Featured
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Article
| Open Access
Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial
In the phase 2 HUDSON study, patients with advanced non-small-cell lung cancer received anti-PD-L1 combined with biomarker-guided therapy targeting ATR kinase, PARP, STAT3 or CD73, leading to encouraging clinical benefit in response to combination of the ATR kinase inhibitor ceralasertib with durvalumab.
- Benjamin Besse
- , Elvire Pons-Tostivint
- & John V. Heymach
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Article |
Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma
Cohort-scale integration of clinical and proteomic data from tumor tissues in patients with pancreatic ductal adenocarcinoma led to the identification of a prognostic risk model for patient stratification as well as biomarkers of response to adjuvant chemotherapy, validated in independent external cohorts.
- Lingxi Jiang
- , Jiejie Qin
- & Baiyong Shen
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Research Briefing |
Machine learning improves prediction of clinical outcomes for invasive breast cancers
A prognostic model for invasive breast cancer that is based on interpretable measurements of epithelial, stromal, and immune components outperforms histologic grading by expert pathologists. This model could improve clinical management of patients diagnosed with invasive breast cancer and address the concerns of pathologists about artificial intelligence (AI) trustworthiness by providing transparent and explainable predictions.
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Article |
Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses
A risk score based on a 34-gene signature for outcome prediction in meningioma was developed and validated in large multi-institutional cohorts and showed better performance in discriminating postoperative menignioma outcomes compared with existing meningioma classification systems.
- William C. Chen
- , Abrar Choudhury
- & David R. Raleigh
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Brief Communication
| Open Access
Liquid biopsy epigenomic profiling for cancer subtyping
In a large multi-cancer cohort, a single liquid biopsy assay enables the detection of four epigenomic modifications, allowing the monitoring of expression of potential drug targets and resistance genes.
- Sylvan C. Baca
- , Ji-Heui Seo
- & Matthew L. Freedman
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Article |
Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial
Treatment of patients with metastatic salivary gland cancer with anti-PD-1 and anti-CTLA-4 led to encouraging clinical benefit in certain histologic subtypes, with translational analyses showing pre-existing T cell clonal expansion in responding tumors.
- Joris L. Vos
- , Bharat Burman
- & Luc G. T. Morris
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Article
| Open Access
Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results
In patients with DNA damage response-deficient solid tumors, the oral ATR kinase inhibitor camonsertib was well tolerated; a recommended phase 2 dose was identified; and encouraging anti-tumor activity was observed, with the highest response rate observed in patients with ovarian cancer.
- Timothy A. Yap
- , Elisa Fontana
- & Ezra Rosen
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Research Briefing |
High-resolution circulating tumor DNA testing predicts survival in metastatic lung cancer clinical trials
Data from circulating tumor DNA (ctDNA) testing were generated for over 1,900 samples across at least 3 time points in a phase 3 clinical trial and used to build a machine learning model to predict patient survival. The model accurately identified patients with a high risk of disease recurrence and could provide a basis for assigning therapies in phase 1/2 clinical trials.
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Article
| Open Access
A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer
A machine learning model that uses longitudinal ctDNA metrics robustly predicts survival in two phase 3 trials of patients with metastatic NSCLC, which may improve therapy selection and risk stratification.
- Zoe June F. Assaf
- , Wei Zou
- & Katja Schulze
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Brief Communication |
High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial
High-dose ipilimumab plus nivolumab in locoregionally advanced urothelial cancer led to a higher pathological complete response rate than low-dose ipilimumab in cohort 2. Presurgical absence of plasma (but not urinary) circulating tumor DNA correlated with clinical outcome.
- Jeroen van Dorp
- , Christodoulos Pipinikas
- & Michiel S. van der Heijden
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Research Briefing |
Persistent mutations render cancer cells susceptible to immunotherapy
Tumor mutation burden is an imperfect predictor of response to immunotherapies. Mutations in regions of the genome unlikely to undergo loss during tumor evolution constitute a persistent tumor mutation burden that may drive sustained immunological tumor control in the context of cancer immunotherapy.
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Correspondence |
Accelerated approvals hit the target in precision oncology
- Vivek Subbiah
- , Lori J. Wirth
- & Gautam U. Mehta
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Article
| Open Access
RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer
The presence of inactivating mutations in RNF43, a negative regulator of WNT, in tumor cells predicts improved response rates and survival outcomes in patients with metastatic BRAFV600E colorectal cancer treated with anti-BRAF/EGFR therapy.
- Elena Elez
- , Javier Ros
- & Rodrigo A. Toledo
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Article |
Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer
DNA and RNA sequencing in large cohorts of patients with rectal cancer treated with neoadjuvant therapies identifies biomarkers of response that could inform patient selection for non-operative treatment strategies.
- Walid K. Chatila
- , Jin K. Kim
- & Julio Garcia-Aguilar
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Article |
Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma
Multiomics analysis of tumor samples from the phase 1b GO30140 and phase 3 IMbrave150 trials reveals baseline immune and genetic features that might identify patients with advanced hepatocellular carcinoma who will benefit from atezolizumab and bevacizumab combination therapy.
- Andrew X. Zhu
- , Alexander R. Abbas
- & Yulei Wang
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Article
| Open Access
Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.
- Lacey J. Padrón
- , Deena M. Maurer
- & Robert H. Vonderheide
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Article |
Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial
In the phase 3 IMbassador250 clinical trial, a checkpoint immunotherapy combination with enzalutamide did not improve survival over enzalutamide alone in patients with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The study uncovered genomic and immune biomarkers that may identify patients deriving benefit.
