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Dana-Farber Research Publication 01.01.2023

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January 1, 2023

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors. If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know at:


Cancer Discovery

BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

Panditharatna E, Marques JG, Wang T, Trissal MC, Liu I, Jiang L, Groves A, Dharia NV, Li D, Hoffman SE, Kugener G, Shaw ML, Mire HM, Hack OA, Dempster JM, Lareau C, Dai L, Sigua LH, Wyatt M, Kalani Z, Goodale A, Vazquez F, Piccioni F, Doench JG, Root DE, Anastas JN, Jones KL, Conway AS, Stopka S, Regan MS, Liang Y, Seo HS, Song K, Bashyal P, Jerome WP, Mathewson ND, Dhe-Paganon S, Suv?† ML, Nguyen QD, Ligon KL, Shi Y, Agnihotri S, Agar NYR, Stegmaier K, Stiles CD, Golub TR, Qi J, Filbin MG

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell-like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas.

SIGNIFICANCE: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1-BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma. See related commentary by Beytagh and Weiss, p. 2730. See related article by Mo et al., p. 2906.



Cancer Discovery

MinimuMM-Seq: Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Dutta AK, Alberge JB, Lightbody ED, Boehner CJ, Dunford A, Sklavenitis-Pistofidis R, Cowan AN, Su NK, Horowitz EM, Barr H, Hevenor L, Beckwith JB, Perry J, Cao A, Lin Z, Nadeem O, Stewart C, Getz G, Ghobrial IM

Multiple Myeloma (MM) develops from well-defined precursor stages, however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. We enumerated circulating tumor cells (CTCs) from 261 patients (84 MGUS, 155 SMM, and 22 MM), with neoplastic cells detected in 84%. We developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. Application to CTCs in a cohort of 51 patients, 24 with paired BM, was able to detect 100% of clinically reported BM biopsy events and could replace molecular cytogenetics for diagnostic yield and risk classification. Longitudinal sampling of CTCs in 8 patients revealed major clones could be tracked in the blood, with clonal evolution and shifting dynamics of subclones over time. Our findings provide proof of concept that CTC detection and genomic profiling could be used clinically for monitoring and managing disease in MM.



Cancer Discovery

Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia

Uckelmann HJ, Haarer EL, Takeda R, Hatton C, Marinaccio C, Antonissen NJC, Wen Y, Armstrong SA

The dysregulation of developmental and stem cell associated genes is a common phenomenon during cancer development. Around half of acute myeloid leukemia (AML) patients express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncogene mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA Polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.




Examining the Cooperation Between Extrachromosomal DNA Circles

Zhang J, Zhang CZ

In a departure from previous findings, new results suggest that free-floating pieces of DNA which carry additional copies of cancer-driving genes do not tend to cluster or have increased transcription.



JAMA Oncology

Atezolizumab Plus Bevacizumab in TMB-High Non-Small Cell Lung Cancers-The Hunt for Predictive Biomarkers to Optimize Treatment Selection

Ricciuti B, Awad MM

Expression of programmed cell death 1 (PD-1) ligand 1 (PD-L1) on tumor cells represents the most widely used clinical biomarker for predicting response to immune checkpoint inhibition in non?small cell lung cancer (NSCLC). However, even among advanced NSCLCs with high PD-L1 expression on 50% or more of tumor cells, only a minority of patients will respond to treatment with first-line PD-L1 inhibitors, such as pembrolizumab, atezolizumab, and cemiplimab, highlighting the pressing need to identify more effective therapeutic strategies as well as more precise biomarkers of immunotherapy activity in lung cancer.



JAMA Oncology

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients with Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial

Lin NU, Krop I, Winer E

IMPORTANCE: It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs.

OBJECTIVE: To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up.

DESIGN, SETTING, AND PARTICIPANTS: HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed.

INTERVENTIONS: Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle).

MAIN OUTCOMES AND MEASURES: Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock.

RESULTS: At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]).

CONCLUSIONS AND RELEVANCE: This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs.

TRIAL REGISTRATION: Identifier: NCT02614794.



Journal of Clinical Oncology

Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results from SOFT

Burstein HJ, Gelber RD, Regan MM

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The Suppression of Ovarian Function Trial (SOFT; identifier: NCT00066690) randomly assigned premenopausal women with hormone receptor-positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2-negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence.



