Welcome to Dana-Farber's Research News
February 1, 2026
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 January 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.
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Correction: Our previous issue inadvertently ran the wrong abstract under the Blood article Acalabrutinib to Assail CLL in the Frail (Ryan CE, Davids MS). The correct information appears here. Blood Acalabrutinib to assail CLL in the Frail Ryan CE, Davids MS This investigator-initiated, phase 2 study conducted by the German CLL Study Group included a 52-patient safety population, of which 46 patients were included in the full analysis set (predefined as those patients who received ?3 complete cycles of treatment). The study met its primary end point, with an overall response rate of 93% (43/46, all partial responses) in the full analysis set (see figure). Although the median follow-up of 19 months is short for a frontline CLL trial, the 1-year progression-free survival (PFS) and overall survival rates of 93% and 96%, respectively, are promising in an older population. All patients experienced at least 1 adverse event (AE), and severe AEs were reported in nearly two-thirds of patients (64%). Notably, just over half of patients (53%) in the full analysis set reported an improvement in their self-perceived frailty, as reflected by their FRAIL (Fatigue, Resistance, Ambulation, Illness, and Loss of weight) score after 6 cycles of treatment. |
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Annals of Oncology Mayer EL, Kim SE, Faggen M, Sinclair N, Sanz-Altamira P, Berwick S, Malcolm A, Varella L, Sammons S, Schumer S, Poorvu PD, Wallace E, Pasternak E, Tayob N, Tolaney SM BACKGROUND: Adjuvant abemaciclib with endocrine therapy (ET) improves clinical outcomes in patients with high-risk node-positive early-stage hormone receptor-positive/HER2-negative (HR-positive/HER2-negative) breast cancer (BC), based on the monarchE trial. Patients may experience tolerability issues at the standard abemaciclib dose [150 mg twice daily (b.i.d.)], potentially leading to early treatment discontinuation, particularly within the initial weeks of therapy. TRADE is a prospective, single-arm, phase II study evaluating whether dose escalation of adjuvant abemaciclib improves drug tolerability. PATIENTS AND METHODS: Eligible patients had node-positive HR-positive/HER2-negative BC and were candidates for adjuvant abemaciclib with ET. Participants initiated abemaciclib at 50 mg b.i.d. for 2 weeks, then escalated to 100 mg b.i.d. for 2 weeks, then escalated to the final dose level (150 mg b.i.d.). Dose escalation required the absence of ongoing grade 3-4 or persistent grade 2 toxicity. The primary endpoint, measured at 12 weeks, was a composite rate of abemaciclib discontinuation for any reason or inability to reach or maintain the target dose. RESULTS: In 89 evaluable patients, the initial dose escalation strategy significantly reduced the composite rate at 12 weeks versus a historical value of 40% from monarchE. In total, 26/89 participants (29.2%, 90% confidence interval 21.3% to 38.2%, P = 0.023) met the endpoint: 6 (6.7%) for early discontinuation, 8 (9.0%) for inability to reach 150 mg, and 12 (13.5%) for dose reduction from 150 mg. The majority (70.8%) reached and maintained 150 mg b.i.d. dosing. CONCLUSION: Use of an adjuvant abemaciclib dose escalation strategy allowed more patients to reach and maintain target dosing at 12 weeks than observed in monarchE. Early discontinuation was infrequent, and 93.3% of patients were continuing therapy at 12 weeks. This dosing strategy could be considered when initiating adjuvant abemaciclib. |
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Blood Brown JR Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired ?1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/Y/L, 26%), kinase-impaired L528W (16%), C481S/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate-binding pocket, D539A/G/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov. |
