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Dana-Farber Research Publication 10.1.2022

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October 1, 2022

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: Michael_buller@dfci.harvard.edu.

Blood

AML Relapse After a TIGIT Race

Penter L, Wu CJ

In this issue of Blood, Gournay et al dissect donor immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) with mass cytometry and identify T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD161-expressing CD4+ T cells as early immune correlates of subsequent acute myelogenous leukemia (AML) relapse after HSCT.


Blood

Clonal Hematopoiesis of Indeterminate Potential and Risk of Death from COVID-19

Miller P, Fell G, Foy B, Scherer A, Gibson CJ, Sperling AS, Nakao T, Uddin MM, Warren H, Bry L, Pozdnyakova O, Frigault MJ, Neuberg D, Higgins JM, Mansour M, Natarajan P, Kim AS, Ebert BL

Clonal hematopoiesis is an age-related phenomenon in which a clonal population of blood cells emerges and is often detected by the presence of a mutation present in a peripheral blood sample. Clonal hematopoiesis of indeterminate potential (CHIP) is a subtype of clonal hematopoiesis found in individuals without a hematologic malignancy in which a somatic pathogenic mutation in a gene mutated in myeloid neoplasia is present in at least 2% of the sequenced blood DNA (termed variant allele fraction, or VAF). CHIP is associated with increased mortality and risk of adverse outcomes including cardiovascular and pulmonary disease (COPD). These associations, which are largely driven by CHIP clones with VAF greater than 0.1, are thought to arise from augmentation of inflammasome-mediated IL-1ß and IL-6 production by mutant macrophages.


Blood

TET2-Mutant Clonal Hematopoiesis and Risk of Gout

Agrawal M, Niroula A, Cunin P, McConkey M, Shkolnik V, Kim PG, Wong WJ, Weeks LD, Lin AE, Miller PG, Gibson CJ, Sekar A, Schaefer IM, Neuberg D, Stone RM, Uddin MM, Griffin GK, Natarajan P, Nigrovic PA, Rao DA, Ebert BL

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1b (IL-1b). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1b, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ?2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ?10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ?10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1b secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1b in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1b levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.


Blood

The End of the Beginning: Application of Single Cell Sequencing to Chronic Lymphocytic Nagler A, Wu CJ

Single cell analysis has emerged over the past decade as a transformative technology informative for the systematic analysis of complex cell populations such as in cancers and the tumor immune microenvironment. The methodologic and analytical advancements in this realm have rapidly evolved, scaling from but a few cells at its outset to the current capabilities of processing and analyzing hundreds of thousands of individual cells at a time. The types of profiling attainable at individual cell resolution now range from genetic and transcriptomic characterization and extend to epigenomic and spatial analysis. Additionally, the increasing ability to achieve multi-omic integration of these data layers now yield ever richer insights into diverse molecular disease subtypes and the patterns of cellular circuitry on a per-cancer basis. Over the years, chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genomic investigation, given the ready accessibility of pure leukemia cells and immune cells from circulating blood of patients with this disease. Herein, we review the recent forays into the application of single cell analysis to CLL, which are already revealing new understanding of the natural progression of CLL, the impact of novel therapies, and the interactions with co-evolving non-malignant immune cell populations. As we emerge from the 'end of the beginning' of this technologic revolution, CLL stands poised to reap the benefits of single cell analysis from the standpoints of uncovering fresh fundamental biology, and of providing a path to devising regimes of personalized diagnosis, treatment, and monitoring.