Journal of Clinical Oncology

A Process Framework for Ethically Deploying Artificial Intelligence in Oncology

Hantel A, Clancy DD, Kehl KL, Marron JM, Van Allen EM, Abel GA

Artificial Intelligence (AI) is an emerging technology that uses complex algorithms to arrive at an outcome over a range of circumstances, leveraging the ability of computer systems to perform tasks that would usually require human levels of intelligence. The use of AI in cancer care is rapidly expanding: a May 2022 PubMed search of the term cross-referenced with cancer revealed approximately 26,000 citations, with more than 60% published in the past five years. Ethical considerations for AI in oncology include patient equity, privacy, and autonomy; the roles of human- and machine-based judgment; and the patient-oncologist relationship. Relative to other parts of medicine, the implications of oncology AI are outsized, and some are idiosyncratic. Oncology AI tools apply to not one but two genomes (germline and somatic); can greatly complicate the existing weight of bias, discrimination, and structural racism in cancer care; and can subtly undermine patient and physician autonomy, leading to cancer care that is algorithmic rather than patient-centered. These diverse concerns, in the context of unreserved enthusiasm for AI, challenge a future where oncology AI is both widely implemented and ethically acceptable. We propose that adapting a process-focused approach for deploying AI in cancer care, such as the accountability for reasonableness framework (A4R), can address these concerns and realize a future where oncology AI is ethically deployed



Journal of Clinical Oncology

Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment

Yurgelun MB, Uno H, Furniss CS, Ukaegbu C, Horiguchi M, Chittenden A, Garber JE, Syngal S

PURPOSE: With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment.

MATERIALS AND METHODS: PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and eight category B genes [ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively.

RESULTS: PREMMplus (score 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have 2.5% probability of a PGV.

CONCLUSION: PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores 2.5% should be considered for MGPT.



Journal of Clinical Oncology

Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651

Haddad RI

PURPOSE: CheckMate 651 ( identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS 20 populations.

RESULTS: Among 947 patients randomly assigned, 38.3% had CPS 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME.

CONCLUSION: CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.



Journal of the National Cancer Institute

Variation in Cardiac Dose Explains a "Fraction" of the Disparities Among Breast Cancer Patients

Punglia RS, Hassett MJ

Most studies on disparities in cancer have focused on differences in stage of diagnosis and access to treatment. Breast cancer death rates are highest among vulnerable populations, including Black women, the disadvantaged, older persons, and those living in rural settings. Few prior studies have investigated differences in the characteristics of administered treatments as a potential explanation for observed disparities in outcomes. In medical oncology, an analysis of chemotherapy administered to breast cancer patients found Black women received 10% lower relative dose intensity compared with White women. In this issue of the Journal, Dr Chapman and colleagues present a novel and intricate analysis of the mediators of racial disparities among women receiving whole breast radiation therapy, using mean heart dose as the vehicle for their examination.



Lancet Oncology

Fluorouracil and Dose-Dense Adjuvant Chemotherapy in Breast Cancer: Lessons Learned from the 20-Year-Old GIM2 Trial

Morganti S, Tolaney SM

In 1976, approximately 50 years ago, the first randomised study leading to approval of adjuvant chemotherapy for breast cancer was reported. Chemotherapy remains a pillar of breast cancer treatment; however, in the past 50 years, we have learned that breast cancer is a heterogeneous disease and treatment should be tailored accordingly. We moved from a one-size-fits-all approach to a more personalised one, in which treatment decisions hinge upon the estimated risk of recurrence based not just on clinicopathological risk, but sometimes also on genomic information.



Nature Cancer

Bicarbonate Transport as a Vulnerability in Pancreatic Cancer

Qiang L, Dougan SK

Pancreatic ductal cells transport bicarbonate from blood to pancreatic juice. A study shows that pancreatic cancer retains SLC4A4-mediated bicarbonate import to fuel cancer growth via enhanced glycolysis and establish a pro-tumorigenic immune microenvironment. Targeting SLC4A4 mitigates acidosis and can be combined with checkpoint blockade.



Nature Communications

Breast Cancer Prevention by Short-Term Inhibition of TGFb Signaling

Aleckovic M, Cristea S, Gil Del Alcazar CR, Yan P, Ding L, Krop ED, Harper NW, Rojas Jimenez E,
Lu D, Gulvady AC, Foidart P, Seehawer M, Diciaccio B, Murphy KC, Pyrdol J, Anand J, Garza K, Wucherpfennig KW, Tamimi RM, Michor F, Polyak K

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFb signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFŒ? in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.



