Annals of Oncology
Neratinib and Ado-Trastuzumab Emtansine for Pretreated and Untreated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022
Freedman RA, Heiling HM, Li T, Tayob N, Davis R, Pereslete AM, DeMeo MK, Cotter C, Chen WY, Parsons HA, Moy B, Savoie J, Lin NU
BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM.
PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed.
RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ?6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months.
CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.
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Blood
JAK2-Mutant Clonal Hematopoiesis is Associated with Venous Thromboembolism
Zon RL, Sekar A, Oren O, Niroula A, Gibson CJ, Griffin G, Uddin MM, Neuberg D, Natarajan P, Ebert BL
Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms (MPNs), are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among older individuals and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400?000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1.17 (95% confidence interval [CI], 1.09-1.3; P = .002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1.02 (95% CI, 0.81-1.23; P = .81). TET2-mutant CHIP was associated with incident VTE with a HR of 1.33 (95% CI, 1.05-1.69; P = .02). JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6.58 (95% CI, 2.65-16.29; P = 4.7 × 10-5) and a HR of 4.2 (95% CI, 2.18-8.08; P = 1.7 × 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than heterozygous factor V Leiden and heterozygous prothrombin gene mutation. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.
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Cancer Cell
Midkine as a Driver of Age-Related Changes and Increase in Mammary Tumorigenesis
Yan P, Jimenez ER, Li Z, Bui T, Seehawer M, Nishida J, Foidart P, Stevens LE, Xie Y, Gomez MM, Long HW, Polyak K
Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.
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Cancer Discovery
Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer
Dilly J, Hoffman MT, Abbassi L, Li Z, Parent BD, Hennessey CJ, Jordan AC, Morgado M, Dasgupta S, Uribe GA, Yang A, Kapner KS, Hambitzer FP, Qiang L, Feng H, Geisberg J, Wang J, Evans KE, Roth JA, Cristea S, Van Allen EM, Mancias JD, Shalek AK, Chugh S, Wolpin BM, Raghavan S, Nowak JA, Winter PS, Dougan SK, Aguirre AJ
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
Significance: Acquired resistance may limit the impact of KRAS inhibition in patients with PDAC. Using clinical samples and multiple preclinical models, we define heterogeneous genetic and non-genetic mechanisms of resistance to KRAS inhibition that may guide combination therapy approaches to improve the efficacy and durability of these promising therapies for patients. See related commentary by Marasco and Misale, p. 2018.
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Cell
Structural Basis of Respiratory Complex Adaptation to Cold Temperatures
Shin YC, Latorre-Muro P, Bennett CF, Burger N, Paulo JA, Gygi SP, Puigserver P
In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ?25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.
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Cell Stem Cell
Regulated GATA1 Expression as a Universal Gene Therapy for Diamond-Blackfan Anemia
Voit RA, Liao X, Caulier A, Antoszewski M, Cohen B, Armant M, Lu HY, Fleming TJ, Kamal E, Wahlster L, Huang MM, Clarke W, Perez-Atayde A, Pellin D, Shimamura A, Williams DA, Sankaran VG
Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.
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Journal of Clinical Oncology
Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses from ATEMPT
Tarantino P, Tayob N, Isakoff SJ, Faggen M, Mulvey T, Constantine M, Tung N, Waks AG, DeMeo M, Burstein HJ, Partridge AH, Kurt BB, Mittendorf EA, Winer EP, Krop IE, Tolaney SM
PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.
METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.
RESULTS: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.
CONCLUSION: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.
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Journal of Clinical Oncology
Anthracyclines in Early Breast Cancer: The Long Goodbye
Grinda T, Burstein HJ
For more than 50 years, through successive iterations of regimens incorporating alkylating agents, anthracyclines, and taxanes, adjuvant cytotoxic chemotherapy has improved the prognosis of patients with early breast cancer, reducing recurrence and cancer-related death. Remarkable progress in supportive care – especially antiemetics and growth factor support – has made treatment feasible and tolerable for a greater percentage of patients, although longer-term risks remain, including neuropathy, fatigue, and deconditioning. Anthracyclines in particular are persistently linked to rare instances of cardiac injury or myelodysplasia/acute myeloid leukemia (AML).