Blood

Whole-Genome CRISPR Screening Identifies N-Glycosylation as a Genetic and Therapeutic Vulnerability in CALR-Mutant MPNs

Jutzi JS, Marneth AE, Ciboddo M, Guerra-Moreno A, Kosmidou A, Hamel R, Lozano P, Doench JG, Elf S, Mullally A

Calreticulin (CALR) mutations are frequent, disease-initiating events in myeloproliferative neoplasms (MPNs). Although the biological mechanism by which CALR mutations cause MPNs has been elucidated, there currently are no clonally selective therapies for CALR-mutant MPNs. To identify unique genetic dependencies in CALR-mutant MPNs, we performed a whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) knockout depletion screen in mutant CALR-transformed hematopoietic cells. We found that genes in the N-glycosylation pathway (among others) were differentially depleted in mutant CALR-transformed cells as compared with control cells. Using a focused pharmacological in vitro screen targeting unique vulnerabilities uncovered in the CRISPR screen, we found that chemical inhibition of N-glycosylation impaired the growth of mutant CALR-transformed cells, through a reduction in MPL cell surface expression. We treated Calr-mutant knockin mice with the N-glycosylation inhibitor 2-deoxy-glucose (2-DG) and found a preferential sensitivity of Calr-mutant cells to 2-DG as compared with wild-type cells and normalization of key MPNs disease features. To validate our findings in primary human cells, we performed megakaryocyte colony-forming unit (CFU-MK) assays. We found that N-glycosylation inhibition significantly reduced CFU-MK formation in patient-derived CALR-mutant bone marrow as compared with bone marrow derived from healthy donors. In aggregate, our findings advance the development of clonally selective treatments for CALR-mutant MPNs.


Cancer Cell

A Druggable Addiction to De Novo Pyrimidine Biosynthesis in Diffuse Midline Glioma

Pal S, Kaplan JP, Nguyen H, Stopka SA, Regan MS, Nguyen QD, Jones KL, Moreau LA, Peng J, Dipiazza MG, Perciaccante AJ, Hunsel BR, Liu KX, Alexandrescu S, Filbin MG, Agar NYR, Chowdhury D, Haas-Kogan DA

Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pyrimidine biosynthesis pathway. A clinical stage inhibitor of DHODH (rate-limiting enzyme in the de novo pathway) diminishes uridine-5'-phosphate (UMP) pools, generates DNA damage, and induces apoptosis through suppression of replication forks-an "on-target" effect, as shown by uridine rescue. Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs.


Cancer Cell

De Novo Pyrimidine Synthesis is a Targetable Vulnerability in IDH Mutant Glioma

Shi DD, Wang AC, Endress JE, Stopka SA, Regan MS, Gao W, Khanal J, Lee JH, Huang B, Jennings RB, Bonal DM, Cameron AB, Asara JM, Nguyen QD, Signoretti S, Losman JA, Cahill DP, Ligon KL, Agar NYR, Kaelin WG Jr

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.


Cancer Cell

Getting a Handle on KRAS Inhibitor Resistance with Hapten-Mediated Anti-Tumor Immunity

Freed-Pastor WA, Aguirre AJ

Covalent inhibitors of oncogenic KRASG12C have demonstrated impressive clinical responses; however, therapeutic resistance has been commonly observed. In this issue, Zhang and colleagues demonstrate that small molecule KRASG12C inhibitors can generate haptenated major istocompatibility complex (MHC) class I:peptide complexes, which represent attractive targets for immune-based therapies to combat pharmacologic resistance.


Cancer Cell

Personalized Neoantigen Vaccine NEO-PV-01 with Chemotherapy and Anti-PD-1 as First-Line Treatment for Non-Squamous Non-Small Cell Lung Cancer

Awad MM

Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination. Epitope spread to non-vaccinating neoantigens, including responses to KRAS G12C and G12V mutations, were detected post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination revealed effector and cytotoxic phenotypes with increased CD4+ T cell infiltration in the post-vaccine tumor biopsy. Collectively, these data support the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.


Cancer Discovery

Navigating the HER2-Low Paradigm in Breast Oncology: New Standards, Future Horizons

Tarantino P, Tolaney SM

The confirmation of the HER2-low paradigm is expected to have a major impact in breast oncology. About half of all breast cancers harbor HER2-low expression, which can be targeted with the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), leading to a relevant survival benefit in the metastatic setting. Given this observation, treatment algorithms for both hormone receptor-positive and triple-negative breast cancer are expected to significantly evolve in the next future. Several challenges, however, remain in the interpretation of HER2-low expression related to its biological role, its pathologic diagnosis, and the definition itself of HER2-low. In this article, we recapitulate the current knowledge on HER2-low breast cancer, discussing whether it should be considered a distinct subtype, how it should be implemented in the clinic, and how its definition may evolve in the coming years with the evolution of our clinical and translational knowledge.


