) cases were identified at two institutions with dedicated multidisciplinary IBC programs. The non-IBC cohort included consecutive cT4b and cT4c patients. Standard operating procedures (SOPs) were developed for all ambiguous findings and languages. Three different methods were used for the imputation of missing data, resulting in three separate datasets. The sensitivity, specificity, and area under the receiver operator characteristic curve (AUC-ROC) were used to assess the discrimination of the proposed scoring rubric.
RESULTS: The distribution of “true IBC” cases was 19.7% very likely IBC, 49.1% strong possibility of IBC, 0.4% weak possibility of IBC, 0.1% very unlikely IBC, and 30.7% unknown; corresponding groupings for true non-IBC cases were 0.6% very likely IBC, 51.8% strong possibility of IBC, 9.9% weak possibility of IBC, 2.1% very unlikely IBC, and 35.5% unknown. AUC-ROC values for missing data imputation methods were similar (0.83-0.84); exploratory score refinement improved the AUC-ROC to 0.88-0.89.
CONCLUSION: Using the largest multi-institutional IBC clinical database to date, the score has been validated and is available for clinical use at https://www.komen.org/ibc-calc to assist healthcare providers and their patients in IBC diagnosis. Exploratory score refinement demonstrates the potential to increase specificity; however, any change requires separate validation.
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Journal of the National Cancer Institute
Incorporation of Patient-Reported Outcomes in Pediatric Cancer Clinical Trials: Design, Implementation, and Dissemination
Greenzang KA, Janeway K
Understanding the patient experience of treatment toxicities and their impact on health-related quality of life (HRQoL) of cancer treatments requires asking patients themselves using patient-reported outcomes (PROs). Over the past twenty years, the National Institutes of Health (NIH) sponsored several tools, namely Patient-Reported Outcome Measurement Information System (PROMIS) measures and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for precisely this purpose: to ensure valid, reliable tools to collect and detect patient-reported toxicities or adverse events and their impact on HRQoL. These PRO measures have been widely incorporated in clinical trials for adults with cancer. Yet, despite considerable work developing and validating developmentally appropriate versions of these measures for pediatric and adolescent self-report, PRO inclusion in pediatric and adolescent and young adult (AYA) clinical trials has lagged. Here we discuss optimal strategies to integrate validated PRO tools and sound analytic methodologies in clinical trials for children and AYAs with cancer, highlighting lessons learned from recent successes and ongoing experiences developing and opening cross-network trials for children and AYAs through the Children's Oncology Group (COG) for patients with classic Hodgkin lymphoma (cHL), osteosarcoma (OS), and acute lymphoblastic leukemia (ALL).
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Journal of the National Cancer Institute
Prevalence by Therapy Line and Incidence of Breast Cancer Brain Metastases in 18,075 Patients
Sammons SL, Leone JP, Erick TK, Tolaney SM, Lin NU
IMPORTANCE: Brain metastases portend poor prognosis in patients with metastatic breast cancer (MBC). Designing treatment and prevention clinical trials requires knowledge of brain metastases incidence with each line of therapy.
OBJECTIVES: We assessed the prevalence and cumulative incidence of brain metastases in a large MBC patient cohort by subtype and line of therapy, and the impact of HER2-low expression on prevalence.
DESIGN, SETTING AND OUTCOMES: We analyzed brain metastases prevalence in patients with MBC in a nationwide electronic health record-derived de-identified database. The primary outcome was first diagnosis of brain metastases. We estimated prevalence and incidence of brain metastases by MBC subtype, including HER2-low and therapy line. We used the cumulative incidence function to estimate brain metastases risk in patients without brain metastases at initiation of systemic therapy. All p-values are two-sided, and a p-value ? 0.05 indicates statistical significance.
RESULTS: Among 18,075 patients with MBC, 1,102 (6.1%) had at least one brain metastasis at first-line therapy initiation. For the remaining 16,973 patients, cumulative incidence of brain metastases at 60?months was 10% in patients with hormone receptor-positive (HR+)/HER2- disease, 23% for HR+/HER2+ disease, 34% for HR-/HER2+ disease, and 22% for triple-negative breast cancer (TNBC). HER2-low expression within HR+/HER2- and TNBC subtypes had no impact on brain metastases incidence. Brain metastases prevalence increased per line of therapy for patients with all breast cancer subtypes.
CONCLUSIONS: Brain metastases incidence increases per line of therapy for every MBC subtype. The HER2-low biomarker does not impact brain metastases incidence within historical subtypes.
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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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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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Annals of Surgical Oncology
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
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