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Journal of Clinical Oncology
Pooled Long-Term Outcomes with Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients with Advanced Melanoma
Hodi FS
PURPOSE: Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma.
METHODS: Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms.
RESULTS: Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ?65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy.
CONCLUSION: In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.
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Journal of Clinical Oncology
Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients with Breast Cancer
Morganti S, Gibson CJ, Jin Q, Santos K, Patel A, Wilson A, Merrill M, Vincuilla J, Stokes S, Lipsyc-Sharf M, Parker T, King TA, Mittendorf EA, Hughes ME, Tolaney SM, Weeks LD, Tayob N, Lin NU, Garber JE, Miller PG, Parsons HA
PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited.
PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ?0.005.
RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ?0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ?0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC.
CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ?0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.
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Journal of Clinical Oncology
Revumenib Revises the Treatment Landscape for KMT2A-r Leukemia
Menin inhibitors are a novel class of small molecules that are being developed for leukemias harboring chromosomal rearrangements involving the lysine methyltransferase 2A gene (KMT2A-r), since Menin is a molecular dependency in this genetic subtype of leukemia.1 Issa et al report remarkable results from a phase I/II clinical trial of the Menin inhibitor revumenib (Syndax Pharmaceuticals) in a group of patients with heavily pretreated, relapsed/refractory (R/R) KMT2A-r leukemia. On the basis of the detailed understanding of the mechanisms of action of Menin inhibitors, the potential clinical indications are expanding and include patients with a common form of adult acute myeloid leukemia (AML) driven by mutations in the nucleophosmin (NPM1) gene, in addition to a growing list of leukemias driven by dysregulation of HOX/MEIS gene expression.
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JAMA Oncology
Advancing Global Pharmacoequity in Oncology
Erfani P, Okediji RL, Cliff ERS, Bychkovksy BL, Fadelu T
IMPORTANCE: Limited availability and affordability of cancer drugs contribute to staggering disparities in cancer survival between high-income and low- and middle-income countries (LMICs). As infrastructure for cancer care rapidly develops, there is an urgent need to reduce prices and improve access to cancer medicines in LMICs to advance pharmacoequity globally.
OBSERVATIONS: Prior strategies to expand access to cancer medicines in LMICs have primarily relied on charity or differential pricing and have yielded limited results. Policymakers at the World Health Assembly recently proposed several strategies to increase global access to cancer drugs. Reviewing empirical data and lessons learned from medication access programs for HIV, COVID-19, and other infectious diseases, 3 strategies that multilateral organizations can use to reduce prices of cancer drugs in LMICs are discussed herein. These include (1) building regional technology transfer and manufacturing hubs, (2) expanding and streamlining use of compulsory licenses, and (3) implementing global standards for drug price transparency. Counterpoints to the critiques of these policies are critiqued and how programs can use these strategies to build on existing disease-centered initiatives is discussed.
CONCLUSIONS AND RELEVANCE: Lessons learned from the global response to HIV and COVID-19 show that international collaboration and support from the World Health and Trade Organizations can ensure a unified, coordinated agenda for advancing access to care in LMICs. Building on these lessons and implementing similar approaches for cancer drugs can play a critical role in expanding accessibility and affordability of cancer medicines in LMICs. With a growing burden of cancer morbidity and mortality in LMICs, redoubled efforts to deliver essential cancer medications to LMICs would have an immense impact on global cancer control and achieving the United Nations Sustainable Development Goals.
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Lancet Oncology
Landscape of Subsequent Therapies in Perioperative Immunotherapy Trials Across Multiple Cancer Types
Semaan K, Nawfal R, Choueiri TK
Over the past decade, immune checkpoint inhibitor (ICI) therapies have redefined the standard of care in many cancer types across stages and indications. Backed by large randomised controlled trials (RCTs) across several tumour types, perioperative ICI therapies have become an important addition to our treatment options. However, questions regarding the importance of subsequent treatment administered to trial patients in the control group (often placebo or surveillance) after recurrence quickly arose, leading to debates over trial design and application in real-world practice.