Cancer Discovery

NCOA4-Mediated Ferritinophagy Is a Pancreatic Cancer Dependency via Maintenance of Iron Bioavailability for Iron-Sulfur Cluster Proteins

Santana-Codina N, Del Rey MQ, Kapner KS, Zhang H, Gikandi A, Malcolm C, Poupault C, Kuljanin M, John KM, Biancur DE, Lowder KE, Hennessey CJ, Yang A, Shah Nowak JA, Aguirre AJ, Mancias JD

Pancreatic ductal adenocarcinomas (PDAC) depend on autophagy for survival; however, the metabolic substrates that autophagy provides to drive PDAC progression are unclear. Ferritin, the cellular iron storage complex, is targeted for lysosomal degradation (ferritinophagy) by the selective autophagy adaptor NCOA4, resulting in release of iron for cellular utilization. Using patient-derived and murine models of PDAC, we demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability, thereby promoting tumor progression. Quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster protein synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with the development of compensatory iron acquisition pathways. Finally, enhanced ferritinophagy accelerates PDAC tumorigenesis, and an elevated ferritinophagy expression signature predicts for poor prognosis in patients with PDAC. Together, our data reveal that the maintenance of iron homeostasis is a critical function of PDAC autophagy, and we define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC. SIGNIFICANCE: Autophagy and iron metabolism are metabolic dependencies in PDAC. However, targeted therapies for these pathways are lacking. We identify NCOA4-mediated selective autophagy of ferritin ("ferritinophagy") as upregulated in PDAC. Ferritinophagy supports PDAC iron metabolism and thereby tumor progression and represents a new therapeutic target in PDAC. See related commentary by Jain and Amaravadi, p. 2023. See related article by Ravichandran et al., p. 2198. This article is highlighted in the In This Issue feature, p. 2007.


JAMA Oncology

Evaluation of Treatment with Talazoparib and Avelumab in Patients with Recurrent Mismatch Repair Proficient Endometrial Cancer

Konstantinopoulos PA, Gockley AA, Xiong N, Krasner C, Horowitz N, Campos S, Wright AA, Liu JF, Shea M, Yeku O, Castro C, Polak M, Lee EK, Sawyer H, Bowes B, Cheng SC, Tayob N, Bouberhan S, Spriggs D, Penson RT, Nucci MR, Matulonis UA

IMPORTANCE: Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.

OBJECTIVE: To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.

DESIGN, SETTINGS, AND PARTICIPANTS: This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies.

INTERVENTIONS: Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects.

MAIN OUTCOMES AND MEASURES: Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity.

RESULTS: Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit.

CONCLUSIONS AND RELEVANCE: The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02912572.


JAMA Oncology

AML Relapse After a TIGIT Race

Duma N

Identical degrees do not always lead to equal opportunity. I grew up as a child of 2 attorneys who graduated at the same time from the same law school, but only 1 faced gender bias throughout her career. In addition to encountering sexism and harassment while practicing law full-time, my mother was expected to care for me, my brother, and our home. Even with a supportive spouse, these obligations certainly influenced her career choices. My childhood’s household division-of-labor was not unique, and the field of medicine is not immune. A 2019 study reported that within just 6 years of completing medical training, women physicians are substantially more likely to report cutting back on their hours and cite family responsibilities as the major factor behind this career decision. This gap in work hours so early in a career may propagate further gender inequities, such as salary and future promotions.