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Blood Mechanisms of Immune Escape and Extramedullary Tropism in Leukemia Cutis Penter L, Maurer K, Cieri N, Lu WS, Lyu H, Li S, Livak KJ, Ritz J, Davids MS, Garcia JS, Soiffer RJ, Wu CJ The mechanisms that lead to extramedullary tropism of acute myeloid leukemia (eAML) remain obscure and no specific therapeutic approaches for this entity exist. Because the long-term survival of eAML is poor, a deeper understanding of the immune microenvironment and leukemia phenotypes underlying this entity is warranted. Here, we performed bulk and single-cell transcriptome profiling of 23 eAML biopsies from 10 patients with isolated extramedullary disease in skin and subcutaneous tissue. Unlike normal healthy skin, we found leukemia cutis to be heavily immune infiltrated; in extramedullary relapse after allogeneic stem cell transplantation, >90% of T/natural killer cells were donor derived. eAML-associated T cells expressed a clear signature of T-cell exhaustion, dissimilar to leukemia-associated immune populations in bone marrow relapse (n = 7) but related to acute and chronic skin inflammation. Furthermore, HLA class II was downregulated in 4 of 7 leukemia cutis specimens, consistent with an immune escape phenotype in eAML. Extramedullary and bone marrow-resident leukemia cells differed with regard to the expression of 8 homing receptor molecules (ICAM1 [encoding CD54], PECAM1 [CD31], ITGA4, ITGA6, ITGAL, ITGB4, ITGA5, and ITGAV). Serial samples obtained from 1 leukemia cutis throughout consecutive immune checkpoint blockade with ipilimumab followed by nivolumab showed a consistently high degree of overlap between local and circulating T-cell receptor sequences, suggesting that only a minority of eAML-associated T cells are leukemia specific. Our analysis reveals eAML to associate with complex changes in leukemia and T-cell gene expression profiles that suggest multiple potential avenues for therapeutic targeting. |
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Cancer Cell Decoding the Spatial Dynamics of Tumor and Immune Cell Interactions in Solid Cancers Minogue E, Baldominos P, Hsu L, Haigis MC, Agudo J The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy. |
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Cancer Discovery Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer Kotýnková K, Karsli Uzunbas G, Tomono H, Andersen S, Denney D, Lewis TA, Kaplan B, Cherniack AD, Meyerson M, Greulich H Exon 20 insertions of HER2, encoded by erb-b2 receptor tyrosine kinase 2 (ERBB2), and other activating HER2 mutations occur in 2% to 4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. In this study, we report the preclinical activity of sevabertinib in lung cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of neuregulin-1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer. SIGNIFICANCE: Additional therapeutic options are needed for patients with lung cancer with HER2 activating mutations, including exon 20 insertions. Sevabertinib shows activity against ERBB2-encoded HER2 exon 20 insertions in preclinical models of lung cancer, corroborated by early data from a phase 1/2 clinical trial. |
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Gastroenterology Chemical Perturbations Impacting Histone Acetylation Govern Colorectal Cancer Differentiation Likasitwatanakul P, Li Z, Doan P, Spisak S, Raghawan AK, Liu Q, Liow P, Lee S, Chen D, Bala P, Sahgal P, Aitymbayev D, Thalappillil JS, Papanastasiou M, Hawkins W, Carr SA, Park H, Cleary JM, Qi J, Sethi NS BACKGROUND & AIMS: Aberrant epigenetic programs that suppress differentiation and enhance plasticity drive colorectal cancer (CRC), yet the molecular determinants underlying these processes remain elusive. We aimed to identify and characterize epigenetic regulators of CRC differentiation, uncovering mechanisms that reprogram cancer cell states. METHODS: A small-molecule library targeting epigenetic regulators was screened using an endogenous dual-reporter system. We evaluated lead compounds in mouse and human CRC models via histopathology, cellular assays, epigenetic studies, mass spectrometry-based histone modification profiling, and single-cell RNA sequencing. Integrative analyses of drug-induced chromatin dynamics, gene expression, target engagement, and histone marks elucidated molecular mechanisms. Focused genetic screens were conducted to identify regulators of histone deacetylase (HDAC)1/2-mediated differentiation. RESULTS: We found that inhibition of the HDAC1/2 catalytic domain promotes CRC differentiation and suppresses tumor growth. Unbiased profiling of histone modifications identified acetylation of