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Lancet Oncology
The State of the Science of Oral Selective Oestrogen Receptor Degraders
Fanucci K, Mayer EL
Medications targeting the oestrogen receptor are foundational therapies for patients with oestrogen receptor-positive metastatic breast cancer, but, despite the efficacy of these agents used alone or in combination with a targeted partner, nearly all patients’ cancers will eventually progress. A primary mechanism of acquired resistance to endocrine therapy for oestrogen receptor-positive disease is the development of ESR1 mutations that affect the ligand-binding domain of the oestrogen receptor, rendering it constitutively active and less sensitive to traditional endocrine therapies.1 These mutations are kinetic, appearing with higher frequency after longer duration of exposure to aromatase inhibitors. Novel oral selective oestrogen receptor degraders (SERDs), which both antagonise the oestrogen receptor and lead to receptor degradation, were developed to overcome endocrine resistance, and might have preferential activity in cancers that have ESR1 mutations. These drugs offer improved bioavailability and increased ease of administration compared with the intramuscularly administered SERD fulvestrant and have become a promising therapy for patients with endocrine-resistant oestrogen receptor-positive disease.
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Nature Communications
Shareable Artificial Intelligence to Extract Cancer Outcomes from Electronic Health Records for Precision Oncology Research
Kehl KL, Paul MA, Trukhanov P, Xu W, Choueiri TK
Databases that link molecular data to clinical outcomes can inform precision cancer research into novel prognostic and predictive biomarkers. However, outside of clinical trials, cancer outcomes are typically recorded only in text form within electronic health records (EHRs). Artificial intelligence (AI) models have been trained to extract outcomes from individual EHRs. However, patient privacy restrictions have historically precluded dissemination of these models beyond the centers at which they were trained. In this study, the vulnerability of text classification models trained directly on protected health information to membership inference attacks is confirmed. A teacher-student distillation approach is applied to develop shareable models for annotating outcomes from imaging reports and medical oncologist notes. 'Teacher' models trained on EHR data from Dana-Farber Cancer Institute (DFCI) are used to label imaging reports and discharge summaries from the Medical Information Mart for Intensive Care (MIMIC)-IV dataset. 'Student' models are trained to use these MIMIC documents to predict the labels assigned by teacher models and sent to Memorial Sloan Kettering (MSK) for evaluation. The student models exhibit high discrimination across outcomes in both the DFCI and MSK test sets. Leveraging private labeling of public datasets to distill publishable clinical AI models from academic centers could facilitate deployment of machine learning to accelerate precision oncology research.
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Nature Medicine
A Multi-Modal Single-Cell and Spatial Expression Map of Metastatic Breast Cancer Biopsies Across Clinicopathological Features
Klughammer J, Abravanel DL, Segerstolpe Å, Blosser TR, Ashenberg O, Slyper M, Vigneau S, Jané-Valbuena J, Chen J, Cohen O, Cullen N, DelloStritto LK, Dionne D, Files J, Frangieh A, Helvie K, Hughes ME, Inga S, Kanodia A, Lako A, MacKichan C, Mages S, Murray E, Napolitano S, Nguyen K, Ortiz R, Patel M, Pfaff KL, Porter CBM, Rotem A, Strauss S, Thorner AR, Turner M, Wakiro I, Waldman J, Wu J, Gómez Tejeda Zañudo J, Zhang D, Lin NU, Tolaney SM, Winer EP, Chen F, Rodig SJ, Zhuang X, Rozenblatt-Rosen O, Johnson BE, Regev A, Wagle N
Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.
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Proceedings of the National Academy of Sciences of the U.S.A.