Journal of Clinical Oncology

Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

Madanat-Harjuoja LM, Klega K, Thorner AR, Nag A, Diller LR, Mullen EA, Crompton BD

PURPOSE: The utility of circulating tumor DNA (ctDNA) analyses has not been established in the risk stratification of Wilms tumor (WT). We evaluated the detection of ctDNA and selected risk markers in the serum and urine of patients with WT and compared findings with those of matched diagnostic tumor samples.

PATIENTS AND METHODS: Fifty of 395 children with stage III or IV WT enrolled on Children's Oncology Group trial AREN0533 had banked pretreatment serum, urine, and tumor available. Next-generation sequencing was used to detect ctDNA. Copy-number changes in 1q, 16q, and 1p, and single-nucleotide variants in serum and urine were compared with tumor biopsy data. Event-free survival (EFS) was compared between patients with and without ctDNA detection.

RESULTS: ctDNA was detected in the serum of 41/50 (82%) and in the urine in 13/50 (26%) patients. Agreement between serum ctDNA detection and tumor sequencing results was as follows: 77% for 1q gain, 88% for 16q deletions, and 70% for 1p deletions, with ƒ?-coefficients of 0.56, 0.74, and 0.29, respectively. Sequencing also demonstrated that single-nucleotide variants detected in tumors could be identified in the ctDNA. There was a trend toward worse EFS in patients with ctDNA detected in the serum (4-year EFS 80% v 100%, P = .14).

CONCLUSION: ctDNA demonstrates promise as an easily accessible prognostic biomarker with potential to detect tumor heterogeneity. The observed trend toward more favorable outcome in patients with undetectable ctDNA requires validation. ctDNA profiling should be further explored as a noninvasive diagnostic and prognostic tool in the risk-adapted treatment of patients with WT.


Journal of Clinical Oncology

Evolving Role of Prostate-Specific Membrane Antigen-Positron Emission Tomography in Metastatic Hormone-Sensitive Prostate Cancer: More Questions than Answers?

Jacene H, Taplin ME, Sweeney C

Although most men with metastatic hormone-sensitive prostate cancer (mHSPC) die of prostate cancer (PCa), there remains significant outcome variability, with approximately 18.5% living 10 years or longer. Prognosis and management are determined in part by disease extent detected on conventional imaging (CIM; 99mTc Bone and computed tomography [CT] scan; Data Supplement, online only). With the advent of multiple new life-prolonging therapies, clinicians can better personalize therapy on the basis of these findings. However, the availability of new imaging modalities with varying performance characteristics has added more variables that affect clinical decision making.


Journal of Clinical Oncology

Long-Term Benefits of Tagraxofusp for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm

Lane AA

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. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy. We report long-term results, including data from the continued access phase, of the largest prospective BPDCN trial evaluating the CD123-targeted therapy tagraxofusp (TAG) in adults with treatment-naive and relapsed/refractory BPDCN. The primary outcome was complete response (CR) + clinical CR (CRc: CR with residual skin abnormality not indicative of active disease). Eighty-four (65 treatment-naive and 19 relapsed/refractory) of 89 patients received TAG 12 μg/kg once daily; the median follow-up was 34.0 months. For treatment-naive patients, the overall response rate was 75%; 57% achieved CR + CRc. The median time to remission was 39 (range, 14-131) days, and the median CR + CRc duration was 24.9 (95% CI, 3.8 to not reached) months. Nineteen patients (51%) with CR + CRc were bridged to stem-cell transplant, with a median CR + CRc duration of 22.2 (range, 1.5-57.4) months. Most common adverse events were increased alanine (64%) or aspartate (60%) aminotransferase and hypoalbuminemia (51%); most occurred in cycle 1 and were transient. Capillary leak syndrome occurred in 21% of patients (grade 3: 7%). In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant. TAG was generally well-tolerated with a predictable and manageable safety profile.


Journal of Clinical Oncology

Reply to K.L. Campbell Et Al

Ligibel JA

We appreciate the interest shown by Campbell et al in the ASCO guideline “Exercise, Diet, and Weight Management During Cancer Treatment” and agree that exercise has important benefits for patients undergoing cancer treatment. We see the new ASCO guideline and the American College of Sports Medicine (ACSM) “Exercise Guidelines for Cancer Survivors” as complementary efforts, providing important guidance for the oncology clinician and exercise professional communities, respectively.