Nature Genetics

The Landscape of Tumor Cell States and Spatial Organization in H3-K27M Mutant Diffuse Midline Glioma Across Age and Location

Liu I, Jiang L, Hack OA, Jeong D, Shaw ML, Englinger B, LaBelle J, Mire HM, Trissal M,
Panditharatna E, Vogelzang J, Suva ML, Ligon KL, Alexandrescu S, Arrillaga-Romany I, Gojo J,
Filbin MG

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.



New England Journal of Medicine

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Brown JR

BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available.

METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05.

RESULTS: At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P‚Äâ=‚Äâ0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death.

CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE number, NCT03734016.).



Proceedings of the National Academy of Sciences of the U.S.A.

CCAR2 Functions Downstream of the Shieldin Complex to Promote Double-Strand Break End-Joining

Iyer DR, Harada N, Clairmont C, Jiang L, Martignetti D, Nguyen H, He YJ, Chowdhury D, D'Andrea AD

The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1-/-SHLD2-/- cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.



American Journal of Dermatopathology

Shared Clonal Origin of Multiple Histiocytic and Dendritic Neoplasms and Polycythemia Vera, Follicular Lymphoma in 1 Patient

Larocca C, Shanmugam V, Zemmour D, Antin JH, Lane AA



American Journal of Hematology

Follicular Lymphoma: 2023 Update on Diagnosis and Management

Jacobsen E



Annals of Applied Statistics

Hierarchical Resampling for Bagging in Multistudy Prediction with Applications to Human Neurochemical Sensing

Loewinger G, Parmigiani G



Annals of Surgical Oncology

ASO Visual Abstract: Clinicopathologic Features, Treatment Patterns, and Disease Outcomes in a Modern, Prospective Cohort of Young Women Diagnosed with Ductal Carcinoma In Situ

Tesch ME, Collins LC, Wong JS, Dominici L, Come SE, Partridge AH



Annals of Surgical Oncology

Clinicopathologic Features, Treatment Patterns, and Disease Outcomes in a Modern, Prospective Cohort of Young Women Diagnosed with Ductal Carcinoma In Situ

Tesch ME, Collins LC, Wong JS, Dominici L, Come SE, Partridge AH



Annals of Surgical Oncology

Expanding the Staging Criteria for T1-2N0 Hormone-Receptor Positive Breast Cancer Patients Enrolled in TAILORx

Kantor O, Burstein HJ, King TA, Winer EP, Mittendorf EA



Best Practice and Research Clinical Haematology

Consolidation Chemotherapy in AML: Are We Playing with a Full Deck of Cards?

Stone RM



Blood Advances

Loss-of-Function Lesions Impact B-Cell Development and Fitness but are Insufficient to Drive CLL in Mouse Models

Liu Y, Valtis YK, Paolino JD, Place AE, Brunner AM, Weeks LD, Silverman LB, Vrooman LM,
Neuberg D, Stone RM, DeAngelo DJ, Luskin MR



Blood Cancer Discovery

In Vivo Modeling of CLL Transformation to Richter's Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Ten Hacken E, Sewastianik T, Yin S, Brunsting Hoffmann G, Clement K, Penter L, Redd RA, Ruthen N, Fell G, Parry EM, Lucas F, Baranowski K, Southard J, Joyal H, Billington L, Regis FFD, Witten E, Uduman M, Knisbacher BA, Li S, Lyu H, Davids MS, Getz G, Livak KJ, Neuberg DS, Carrasco RD, Wu CJ



Breast Cancer Research and Treatment

Breast Cancer Knowledge and Understanding Treatment Rationales Among Diverse Breast Cancer Survivors

Freedman RA, Lederman RI, Gagnon H, Gundersen DA, Revette AC, Odai-Afotey A, Kantor O, Keating NL



British Journal of Cancer

Adverse Prognostic Impact of the Loss of STAG2 Protein Expression in Patients with Newly Diagnosed Localised Ewing Sarcoma: A Report from the Children's Oncology Group

Shulman DS, Nag A, Thorner AR, Lessnick SL, Stegmaier K, Janeway KA, DuBois SG, Church AJ, Crompton BD




Incidence, Characteristics, and Management of Central Nervous System Metastases in Patients with Inflammatory Breast Cancer

Warren LEG, Niman SM, Remolano MC, Landry JM, Nakhlis F, Bellon JR, Aizer AA, Lin NU, Tolaney SM, Regan MM, Overmoyer BA, Lynce F