lysine 27 on histone H3 protein subunit (H3K27ac) and acetylation of lysine 9 on histone H3 protein subunit (H3K9ac) as critical regulatory marks, with genome-wide analyses demonstrating their enrichment at HDAC1/2-bound regions associated with open chromatin and up-regulated differentiation genes. Disrupting H3K27ac by targeted degradation of acetyltransferase E1A binding protein P300 reversed the differentiation phenotype induced by HDAC1/2 inhibition in a patient-derived CRC organoid. Genetic screens revealed that death-associated protein kinase 3 contributes to H3K27ac-mediated CRC differentiation induced by HDAC1/2 inhibition. CONCLUSIONS: Our findings establish histone acetylation as a chemically targetable mechanism governing CRC cell fate and demonstrate that epigenetic reprogramming can be leveraged as a therapeutic strategy. By identifying HDAC1/2 inhibition as a driver of differentiation and revealing H3K27ac as a key regulatory mark, this study provides a framework for targeting chromatin-modifying enzymes to counteract CRC plasticity and improve treatment outcomes. |
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JAMA Patel AK, Sethi NS, Park H IMPORTANCE: Globally, 968?350 new cases and 659?853 deaths from gastric cancer were reported in 2022. In the US, 30?300 new cases and 10?780 deaths were estimated in 2025. OBSERVATIONS: Gastric cancer is more common in men, and the median age at diagnosis is 68 years. Most gastric cancers (>90%) are adenocarcinomas. Worldwide, 85% of cases arise from the stomach body or antrum and 15% from the cardia. In the US, more than 90% of patients diagnosed with gastric cancer present with symptoms such as weight loss and abdominal pain. At presentation, approximately 13% have localized disease (limited to the stomach), 15% to 25% have locally advanced disease, defined as a tumor that has spread to regional lymph nodes, and 35% to 65% have metastatic disease. Helicobacter pylori infection is a treatable risk factor associated with 90% of gastric body and antrum cancers globally. Additional modifiable risk factors include smoking, alcohol, obesity, and salt intake. In countries with high incidence such as Japan and Korea, routine endoscopic screening beginning at age 40 years is associated with improved survival. Diagnosis is made by endoscopic biopsy. Patients with localized gastric cancer are treated with surgical resection and have a 5-year relative survival rate of 75% with treatment. Patients with more advanced-stage disease should receive gastrectomy, perioperative chemotherapy with 5-fluorouracil, oxaliplatin, and docetaxel and immunotherapy (durvalumab). Metastatic or unresectable disease may be treated with chemotherapy, immunotherapy, and/or targeted therapy depending on biomarkers, including programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (ERBB2; formerly HER2 or HER2/neu), and claudin-18, isoform 2 (CLDN18.2). For PD-L1-expressing gastric cancer, adding immune checkpoint inhibitors, such as nivolumab and pembrolizumab, is associated with an additional 3 months of survival when compared with chemotherapy alone. For gastric cancers overexpressing the ERBB2 or CLDN18.2 proteins, the addition of trastuzumab or zolbetuximab, respectively, is associated with an additional 3 to 4 months' survival. Early supportive care focusing on symptom management and on nutritional and psychosocial support is associated with 3 months of survival benefit. Less than 10% of patients with metastatic gastric cancer survive more than 5 years. CONCLUSIONS AND RELEVANCE: Approximately 30?300 new cases of gastric cancer are diagnosed annually in the US. Localized gastric cancer is treated with gastrectomy, and locally advanced disease is treated with surgery and chemoimmunotherapy. For patients with unresectable or metastatic gastric cancer, chemotherapy with immune checkpoint inhibitors and targeted therapies such as trastuzumab or zolbetuximab improves survival by several months. |