Lancet Oncology

Call for Action: Expanding Global Access to Hereditary Cancer Genetic Testing

Bychkovsky B, Rana HQ, Taghian A, Koeller DR, Sandoval RL

Globally, access to hereditary cancer genetic testing (CGT) remains inadequate, despite the important implications for clinical care when a pathogenic variant is identified. The disparity in access to testing is particularly evident in low-income and middle-income countries (LMICs), where CGT is often unavailable or prohibitively expensive, especially in public health systems. Even when testing is affordable to patients, logistical barriers further restrict access because patients assume indirect costs (eg, transportation to appointments and missed work).


Lancet Oncology

Pembrolizumab Versus Placebo as Post-Nephrectomy Adjuvant Therapy for Clear Cell Renal Cell Carcinoma (KEYNOTE-564): 30-Month Follow-Up Analysis of a Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial

Choueiri TK

BACKGROUND: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.

METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.

FINDINGS: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30¬?1 months (IQR 25¬?7-36¬?7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0¬?63 [95% CI 0¬?50-0¬?80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.

INTERPRETATION: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.

FUNDING: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.


Nature

Structure-Function Analysis of the SHOC2-MRAS-PP1C Holophosphatase Complex

Kwon JJ, Hajian B, Bian Y, Amor AJ, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Perry CK, Burgin A, Lemke CT, Hahn WC, Aguirre AJ

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development.


Title

AML Relapse After a TIGIT Race

Author

TEXT


Nature Genetics

Genetic Determinants of Chromatin Reveal Prostate Cancer Risk Mediated by Context-Dependent Gene Regulation

Baca SC, Zacharia S, Seo JH, Anderson J, Fay AP, Kalita C, Groha S, Pomerantz MM, Wang V, Sweeney CJ, Pasaniuc B, Gusev A, Freedman ML

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.


Advances in Radiation Oncology

Less Time Is Less Motion: Analysis of Practical Efficiencies Gained with a Modified Workflow Integrating Planar kV Midimaging With CBCT for Spine Stereotactic Body Radiation Therapy

Hu DY, Xu Y, Chen YH, Khosravi M, Lyatskaya Y, Bredfeldt JS, Hacker FL, Balboni TA, Spektor A, Cagney D, Mak R, Huynh MA


Advances in Radiation Oncology

Magnetic Resonance-Guided Prostate Stereotactic Body Radiation Therapy with Daily Online Plan Adaptation: Results of a Prospective Phase 1 Trial and Supplemental Cohort

Leeman JE, Cagney DN, Mak RH, Huynh MA, Tanguturi SK, Singer L, Catalano P, Martin NE, D'Amico AV, Mouw KW, Nguyen PL, King MT, Han Z, Williams C, Huynh E


Blood Advances

Clinical Response to Belumosudil in Bronchiolitis Obliterans Syndrome: A Combined Analysis from 2 Prospective Trials

DeFilipp Z, Kim HT, Cutler CS


Blood Cancer Discovery

Transcriptional Plasticity Drives Leukemia Immune Escape

Eagle K, Harada T, Kalfon J, Perez MW, Heshmati Y, Ewers J, Dempster JM, Kugener G, Dharia NV, Stegmaier K, Orkin SH, Pimkin M


Breast Cancer Research and Treatment

Acceptability of a Companion Patient Guide to Support Expert Consensus Guidelines on Surveillance Mammography in Older Breast Cancer Survivors

Freedman RA, Revette AC, Gagnon H, Perilla-Glen A, Kokoski M, Hussein SO, Leone E, Hixon N, Lovato R, Loeser W, Lin NU, Minami CA, LeStage B, Faggen M, Poorvu PD, McKenna J, Keating NL, Schonberg MA


Cancer

Body Weight Changes and Associated Predictors in a Prospective Cohort of Young Breast Cancer Survivors