Cancer Immunology Research

Hippo Signaling Pathway Regulates Cancer Cell-Intrinsic MHC-II Expression

Zeng Z, Gu SS, Ouardaoui N, Tymm C, Yang L, Wong CJ, Li D, Zhang W, Wang X, Weirather JL,
Rodig SJ, Hodi FS, Brown M, Liu XS



Cancer Nursing

Translation of Evidence-Based Interventions Into Oncology Care Settings: An Integrative Review

Cooley ME, Hammer MJ



Cancer Research

Mitochondrial DNA Mutations as Natural Barcodes for Lineage Tracing of Murine Tumor Models

Penter L, Ten Hacken E, Southard J, Li S, Neuberg DS, Livak KJ, Wu CJ



Cancer Research

Spatially-Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-Expressor Phenotypes and Extensive Intra-Tumoral Heterogeneity

Williams HL, Dias Costa A, Zhang J, Raghavan S, Kapner KS, Ginebaugh SP, Väyrynen SA, Yuan C, Wang J, Yang A, Bosse TL, Kalekar RL, Lowder KE, Lau MC, Elganainy D, Morales-Oyarvide V, Rubinson DA, Singh H, Perez K, Cleary JM, Clancy TE, Wang J, Mancias JD, Brais LK, Hill ER,
Hahn WC, Aguirre AJ, Nowak JA, Wolpin BM



Clinical Advances in Hematology and Oncology

Energy Balance in Advanced Breast Cancer: Extending Beyond the Curative Setting

Ligibel JA



Clinical Cancer Research

Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer

Tsuji J, Li T, Grinshpun A, Coorens T, Russo D, Anderson L, Rees R, Nardone A, Patterson C, 
Lennon NJ, Cibulskis C, Leshchiner I, Tayob N, Tolaney SM, Tung N, Krop IE, Winer EP, Stewart C, Getz G, Jeselsohn R



Clinical Cancer Research

Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer

Dias Costa A, Väyrynen SA, Zhang J, Väyrynen JP, Lau MC, Williams HL, Yuan C,
Morales-Oyarvide V, Elganainy D, Singh H, Cleary JM, Perez K, Ng K, Freed-Pastor W, Mancias JD, Dougan SK, Wang J, Rubinson DA, Brais L, Reilly E, Clancy T, Aguirre AJ, Wolpin BM, Nowak JA



Clinical Genitourinary Cancer

Incidence of Germline Variants in Familial Bladder Cancer and Among Patients with Cancer Predisposition Syndromes

Mossanen M, Nassar AH, Stokes SM, Martinez-Chanza N, Kumar V, Nuzzo PV, Kwiatkowski DJ, Garber JE, Curran C, Freeman D, Preston M, Mouw KW, Kibel A, Choueiri TK, Sonpavde G, Rana HQ





Current Hematologic Malignancy Reports

Molecular Pathogenesis of Myeloproliferative Neoplasms

Rolles B, Mullally A



Current Opinion in Neurology

Immunotherapy Approaches for Adult Glioma: Knowledge Gained from Recent Clinical Trials

Andersen BM, Reardon DA



European Journal of Cancer

Nivolumab Plus Ipilimumab Plus Cabozantinib Triplet Combination for Patients with Previously Untreated Advanced Renal Cell Carcinoma: Results from a Discontinued Arm of the Phase III CheckMate 9ER Trial

Choueiri TK



European Urology Oncology

Towards a Better Understanding of Antibody-Drug Conjugates in Urothelial Carcinoma

Labaki C, Bakouny Z, Sonpavde G, Choueiri TK, Van Allen EM



Genomics, Proteomics, and Bioinformatics

Machine Learning Modeling of Protein-intrinsic Features Predicts Tractability of Targeted Protein Degradation

Zhang W, Roy Burman SS, Chen J, Donovan KA, Shu C, Zhang B, Zeng Z, Gu S, Zhang Y, Li D, Fischer ES, Tokheim C, Shirley Liu X



Gynecologic Oncology

The Rapid Evolution of PARP Inhibitor Therapy for Advanced Ovarian Cancer: Lessons Being Learned and New Questions Emerging from Phase 3 Trial Long-Term Outcome Data

Matulonis UA




Investigational Venetoclax Combination Therapy in Acute Myeloid Leukemia - A Systematic Review and Meta-Analysis

Shimony S, Stone RM, DeAngelo DJ, Stahl M



Hematology, ASH Education Program

Selecting Initial Therapy in CLL

Ahn IE, Brown JR



Hematology, ASH Education Program

Sequencing Therapy in Relapsed DLBCL

Odejide OO



Hematology, ASH Education Program

Transplant for TP53-Mutated MDS and AML: Because We Can or Because We Should?