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Journal of Clinical Oncology Valenza C, Zheng Y, Kirkner GJ, Dibble KE, Regan MM, Partridge AH PURPOSE: To evaluate the clinical benefit of extended endocrine therapy (eET) after 5 years of adjuvant treatment with luteinizing hormone-releasing hormone agonists (LHRHa) in premenopausal women with node-positive, hormone receptor-positive early breast cancer (eBC). METHODS: We conducted a cohort study analysis on two prospectively collected data sets (the Young Women's Breast Cancer Study and IEO Breast Cancer Cohort). Eligible patients were diagnosed with eBC at age ?40 years (between 2005 and 2016), had node-positive, hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRHa with no evidence of recurrence. The primary end point was invasive breast cancer-free survival (IBCFS), calculated from the sixth year after the initiation of adjuvant endocrine therapy (ET; study baseline), and adjusted through the propensity score (PS) weighting analysis. RESULTS: A total of 501 patients were included in the analysis: 287 received eET for a median duration of 3.7 years (IQR, 2.3-5.0), including 48% tamoxifen monotherapy and 52% LHRHa plus tamoxifen or aromatase inhibitor. After a median follow-up of 7.3 years from the study baseline, the PS weighted IBCFS rates at 5 years were 85% in the eET group and 78% in the non-eET group (hazard ratio [HR], 0.63 [95% CI, 0.44 to 0.89]; P = .0135). The PS weighted distant recurrence-free survival rates at 5 years were 91% and 83% in the eET and non-eET group, respectively (cause-specific HR, 0.49 [95% CI, 0.31 to 0.79]). In both groups, bone fractures and major cardiovascular events were reported in 1% of patients. CONCLUSION: In this cohort study analysis, extending ET in premenopausal patients with node-positive eBC after 5 years of LHRHa treatment was associated with a clinically meaningful reduction in both invasive and distant breast cancer recurrences. |
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Journal of Clinical Oncology If Exercise Were a Pill, We'd All Prescribe It to Patients with Cancer. But It's Not Ligibel JA Exercise improves quality and quantity of life in patients with cancer. Decades of research shows that exercise reduces side effects of cancer treatment and improves quality of life in patients during and after cancer treatment, leading the American Society of Clinical Oncology and other groups to recommend exercise for patients with cancer. The Challenge trial (ClinicalTrials.gov identifier: NCT00819208) fills a critical gap by demonstrating that exercise after diagnosis improves disease-free and overall survival. The CHALLENGE trial randomly assigned 889 patients with Stage II to III colon cancer who were free of disease after completing adjuvant chemotherapy to a 3-year supervised aerobic exercise intervention or usual care. Patients randomly assigned to the exercise intervention experienced a 28% improvement in disease-free survival, with a reduction both in the incidence of distant metastatic disease and in second primary cancers and, even more strikingly, a 37% improvement in overall survival. |
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Journal of Clinical Oncology Precision Oncology 2.0: Guiding Magic Bullets with Expression-Based Liquid Biopsy Gulati GS, Choueiri TK, Freedman ML, Baca SC In the early 20th century, Paul Ehrlich coined the term “magic bullet” to describe a therapy that could selectively eliminate disease without harming healthy tissues. A century later, Ehrlich's vision is being realized in oncology. A deeper understanding of the differences between tumor and normal tissue has fueled an explosion of therapies targeting oncogenic drivers and tumor-specific markers. The first wave of magic bullets was enabled by large-scale genetic profiling, which revealed dozens of druggable alterations and drove unprecedented growth in targeted therapies. |
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Journal of the National Cancer Institute Frequency and Clinical Features of Germline Pathogenic Variants in Sarcoma: A Case-Control Study Rodriguez-Hernandez A, Horiguchi M, Bychkovsky BL, Buehler RM, George S, Merriam P, Garber JE, Rana HQ BACKGROUND: Germline multigene panel testing is not yet integrated into standard care for patients with sarcoma. This study aimed to assess the frequency and distribution of germline pathogenic variants in patients with sarcoma compared with cancer-free controls and identify differences between patients with and without germline pathogenic variants. METHODS: This retrospective cohort included 488 sarcoma patients and 2440 cancer-free controls matched 1:5 by age, sex, and ethnicity. Multigene panel testing was performed between 2016 and 2024 at a single germline testing laboratory. The frequency of germline pathogenic variants in selected genes was compared using Fisher exact test with odds ratios (ORs) and 95% confidence intervals. Additionally, within the case-only cohort, clinical characteristics were evaluated to assess associations with the presence of germline pathogenic variants in any gene. RESULTS: Among 488 patients with sarcoma, 67.8% (n?