Sella T, Zheng Y, Tan-Wasielewski Z, Poorvu PD, Tayob N, Gelber SI, Come SE, Peppercorn JM, Partridge AH, Ligibel JA


Cancer

Efficacy of Neoadjuvant Chemotherapy in Male Breast Cancer Compared with Female Breast Cancer

Leone JP, Hassett MJ, Tolaney SM, Leone BA, Winer EP, Lin NU


Cancer

In Pursuit of Equity in Cancer Care: Moving Beyond the Affordable Care Act

Lam MB


Cancer Imaging

Will Ultra-Extended Field-of-View Scanners be an Expensive Folly or the Next Clinical Standard for PET/CT?

Van den Abbeele AD


Cancer Immunology Research

Regulatory Programs of B-cell Activation and Germinal Center Reaction Allow B-ALL Escape from CD19 CAR T-cell Therapy

Im NG, Guillaumet-Adkins A, Wal M, Rogers AJ, Frede J, Havig CC, Yang J, Anand P, Stegmann SK, Waldschmidt JM, Sotudeh N, Niu L, Voisine J, Grassberger C, Lohr JG, Knoechel B

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Cancer Research

FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits

Tsai JW, Cejas P, Wang DK, Wu DW, Zhou N, Syamala S, Dubois FPB, Crane A, Pelton K, Vogelzang J, Sousa C, Condurat AL, Dixon-Clarke SE, Zhou KN, Lu SD, Gonzalez EM, Chacon MS, Digiacomo JJ, Kumbhani R, Novikov D, Hunter J, McFarland JM, Getz G, Aguet F, Ligon KL, Hovestadt V, Long H, Bandopadhayay P


Cancer Research

MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer

Tani T, Springer BF, Shibata H, Mahadevan NR, Campisi M, Thai TC, Haratani K, Sundararaman SK, Knelson EH, Vajdi A, Uppaluri R, Paweletz CP, Lizotte PH, Gokhale PC, Janne PA, Barbie DA


Cancer Treatment Reviews

Clinical Trial Data of Anti-PD-1/PD-L1 Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: A Review

Haddad RI


Clinical and Translational Radiation Oncology

Splenic Irradiation Contributes to Grade ? 3 Lymphopenia After Adjuvant Chemoradiation for Stomach Cancer

Mamon HJ


Clinical Cancer Research

Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases

Kabraji S, Ni J, Li T, Wang Y, Pereslete A, Hsu L, DiPiro PJ, Hughes M, Winer EP, Zhao JJ, Lin NU


Clinical Cancer Research

Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma

Denize T, Hou Y, Pignon JC, Walton E, West DJ, Freeman GJ, Braun DA, Wu CJ, McDermott D, Choueiri TK, Shukla SA, Signoretti S


Endocrine-Related Cancer

SDHx Mutations and Temozolomide in Malignant Pheochromocytoma and Paraganglioma

Perez K, Jacene H, Hornick JL, Ma C, Vaz N, Brais LK, Alexander H, Baddoo W, Astone K, Chan JA


European Journal of Cancer

Estimating Long-Term Mortality in Women with Hormone Receptor-Positive Breast Cancer: The 'ESTIMATE' Tool/a>

Leone JP, Graham N, Tolaney SM, Freedman RA, Hassett MJ, Winer EP, Lin NU, Tayob N


European Urology

Obesity in Relation to Renal Cell Carcinoma Incidence and Survival in Three Prospective Studies

Graff RE, Wilson KM, Chang SL, McDermott DF, Choueiri TK, Cho E, Signoretti S, Giovannucci EL, Preston MA


Experimental Hematology and Oncology

Therapeutic Activation of G Protein-Coupled Estrogen Receptor 1 in Waldenström Macroglobulinemia

