This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from December 16 through December 31.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing ericd_schuller@dfci.harvard.edu.
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Blood
Causes and Consequences of Clonal Hematopoiesis
Weeks LD, Ebert BL
Clonal hematopoiesis (CH) is described as the outsized contribution of expanded clones of hematopoietic stem and progenitor cells (HSPCs) to blood cell production. The prevalence of CH increases dramatically with age. CH can be caused by somatic mutations in individual genes or by gains and/or losses of larger chromosomal segments. CH is a premalignant state; the somatic mutations detected in CH are the initiating mutations for hematologic malignancies, and CH is a strong predictor of the development of blood cancers. Moreover, CH is associated with nonmalignant disorders and increased overall mortality. The somatic mutations that drive clonal expansion of HSPCs can alter the function of terminally differentiated blood cells, including the release of elevated levels of inflammatory cytokines. These cytokines may then contribute to a broad range of inflammatory disorders that increase in prevalence with age. Specific somatic mutations in the peripheral blood in coordination with blood count parameters can powerfully predict the development of hematologic malignancies and overall mortality in CH. In this review, we summarize the current understanding of CH nosology and origins. We provide an overview of available tools for risk stratification and discuss management strategies for patients with CH presenting to hematology clinics.
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Journal of Clinical Oncology
Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization
Rahman R, Trippa L, Lee EQ, Arrillaga-Romany I, Fell G, Touat M, McCluskey C, Wiley J, Gaffey S, Chukwueke UN, Beroukhim R, Nayak L, McFaline-Figueroa JR, Batchelor TT, Rinne ML, Bi WL, Arnaout O, Peruzzi PP, Haas-Kogan D, Tanguturi S, Aizer A, Doherty L, Lavallee M, Fisher-Longden B, Dowling S, Geduldig J, Watkinson F, Pisano W, Malinowski S, Ramkissoon S, Santagata S, Meredith DM, Chiocca EA, Reardon DA, Alexander BM, Ligon KL, Wen PY
PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design.
PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780).
RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05).
CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.
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Annals of Surgical Oncology
Defining the Biology of Estrogen Receptor-Low-Positive Breast Cancer
Higgins T, Kantor O, Harrison B, Giordano J, McGrath M, Burstein HJ, Schnitt SJ, Rahman T, Vora H, Garrido-Castro A, Tolaney SM, King TA, Mittendorf EA
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Breast Cancer Research and Treatment
Clinical Outcomes After 1 Versus 2-3 Lines of Neoadjuvant Therapy in Stage III Inflammatory Breast Cancer
Nakhlis F, Niman SM, Troll E, Ryan S, Yeh E, Warren L, Bellon J, Harrison B, Overmoyer B, Tolaney SM, Regan M, Lynce F
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Cancer Research Communications
Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma
Mouhieddine TH, Nzerem C, Redd R, Dunford A, Leventhal M, Sklavenitis-Pistofidis R, Tahri S, El-Khoury H, Steensma DP, Ebert BL, Soiffer RJ, Ghobrial IM, Sperling AS, Stewart C, Getz G
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Cell Reports
Heterogeneity and Transcriptional Drivers of Triple-Negative Breast Cancer
Jovanović B, Temko D, Stevens LE, Seehawer M, Fassl A, Murphy K, Anand J, Garza K, Gulvady A, Qiu X, Harper NW, Daniels VW, Xiao-Yun H, Ge JY, Alečković M, Pyrdol J, Hinohara K, Egri SB, Papanastasiou M, Vadhi R, Font-Tello A, Witwicki R, Peluffo G, Trinh A, Shu S, Diciaccio B, Ekram MB, Subedee A, Herbert ZT, Wucherpfennig KW, Letai AG, Jaffe JD, Sicinski P, Brown M, Dillon D, Long HW, Michor F, Polyak K
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Journal of Thoracic Oncology
Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma
Luo J, Sanchez M, Lee E, Hertzler H, Luong N, Mazzola E, Finstein B, Tamen R, Brisbane G, Nguyen T, Cheng ML, Khalil H, Sholl LM, Nishino M, Jänne PA, DuBois SG, Hanna GJ, Shapiro GI, French CA
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