=?331) were female, with a median age at sarcoma diagnosis of 47?years (range = 0.5-87.5 years). Cases had a higher frequency of germline pathogenic variants compared with controls (26.2% vs 10.5%; OR = 3.05, P?<?.001). We observed a higher frequency of germline pathogenic variants in TP53, BRCA2, CHEK2, NF1, SDHA, BRIP1, POT1, RB1, and CDH1 among patients with sarcoma compared with controls. Age at sarcoma diagnosis did not differ between groups. CONCLUSIONS: This study confirms the high detection rate of germline pathogenic variants in patients with sarcoma and describes several associated genes. These findings indicate that age at sarcoma diagnosis may not reliably predict germline pathogenic variants. Expanding germline testing for patients with sarcoma would enhance personalized treatment strategies and familial risk assessment. |
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Journal of the National Cancer Institute Nader-Marta G, Chu X, Kurt BB, DeMeo M, Tung NM, Schnitt SJ, Tayob N, Mayer EL BACKGROUND: Tumor-infiltrating lymphocytes (TILs), assessed by visual examination, are prognostic and predictive in early-stage triple-negative breast cancer. Computational assessment may provide a complementary approach. We evaluated the prognostic value of TILs by visual examination and computational assessment. METHODS: Cisplatin vs Paclitaxel for Triple Negative Breast Cancer (TBCRC030; ClinicalTrials.gov identifier NCT01982448) was a randomized phase 2 trial enrolling patients with BRCA1/2-proficient stage I to III triple-negative breast cancer to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathological response at surgery. The TILs were visually scored on digitized pretreatment biopsies per International TILS Working Group recommendations. Computational assessment used the 4D Path QPOR platform to generate TILs, an immune heterogeneity index, and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden 0/1 was assessed using receiver operating characteristic curves and odds ratios (ORs) with 95% CIs; all statistical tests were 2-sided. RESULTS: Of 139 response-evaluable patients, 121 had matched visual examination and computational assessment data (59 on cisplatin, 62 on paclitaxel). Median visual examination TILs were higher in responders (40.0% vs. 10.0%; P?=?.002) and predicted response (OR?=?1.86, 95% CI?=?1.24 to 2.87; area under the curve?=?0.69, 95% CI?=?0.57 to 0.80). Computational assessment CmbI differed by response group and predicted residual cancer burden 0/1 (OR?=?3.20, 95% CI?=?1.05 to 11.07; area under the curve?=?0.62, 95% CI?=?0.51 to 0.73). Computational assessment TILs and immune heterogeneity index were not predictive. Visual examination TILs and computational assessment CmbI predicted response to paclitaxel (OR?=?2.91, 95% CI?=?1.56 to 6.14; OR?=?9.17, 95% CI?=?2.01 to 66.39, respectively) but not to cisplatin. CONCLUSION: Visual examination TILs and computational assessment CmbI were each associated with response to neoadjuvant chemotherapy in triple-negative breast cancer in the overall cohort and the paclitaxel arm. Computational assessment CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches. |
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Nature Nutrient Requirements of Organ-Specific Metastasis in Breast Cancer Abbott KL, Subudhi S, Ferreira R, Steinbuch SC, Honeder SE, Kumar AS, Riedmayr LM, Duquette M, Ali A, Nakano MA, Ferraro GB, Do BT, Sánchez-Rivera FJ, Church GM, Jain RK, Vander Heiden MG Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases. |