Morelli E, Hunter ZR, Fulciniti M, Gulla A, Treon SC, Munshi NC


Expert Opinion on Pharmacotherapy

Current Therapeutic Options for Glioblastoma and Future Perspectives

Aquilanti E, Wen PY


Future Oncology

EPIK-O/ENGOT-OV61: Alpelisib Plus Olaparib vs Cytotoxic Chemotherapy in High-Grade Serous Ovarian Cancer (Phase III Study)

Konstantinopoulos PA, Matulonis UA


Future Oncology

MAJIC: A Phase III Trial of Acalabrutinib Venetoclax Versus Venetoclax Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Ryan CE, Davids MS


International Journal of Radiation Oncology, Biology, Physics

Beyond Mean Heart Dose: Cardiac Metrics for the Modern Era

Jimenez RB, Bellon JR


JAMA Network Open

Change in the Parent-Clinician Relationship Throughout the First Year of Treatment in Pediatric Oncology

Mack JW, Jaung T, Uno H


JAMIA Open

Framework for Integrating Electronic Patient-Reported Data in Routine Cancer Care: An Oncology Intake Questionnaire

McCleary NJ, Haakenstad EK, Cleveland JLF, Manni M, Hassett MJ, Schrag D


JCI Insight

Patterns of Structural Variation Define Prostate Cancer Across Disease States

Zhou M, Zhang Z, Carrot-Zhang J, Beroukhim R, Van Allen EM, Choudhury AD, Freedman ML, Taplin ME, Meyerson M, Viswanathan SR


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

Breast Medical Oncologists' Perspectives of Telemedicine for Breast Cancer Care: A Survey Study

Stavrou E, Qiu J, Zafar A, Tramontano AC, Isakoff S, Winer E, Manz C


JCO Oncology Practice

Ethics Consultation in Oncology: The Search for Quality in Quantity

Marron JM, Hantel A, Abel GA, Peppercorn JM


JCO Oncology Practice

How Safe Is Cancer Care?

Jacobson JO, Peppercorn J


Journal of Nursing Administration

Ambulatory Oncology Nurses Weigh in About 12-Hour Shifts

Jabaley T, Bagley J, Beardslee B, Hammer MJ


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 Palliative Medicine

Cancer Patients' Experiences with and Perspectives on the Medicinal Cannabis "High"

Tung SC, Nayak MM, Chai PR, Tulsky J, Sannes TS, Yusufov M, Braun IM


Journal of Palliative Medicine

Developing and Field Testing BOLSTER: A Nurse-Led Care Management Intervention to Support Patients and Caregivers following Hospitalization for Gynecologic Cancer-Associated Peritoneal Carcinomatosis

Pozzar RA, Enzinger AC, Poort H, Furey A, Orechia M, Thompson E, Tavormina A, Fenton ATHR, Jaung T, Braun IM, DeMarsh A, Cooley ME, Wright AA


Journal of the American Medical Informatics Association

21st Century Cures Act: Ethical Recommendations for New Patient-Facing Products

Durieux BN, Lindvall C


Journal of Urology

Neoadjuvant Novel Hormonal Therapy Followed by Prostatectomy versus Up-Front Prostatectomy for High-Risk Prostate Cancer: A Comparative Analysis

Ravi P, Kwak L, Xie W, Kelleher K, Acosta AM, Kibel AS, Taplin ME


Lancet Digital Health

Clinical Validation of Deep Learning Algorithms for Radiotherapy Targeting of Non-Small-Cell Lung Cancer: An Observational Study

Hosny A, Bitterman DS, Guthier CV, Qian JM, Roberts H, Perni S, Saraf A, Peng LC, Pashtan I, Ye Z, Kann BH, Kozono DE, Christiani D, Aerts HJWL, Mak RH


Leukemia Research

Patient Experience Before and After Treatment with Idecabtagene Vicleucel (ide-cel, bb2121): Qualitative Analysis of Patient Interviews in the KarMMa Trial

Munshi NC


Molecular Cancer Research

Dependence on the MUC1-C Oncoprotein in Classic, Variant, and Non-Neuroendocrine Small Cell Lung Cancer