Lindsley RC



International Journal of Cancer

An International Report on Bacterial Communities in Esophageal Squamous Cell Carcinoma

Nomburg J, DeCaprio JA, Meyerson M



International Journal of Radiation Oncology, Biology, Physics

Stereotactic Magnetic Resonance-Guided Adaptive Radiation Therapy (SMART) for Abdominopelvic Oligometastases

Yang DD, Huynh E, Williams CL, Han Z, Ampofo N, Vastola ME, Sangal P, Mak RH, Leeman JE,
Huynh MA



JAMA Otolaryngology – Head and Neck Surgery

Association of Pretreatment Circulating Tumor Tissue-Modified Viral HPV DNA With Clinicopathologic Factors in HPV-Positive Oropharyngeal Cancer

Rettig EM, Wang AA, Tran NA, Carey E, Dey T, Schoenfeld JD, Sehgal K, Guenette JP, Margalit DN, Sethi R, Uppaluri R, Tishler RB, Annino DJ, Goguen LA, Jo VY, Haddad RI, Hanna GJ



JCO Oncology Practice

A Perfect Storm Averted: Flawed Systems, a Dropped Ball, and Cognitive Biases Delay a Critical Diagnosis

Roberts TJ, Sellars MC, Sands JM, Jacobson JO



JCO Oncology Practice

How Safe Is Cancer Care?

Jacobson JO, Peppercorn J



Journal of Cancer Education

Resident-Reported Impact of a Novel Oncology Curriculum for Internal Medicine Residents

Tsai FD, Stuver S, Stern R, Winkler M, Vallurupalli M, Luskin MR, Braun D, Parent A, Kilbridge KL



Journal of Adolescent and Young Adult Oncology

Clinical Trial Enrollment Among Adolescent and Young Adults with Primary Central Nervous System Tumors Treated at the Dana-Farber Cancer Institute

Sarvode S, Vogelzang JR, Sarvode Mothi S, Warren KE, Reardon DA, Yeo KK



Journal of Adolescent and Young Adult Oncology

Validation of the Three-Item Insomnia Severity Index Short Form in Young Adult Cancer Survivors: Comparison with a Structured Diagnostic Interview

Chevalier LL, Michaud AL, Zhou ES, Chang G, Recklitis CJ



Journal of Clinical Sleep Medicine

Building a Deeper Understanding of Social Relationship Health in Adolescents with Narcolepsy Disorder

Zhou ES, Revette A, Heckler GK, Worhach J, Maski K, Owens JA



Journal of Clinical Sleep Medicine

The Impact of Narcolepsy on Social Relationships in Young Adults

Davidson RD, Biddle K, Nassan M, Scammell TE, Zhou ES



Journal of Pain and Symptom Management

Creating KidneyPal: A Specialty-Aligned Palliative Care Service for People with Kidney Disease

Lakin JR, Sciacca K, Leiter R, Killeen K, Gelfand S, Tulsky JA, Anderson S, Zupanc SN, Williams T, Mandel EI



Journal of Pain and Symptom Management

Specialty-Aligned Palliative Care: Responding to the Needs of a Tertiary Care Health System

Gelfand SL, Lakin JR, Sciacca KR, Rivkin ER, Eves JC, Anderson S, Mandel EI, Desai AS, Jain N, Landzberg MJ, Lever NM, Schaefer KG, Leiter RE, Tulsky JA



Journal of Palliative Medicine

Estimating the Impact of Inpatient Palliative Care Consultations on Health Care Costs in a Low- and Middle-Income Country

Osman H



Journal of the American College of Radiology

Radiologists' Contribution to Variation in Detecting Clinically Significant Prostate Cancer in Men with Prostate MRI

Naik S, Burk KS, Budiawan E, Lacson R, Lee LK, Fennessy FM, Tempany C, Cole AP, Trinh QD,
Kibel AS, Khorasani R




CALR-Mutated Cells are Vulnerable to Combined Inhibition of the Proteasome and the Endoplasmic Reticulum Stress Response

Jutzi JS, Marneth AE, Hem J, Guerra-Moreno A, Rolles B, Bhatt S, Carr SA, Pozdnyakova O,
van Galen P, Mullally A