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Nature Genetics Zhang CZ, Mendez-Dorantes C, Burns KH, Pellman D Segmental copy-number gains are major contributors to human genetic variation and disease, but how these alterations arise remains incompletely understood. Here, based on the analyses of both experimental evolution and human disease genomes, we describe a general mechanism of segmental copy-number gain from a rearrangement process termed 'breakage-replication/fusion'. The hallmark genomic feature of breakage-replication/fusion is adjacent parallel breakpoints: two or more rearrangement breakpoints derived from replication of a single ancestral DNA end. We show that adjacent parallel breakpoints are a widespread feature of DNA duplications in human disease genomes and experimental models of chromothripsis. In addition to adjacent parallel breakpoints, breakage-replication/fusion also explains two other patterns of complex rearrangements with unclear provenance: chains of short (?1?kb) insertions and high-level amplification consisting of inverted segments. Together, these findings revise the mechanistic model for chromothripsis and provide a new conceptual framework for understanding the origin of segmental DNA duplication during genome evolution. |
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New England Journal of Medicine Survival with Osimertinib Plus Chemotherapy in EGFR-Mutated Advanced NSCLC Jänne PA BACKGROUND: The primary analysis of this trial showed that first-line treatment with osimertinib plus chemotherapy with a platinum-based agent and pemetrexed led to significantly longer progression-free survival than osimertinib monotherapy among patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). Results from the planned final analysis of overall survival are needed. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC who had not previously received treatment for advanced disease to receive either osimertinib (80 mg once daily) plus chemotherapy with pemetrexed (500 mg per square meter of body-surface area) and a platinum-based agent (cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or osimertinib monotherapy (80 mg once daily). The key secondary end point was overall survival. RESULTS: A total of 557 patients were randomly assigned to the osimertinib plus platinum-pemetrexed group (279 patients) or the osimertinib monotherapy group (278 patients). The median overall survival was 47.5 months in the osimertinib plus platinum-pemetrexed group and 37.6 months in the osimertinib monotherapy group (hazard ratio for death, 0.77; 95% confidence interval, 0.61 to 0.96; P?=?0.02). Grade 3 or higher adverse events of any cause were reported in 70% of the patients in the osimertinib plus platinum-pemetrexed group and in 34% of the patients in the osimertinib monotherapy group; adverse events leading to the discontinuation of osimertinib were reported in 12% and 7%, respectively. CONCLUSIONS: Among patients with EGFR-mutated advanced NSCLC, first-line treatment with osimertinib plus platinum-pemetrexed led to significantly longer overall survival than osimertinib monotherapy and was associated with an increased risk of reversible adverse events of grade 3 or higher. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.). |
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Proceedings of the National Academy of Sciences of the U.S.A. CHAMP1 Complex Promotes Heterochromatin Assembly and Reduces Replication Stress Li F, Elbakry A, Zhou FY, Ravindranathan R, Nguyen H, Syed A, Sun L, Mukkavalli S, D'Andrea AD Replication stress (RS) is a major driver of genomic instability and a hallmark of cancer cells. Although dynamic heterochromatin remodeling has been implicated in RS response, the precise mechanisms remain unclear. The CHAMP1 complex, composed of CHAMP1, POGZ, HP1?, and the H3K9 methyltransferase SETDB1, is known to regulate heterochromatin assembly at multiple genomic sites. Interestingly, upon RS, the CHAMP1 complex is transiently recruited to stalled replication forks, where it facilitates H3K9me3 deposition and establishes a repressive chromatin environment. The complex is required for stabilization of replication forks, and it shields forks from MRE11-mediated degradation. The complex also reduces RS at specific chromosomal sites, such as the heterochromatin-rich telomeric sites in tumor cells which use the ALT pathway of telomere maintenance. Loss of the CHAMP1 complex results in increased micronuclei formation and heightened sensitivity to RS. Loss of the complex also leads to a compensatory increase in other pathways which reduce RS, such as the FA pathway and the ATR/CHK1 pathway. Notably, CHAMP1 deficiency induces synthetic lethality with FANCM inhibition in ALT-positive tumor cells, and the CHAMP1 complex is essential for the survival of CCNE1-amplified ovarian cancers. These findings uncover a heterochromatin-based mechanism of replication fork stabilization and suggest that CHAMP1 may represent a candidate therapeutic vulnerability in cancers with elevated RS. |