Fushimi A, Morimoto Y, Ishikawa S, Yamashita N, Bhattacharya A, Daimon T, Rajabi H, Jin C, Hagiwara M, Yasumizu Y, Luan Z, Suo W, Kufe D


Molecular Cancer Therapeutics

p53 Pathway Inactivation Drives SMARCB1-Deficient p53-Wildtype Epithelioid Sarcoma Onset Indicating Therapeutic Vulnerability Through MDM2 Inhibition

Zimmerman MW, Chi SN, Aster JC, Look AT


Molecular Oncology

Increased MYBL2 Expression in Aggressive Hormone-Sensitive Prostate Cancer

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


Nature Biotechnology

Haplotype-Resolved Assembly of Diploid Genomes Without Parental Data

Cheng H, Li H


Nature Methods

Cell Type-Specific Inference of Differential Expression in Spatial Transcriptomics

Cable DM, Murray E, Shanmugam V, Zhang S, Zou LS, Diao M, Chen H, Macosko EZ, Irizarry RA, Chen F


Nature Methods

MIRA: Joint Regulatory Modeling of Multimodal Expression and Chromatin Accessibility in Single Cells

Lynch AW, Theodoris CV, Long HW, Brown M, Liu XS, Meyer CA


Nature Reviews Cancer

Structural Variations in Cancer and the 3D Genome

Dubois F, Beroukhim R


Nature Reviews Clinical Oncology

Is Early-Onset Cancer an Emerging Global Epidemic? Current Evidence and Future Implications

Ugai T, Sasamoto N, Lee HY, Ando M, Song M, Kawachi I, Giovannucci EL, Rebbeck TR, Ogino S


Nature Reviews Neurology

Clinical Implications of the 2021 Edition of the WHO Classification of Central Nervous System Tumours

Berger T, Wen PY


NPJ Breast Cancer

STING Agonism Enhances Anti-Tumor Immune Responses and Therapeutic Efficacy of PARP Inhibition in BRCA-Associated Breast Cancer

Pantelidou C, Jadhav H, Kothari A, Liu R, Wulf GM, Guerriero JL, Shapiro GI


NPJ Precision Oncology

Secondary IDH1 Resistance Mutations and Oncogenic IDH2 Mutations Cause Acquired Resistance to Ivosidenib in Cholangiocarcinoma

Cleary JM, Rouaisnel B, Raghavan S, Roller LA, Huffman BM, Singh H, Wen PY, Bardeesy N, Wolpin BM, Losman JA


Oral Oncology

The Mouse Oral Carcinoma (MOC) Model: A 10-Year Retrospective on Model Development and Head and Neck Cancer Investigations

Kono M, Saito S, Egloff AM, Uppaluri R


Palliative Medicine

Opportunities for Computational Tools in Palliative Care: Supporting Patient Needs and Lowering Burden

Durieux BN, Tarbi EC, Lindvall C


Pediatric Blood and Cancer

End-of-Life Care Quality for Children with Cancer Who Receive Palliative Care

Wolfe J


Pediatric Blood and Cancer

Feasibility of Oncology Clinical Trial-Embedded Evaluation of Social Determinants of Health

Aziz-Bose R, Umaretiya PJ, Ilcisin L, Stevenson K, Koch V, Valenzuela A, Silverman LB, Wolfe J, Bona K


Prostate

Association Between Baseline Body Mass Index and Survival in Men with Metastatic Hormone-Sensitive Prostate Cancer: ECOG-ACRIN CHAARTED E3805

Chen YH, Sweeney CJ


Seminars in Nuclear Medicine

Imaging for Radiation Planning in Breast Cancer

Sakellis CG, Jacene HA


Transplantation and Cellular Therapy

Real-World Evidence of Axicabtagene Ciloleucel for the Treatment of Large B Cell Lymphoma in the United States

Jacobson CA, Nikiforow S


Trends in Cell Biology

Moonlighting Translation Factors: Multifunctionality Drives Diverse Gene Regulation

Farache D, Antine SP, Lee ASY