Biochemical Analysis of EGFR Exon20 Insertion Variants InsASV and InsSVD and their Inhibitor Sensitivity
Zhao H, Beyett TS, Jiang J, Rana JK, Schaeffner IK, Santana J, Jänne PA, Eck MJ
Somatic mutations in the epidermal growth factor receptor (EGFR) are a major cause of non-small cell lung cancer. Among these structurally diverse alterations, exon 20 insertions represent a unique subset that rarely respond to EGFR tyrosine kinase inhibitors (TKIs). Therefore, there is a significant need to develop inhibitors that are active against this class of activating mutations. Here, we conducted biochemical analysis of the two most frequent exon 20 insertion variants, V769_D770insASV (insASV) and D770_N771insSVD (insSVD) to better understand their drug sensitivity and resistance. From kinetic studies, we found that EGFR insASV and insSVD are similarly active, but have lower Km, ATP values compared to the L858R variant, which contributes to their lack of sensitivity to 1st-3rd generation EGFR TKIs. Biochemical, structural, and cellular studies of a diverse panel of EGFR inhibitors revealed that the more recently developed compounds BAY-568, TAS6417, and TAK-788 inhibit EGFR insASV and insSVD in a mutant-selective manner, with BAY-568 being the most potent and selective versus wild-type (WT) EGFR. Cocrystal structures with WT EGFR reveal the binding modes of each of these inhibitors and of poziotinib, a potent but not mutant-selective inhibitor, and together they define interactions shared by the mutant-selective agents. Collectively, our results show that these exon20 insertion variants are not inherently inhibitor resistant, rather they differ in their drug sensitivity from WT EGFR. However, they are similar to each other, indicating that a single inhibitor should be effective for several of the diverse exon 20 insertion variants.
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Proceedings of the National Academy of Sciences of the U.S.A.
PARG Inhibitor Sensitivity Correlates with Accumulation of Single-Stranded DNA Gaps in Preclinical Models of Ovarian Cancer
Ravindranathan R, Somuncu O, da Costa AABA, Mukkavalli S, Lamarre BP, Nguyen H, Grochala C, Jiao Y, Liu J, Kochupurakkal B, Parmar K, Shapiro GI, D'Andrea AD
Poly (ADP-ribose) glycohydrolase (PARG) is a dePARylating enzyme which promotes DNA repair by removal of poly (ADP-ribose) (PAR) from PARylated proteins. Loss or inhibition of PARG results in replication stress and sensitizes cancer cells to DNA-damaging agents. PARG inhibitors are now undergoing clinical development for patients having tumors with homologous recombination deficiency (HRD), such as cancer patients with germline or somatic BRCA1/2-mutations. PARP inhibitors kill BRCA-deficient cancer cells by increasing single-stranded DNA gaps (ssGAPs) during replication. Here, we report that, like PARP inhibitor (PARPi), PARG inhibitor (PARGi) treatment also causes an accumulation of ssGAPs in sensitive cells. PARGi exposure increased accumulation of S-phase-specific PAR, a marker for Okazaki fragment processing (OFP) defects on lagging strands and induced ssGAPs, in sensitive cells but not in resistant cells. PARGi also caused accumulation of PAR at the replication forks and at the ssDNA sites in sensitive cells. Additionally, PARGi exhibited monotherapy activity in specific HR-deficient, as well as HR-proficient, patient-derived, or patient-derived xenograft (PDX)-derived organoids of ovarian cancer, and drug sensitivity directly correlated with the accumulation of ssGAPs. Taken together, PARGi treatment results in toxic accumulation of PAR at replication forks resulting in ssGAPs due to OFP defects during replication. Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.