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Science A SWI/SNF-Specific Ig-Like Domain, SWIFT, is a Transcription Factor Binding Platform Jain SU, Williamson KE, Ying AW, Turner AM, Raval S, So K, Allison MJ, Sankar A, Sáme Guerra DD, Mashtalir N, Papanastasiou M, Paulo JA, Gygi SP, Kadoch C Mammalian SWI/SNF chromatin remodeling complexes modulate DNA accessibility and gene expression; however, their genomic targeting mechanisms remain incompletely understood. Here, we identify SWIFT (SWI/SNF Ig-fold for transcription factor interactions), a conserved transcription factor (TF) binding platform on the SMARCD subunits. SWIFT is necessary and sufficient for direct engagement with the transactivation domain of PU.1. A single amino acid mutation disrupts PU.1-mSWI/SNF binding, impairs complex targeting, and attenuates oncogenic transcription and proliferation in PU.1-dependent cancer cells. Dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF and poisons TF-addicted cancer cells. Finally, TFs across diverse families interact with SMARCD paralog-specific SWIFT domains. These results define a major mechanism of cell type- and disease-specific mSWI/SNF chromatin targeting and inform approaches toward therapeutic modulation. |
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Advances in Radiation Oncology Circulating Tumor DNA Predicts Response After Definitive Radiation Therapy for Merkel Cell Carcinoma Murchison K, Camargo A, Margalit D, Schoenfeld JD, Tishler R, Khaddour K, Thakuria M, Silk AW |
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Algorithms for Molecular Biology Improving Spliced Alignment by Modeling Splice Sites with Deep Learning Yang S, Huang N, Li H |
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American Journal of Hematology DeAngelo DJ |
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Biomarker Research Konstantinopoulos P, Fendler W, Chowdhury D |
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Blood Advances Stratifying Survival: The Role of Social Determinants of Health on AML Outcomes by ELN 2022 Criteria Shimony S, Wang Y, Cronin AM, Walsh TP, Charles A, Slopen N, Cho HL, Luskin MR, Abel GA, DeAngelo DJ, Stone RM, Lindsley RC, Hantel A |
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Blood Cancer Discovery Fulciniti M, Fong Ng J, Schavgoulidze A, Cui J, Encinas Mayoral J, Ladisa F, Epstein CB, White CM, Ott CJ, Sperling AS, Samur MK, Anderson KC, Munshi NC |
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Brachytherapy Randomized Trial of Dose De-Escalation in Low-Risk Prostate Cancer Patients Implanted with Pd-103 King M, Sayan M, Orio P |
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Brain Pathology Integration of Omics Data in the Diagnosis and Therapy of Glioblastoma Möller C, Ligon KL |
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Breast Cancer Research Yan P, Polyak K |
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Breast Cancer Research and Treatment Chen EL, Heiling H, Li T, Bellon JR, Nakhlis F, Parsons HA, Martin A, Burstein HJ, Tolaney SM, Snow C, Tayob N, Lin NU, Sammons S |
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Cancer Patterns of Lung Cancer Incidence in Adults Diagnosed Under Age 50 in the United States, 2000-2021 LoPiccolo J, Tramontano AC, Florez N, Johnson BE, Gusev A, Christiani DC, Jänne PA |
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CA Cancer Journal for Clinicians Xie W, Bellmunt J, Berg SA, Efstathiou J, Hirsch M, McDermott DF, McGregor B, Xu W, Choueiri TK |
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Cancer Epidemiology, Biomarkers, and Prevention Pradhan P, Ghobrial IM, Marinac CR, O'Donnell EK, Syngal S, Weeks LD, Rebbeck TR |
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Cancer Immunology Research T-Cell Subset Features and Distributions Evolve across the Colorectal Precancer-Cancer Spectrum Takashima Y, Dias Costa A, Akimoto N, Ugai T, Hornick JL, Mino-Kenudson M, Zhong Y, Ugai S, Haruki K, Yao Q, Matsuda K, Higashioka M, Giannakis M, Song M, Chan AT, Nowak JA, Ogino S |