Leukemia and Lymphoma

Clinical Features and Treatment Outcomes for Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder: A Retrospective Cohort Study from the Dana-Farber Cancer Institute and Updated Literature Review

Said JT, Sun T, Larocca C, Virgen CA, Kupper TS, Fisher DC, Devlin PM, Elco CP, Song JS,
LeBoeuf NR



Leukemia and Lymphoma

Prognostic Value of Minimal Residual Disease Among Patients with Classical Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplantation

Taranto E, Redd R, Jeter E, McHugh K, Crombie JL, Fisher DC, Jacobsen E, Jacobson CA, Kim AI, LaCasce AS, Odejide OO, Joyce RM, Chen YB, Armand P, Merryman RW



Molecular Oncology

Increased MYBL2 Expression in Aggressive Hormone-Sensitive Prostate Cancer

Wang XV, Chen YH, Burton F, Lee GM, Frank D, Sweeney CJ



Nature Reviews Molecular Cell Biology

Mechanisms of Mitochondrial Respiratory Adaptation

Bennett CF, Latorre-Muro P, Puigserver P




Current Studies and Future Directions for Medulloblastoma: A Review from the Pacific Pediatric Neuro-Oncology Consortium (PNOC) Disease Working Group

Cooney T




Efficacy of Cabozantinib in Metastatic MiT Family Translocation Renal Cell Carcinomas

Thouvenin J, Hirsch L, Viswanathan SR, Bakouny Z, Choueiri TK




End-of-Life Care and Advanced Directives in Hispanic/Latinx Patients: Challenges and Solutions for the Practicing Oncologist

Dean JA, Tanguturi SK, Cagney D, Shin KY, Youssef G, Aizer A, Rahman R, Hammoudeh L, Reardon D, Lee E, Dietrich J, Wickersham L, Wen PY, Catalano P, Haas-Kogan D, Alexander BM, Michor F




Randomized Phase II Trial of Sapanisertib TAK-117 vs. Everolimus in Patients with Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy

Choueiri TK



Oral Oncology

Accuracy and Outcomes of Virtual Surgical Planning and 3D-Printed Guides for Osseous Free Flap Reconstruction of Mandibular Osteoradionecrosis

Annino DJ Jr, Hansen EE, Sethi RK, Horne S, Rettig EM, Uppaluri R, Goguen LA




Cost Effectiveness of Adding Pembrolizumab to Platinum and Fluoropyrimidine-Based Chemotherapy as First-Line Treatment for Advanced Esophageal Cancer: A US Healthcare Payer's Perspective

Enzinger PC



Pharmacoepidemiology and Drug Safety

Validation of Algorithms to Select Patients with Multiple Myeloma and Patients Initiating Myeloma Treatment in the National Veterans Affair Healthcare System

La J, DuMontier C, Dharne M, Yildirim C, Corrigan J, Gaziano JM, Driver JA, Munshi NC, Fillmore NR



Protein and Cell

The Early Days of Structural Biology at the Beijing Institute of Biophysics: In Memory of Professor Zhengjiong Lin (1935-2022)

Wang JH




Molecular Characterization and Therapeutic Approaches to Small Cell Lung Cancer: Imaging Implications

Park H, Tseng SC, Sholl LM, Hatabu H, Awad MM, Nishino M



Science Advances

Optimized ACE2 Decoys Neutralize Antibody-Resistant SARS-CoV-2 Variants Through Functional Receptor Mimicry and Treat Infection in Vivo

Torchia JA, Carstensen LS, Xiao T, Mukherjee S, Reeves PM, Sluder AE, Chen B, Poznansky MC, Freeman GJ



Seminars in Respiratory and Critical Care Medicine

Imaging of Drug-Related Pneumonitis in Oncology

Tseng SC, Nishino M



Support Care Cancer

Identifying Participants' Preferences for Modifiable Chemotherapy-Induced Peripheral Neuropathy Prevention Clinical Trial Factors: An Adaptive Choice-Based Conjoint Analysis

Knoerl R, Meyerhardt JA, Reyes K, Salehi E



Target Oncology

Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors

Shapiro GI



Transplantation and Cellular Therapy

Fatigue in Hematopoietic Cell Transplant Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies

Ullrich CK



Trends in Biochemical Sciences

Coordinating Gene Expression During the Cell Cycle

Schade AE, Branigan TB, DeCaprio JA



Trends in Immunology

Does Delayed EBV Infection Contribute to Rising Childhood Cancers?

Zhang B, Panaampon J, Wang Z