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American Journal of Lifestyle Medicine
A Cancer Center Multidisciplinary Lifestyle Medicine Clinic: Description of Program and Patient Population
Millstein RA, Lee H, Lapioli A, Winters L, Sullivan C, Bateman S, Frates E, Comander A, Eisenstat S, Peppercorn J, O'Donnell EK
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Blood Advances
A Real-World Comparison of Commercial Use Axicabtagene Ciloleucel and Lisocabtagene Maraleucel in Large B-Cell Lymphoma
Looka A, Qualls DA, Matthews D, Redd RA, Sakellis C, Duffy C, Dela Cruz J, Saucier A, Armand P, Crombie JL, Fisher DC, Jacobsen ED, Kim AI, LaCasce AS, Merryman RW, Parry EM, Jacobson CA
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Blood Advances
Venetoclax Plus Low Intensity Chemotherapy for Adults with Acute Lymphoblastic Leukemia
Luskin MR, Shimony S, Keating JH, Winer ES, Garcia JS, Stone RM, Flamand Y, Stevenson K, Ryan JA, Letai A, DeAngelo DJ
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Blood Cancer Discovery
Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations
Penter L, Cieri N, Maurer K, Kwok M, Lyu H, Lu WS, Oliveira G, Leshchiner I, Neuberg DS, Kim HT, Li S, Ritz J, Getz G, Garcia JS, Soiffer RJ, Livak KJ, Wu CJ
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British Journal of Haematology
ERK1/2 Pro-Survival Signalling Is Suppressed by Pirtobrutinib in Ibrutinib-Resistant MYD88-Mutated Lymphoma Cells
Munshi M, Liu X, Kofides A, Tsakmaklis N, Hunter ZR, Guerrera ML, Canning A, Gustine JN, Liu S, Hatcher JM, Chen J, Meid K, Sarosiek S, Flynn CA, Branagan AR, von Keudell G, Castillo JJ, Yang G, Treon SP
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Clinical Cancer Research
A Phase II Study of Atezolizumab, Pertuzumab, and High-Dose Trastuzumab for Central Nervous System Metastases in Patients with HER2-Positive Breast Cancer
Giordano A, Jin Q, Binboga Kurt B, Ren S, Li T, Leone JP, Mittendorf EA, Pereslete AM, Davis R, DiLullo M, Tayob N, Mayer EL, Winer EP, Tolaney SM, Lin NU
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Clinical Cancer Research
Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer
Singh H, Kapner KS, Yuan C, Narayan RR, Surana R, Huffman BM, Perez K, Cleary JM, Jordan AC, Dias Costa A, Williams HL, Raghavan S, Dougan SK, Nowak JA, Wolpin BM, Aguirre AJ
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Clinical Cancer Research
Re-Irradiation Plus Pembrolizumab: Phase II Study for Recurrent Glioblastoma Patients
Tanguturi SK, Nayak L, Wong ET, Hertan LM, McCluskey C, Hayden J, Muzikansky A, Nakhawa S, Japo J, Bossi CC, Tian Y, Barlow GL, Speliakos P, Ayoub G, Meredith DM, Ligon KL, Haas-Kogan D, Huang K, Wucherpfennig KW, Wen PY, Reardon DA
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ESMO Open
Clinical Outcomes of Early-Stage Triple-Negative Breast Cancer after Neoadjuvant Chemotherapy According to HER2-Low Status?
Jin Q, Hughes ME, Vincuilla J, Parker T, Tarantino P, Mittendorf EA, King TA, Tolaney SM, Tayob N, Lin NU, Garrido-Castro AC
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European Urology Oncology
Combined Fixed-Duration Systemic Treatment and Metastasis-Directed Radiotherapy for Oligometastatic Hormone-Sensitive Prostate Cancer
Ravi P, Zhong C, Xie W, Kelly E, Whelpley B, Kuczmarski K, Beltran H, Kilbridge KL, King MT, McGregor BA, Morgans AK, Pomerantz M, Taplin ME, Tewari AK, Viswanathan SR, Wei XX, Anh Huynh M, Choudhury AD
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Oncogene
Editorial Expression of Concern: Activation of NF-?B and Upregulation of Intracellular Anti-Apoptotic Proteins Via the IGF-1/Akt Signaling in Human Multiple Myeloma Cells: Therapeutic Implications
Mitsiades CS, Mitsiades N, Poulaki V, Schlossman R, Akiyama M, Chauhan D, Hideshima T, Treon SP, Munshi NC, Richardson PG, Anderson KC
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Patient Education and Counseling
Differences in Code Status Practice Patterns Among Emergency Clinicians Working in Japan and the United States
Numata K, Fujitani S, Funakoshi H, Yoshida M, Nomura Y, Tanii R, Takemura N, Bowman J, Lakin JR, Higuchi M, Liu SW, Kennedy M, Tulsky JA, Neville TH, Ouchi K
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