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Clinical Cancer Research Janeway KA, Dubois SG, Grier H |
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Clinical Cancer Research Hanna GJ, Scarfo N, Shin KY, O'Neill A, Bedard V, Dennis MJ, Sehgal K, Jo VY, Wong K, Haddad RI |
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Clinical Cancer Research Bian W, Machaalani M, El Masri J, Saleh M, Saad E, Ascione L, El Hajj Chehade R, Steiner C, Barrios PM, Berg SA, McGregor B, Mantia C, Ravi P, Xu W, Hirsch MS, Choueiri TK, Serzan M |
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Clinical Cancer Research Real-World Outcomes of Elacestrant in ER+, HER2-, ESR1-Mutant Metastatic Breast Cancer Wander SA, Tolaney SM |
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Clinical and Translational Medicine Phase II Clinical Trial of Nirogacestat in Patients with Relapsed Ovarian Granulosa Cell Tumours Konstantinopoulos PA |
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European Journal of Medicinal Chemistry Allosteric Inhibition of JAK2 with Lysine-Reactive Compounds that Bind the Pseudokinase Domain Primi MC, Tavares MT, Hatcher JM, Kang H, Kresina TAC, Chakraborty S, Leroy E, Schmoker AM, Jeon H, Weisberg EL, Akatsu T, Griffin JD, Scott DA, Eck MJ |
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Fertility and Sterility Sorouri K, Zheng Y, Kirkner GJ, Snow C, Gelber SI, Peppercorn JM, Come SE, Ginsburg ES, Partridge AH |
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Imaging Neuroscience TissUnet: Improved Extracranial Tissue and Cranium Segmentation for Children Through Adulthood Mandzak M, Yang E, Zapaishchykova A, Chen YH, Zielke J, Tak D, Mojahed-Yazdi R, Mussa FR, Ye Z, Vajapeyam S, Benitez V, Salloum R, Chi SN, Aerts HJWL, Poussaint TY, Kann BH |
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International Journal of Cancer Cohesin Mutations and Chromatin Changes in Cancer Swett AD, Tothova Z |
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International Journal of Radiation Oncology, Biology, Physics Howard TP, Walburn T, Benham G, Chirmade S, Yang DD, McGregor BA, Pomerantz MM, Leeman JE, Han Z, Huynh MA |
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Journal of Pain and Symptom Management Differences in Pain Episodes Among Children with Complex Chronic Conditions at End of Life Rosenberg AR |
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Journal of Sexual Medicine Franco I, Bober SL |
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Korean Journal of Radiology Kim KW, Al-Yousef AS, Patel M, Pallod S, Krajewski KM |
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Leukemia Identifying Targeted Therapies for CBFA2T3::GLIS2 Acute Myeloid Leukemia Gonzales F, Schneider C, Alexe G, Lin S, Khalid D, Basanthakumar A, Ellegast JM, Merickel L, Salhotra S, Taillon A, Giaimo M, Perry JA, Degar B, Pikman Y, Stegmaier K |
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Leukemia and Lymphoma Soluble BCMA: A Window into Tumor Burden Monitoring in Waldenström Macroglobulinemia? Guijosa A, Castillo JJ |
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Methods in Cellular Biology Mittenbühler MJ, Smythers AL, Spiegelman BM |
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Nature Microbiology Surface Expression of Antitoxin on Engineered Bacteria Neutralizes Genotoxic Colibactin in the Gut Yang S, Bader AC, Yilmaz ÖH, Romee R |
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Nature Reviews Cancer Convergence of Machine Learning and Genomics for Precision Oncology Reardon B, Van Allen EM |
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Neuro-Oncology A Cellular Epigenetic Classification System for Glioblastoma Jürgensen L, Pooley CS, Boniolo F, Suvà ML, Hovestadt V |
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Pediatric Blood and Cancer Vital Voices: Patient/Family Perspectives to Improve Treatment for Pediatric B-ALL Greenzang KA |
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Pediatric Critical Care Medicine Gouda SR, Snaman JM, D'Anna R, Upham EJ, Dahlberg SE, Rosenberg AR, DeCourcey DD |
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Palliative Medicine Rhee JY, Miller P, Tentor Z, Reich A, Wright AA, Lindvall C |
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