- Thomas Powles
- , Kobe C. Yuen
- & Christopher J. Sweeney
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Article
| Open Access
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
- Anirban Das
- , Sumedha Sudhaman
- & Uri Tabori
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Article |
Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial
Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.
- Michael J. Fisher
- , Chie-Schin Shih
- & D. Wade Clapp
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Article |
Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma
Single-cell analysis of gastric cancer samples tracks the cell of origin of metastatic lesions and identifies an independent prognostic signature of the clinical outcome.
- Ruiping Wang
- , Minghao Dang
- & Linghua Wang
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Letter |
Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i
Clinical activity and biomarker analysis from the COMBI-i trial evaluating PD-1, BRAF and MEK inhibition in patients with metastatic melanoma demonstrate high response rates and uncover molecular correlates of long-term treatment benefit.
- Reinhard Dummer
- , Celeste Lebbé
- & Georgina V. Long
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Article |
Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring
A new approach for whole-genome sequencing of plasma circulating tumor DNA allows for dynamic monitoring of disease burden and ultra-sensitive detection of minimal residual disease.
- Asaf Zviran
- , Rafael C. Schulman
- & Dan A. Landau
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News & Views |
IL-8 and cancer prognosis on immunotherapy
Interleukin-8, produced by intratumoral and circulating myeloid cells, correlates with an immunosuppressive myeloid-enriched tumor microenvironment and adverse cancer prognosis.
- Ziad Bakouny
- & Toni K. Choueiri
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Letter |
Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration
Results from an expansion cohort of the PROFILE 1001 trial describe the anti-tumor activity of crizotinib in people with non-small-cell lung cancer harboring a MET exon 14 alteration.
- Alexander Drilon
- , Jeffrey W. Clark
- & Paul K. Paik
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Article |
High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants
Ultra-sensitive cell-free DNA (cfDNA) sequencing uncovers clonal hematopoiesis as a major source of somatic cfDNA variants in healthy individuals and patients with cancer, and underscores the importance of matched white blood cell DNA sequencing in liquid biopsy procedures.
- Pedram Razavi
- , Bob T. Li
- & Jorge S. Reis-Filho
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Letter |
A clonal expression biomarker associates with lung cancer mortality
TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers.
- Dhruva Biswas
- , Nicolai J. Birkbak
- & Angeles Montero
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Letter |
Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study
Sequencing of circulating tumor DNA from cancer patients is a cost-efficient approach with turnaround time compatible with clinical practice to inform treatment decision-making in a phase 1 trial setting
- Dominic G. Rothwell
- , Mahmood Ayub
- & Matthew G. Krebs
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Letter |
89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer
Initial results from a first-in-human study show that PET imaging with PD-L1 antibodies outperforms immunohistochemistry- or RNA-sequencing-based biomarkers for prediction of clinical response to immunotherapy.
- Frederike Bensch
- , Elly L. van der Veen
- & Elisabeth G. E. de Vries
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Article |
Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.
- David F. McDermott
- , Mahrukh A. Huseni
- & Thomas Powles
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News & Views |
A potential biomarker for anti-PD-1 immunotherapy
A recent study identifies an immune cell type known as classical monocytes in the peripheral blood as a potential biomarker for response to anti-PD-1 immune checkpoint therapy in metastatic melanoma.
- Sangeeta Goswami
- , Sreyashi Basu
- & Padmanee Sharma
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Resource |
The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions
A comprehensive molecular analysis of almost 1,000 pediatric subjects with acute myeloid leukemia (AML) uncovers widespread differences in pediatric AML as compared to adult AML, including a higher frequency of structural variants and different mutational patterns and epigenetic signatures. Future studies are needed to characterize the functional relevance of these alterations and to explore age-tailored therapies to improve disease control in younger patients.
- Hamid Bolouri
- , Jason E Farrar
- & Soheil Meshinchi
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Article |
Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence
Amplification of chromosome 1q21.3 distinguishes cells with tumor-initiating capacity that drive tumor recurrence across different breast cancer subtypes. A droplet digital PCR assay in circulating free tumor DNA identifies patients with early-stage cancer at high risk of relapse and predicts response to therapy in the metastatic setting. Pharmacological blockade of targets within this amplicon using a clinically available compound prevents tumor recurrence, suggesting a potential therapeutic approach to improve the clinical management of patients harboring 1q21.3-amplified breast tumors.
- Jian Yuan Goh
- , Min Feng
- & Qiang Yu
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Article |
Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma
A silent single-nucleotide variant (SNV) affecting the transcription of a long noncoding RNA (lncRNA EGFR-AS1) within the EGFR coding region alters the EGFR isoform ratio and modulates oncogene addiction and response to EGFR tyrosine kinase inhibitors in squamous-cell cancers. Proof-of-concept validation in patients supports the notion that this SNV and levels of the lncRNA could be used to predict response to therapy in a clinical setting. These results, together with findings by Bal et al., uncover the functional role of noncoding RNAs in modulating the response to targeted therapies in cancer.
- Daniel S W Tan
- , Fui Teen Chong
- & N Gopalakrishna Iyer
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Article |
Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients
MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.
- Ahmet Zehir
- , Ryma Benayed
- & Michael F Berger
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News & Views |
Improving treatment of liver metastases by targeting nonangiogenic mechanisms
A recent study confirms an association between vessel co-option and resistance to bevacizumab, an anti-vascular endothelial growth factor-A (VEGFA) antibody, in patients with liver metastases. The authors suggest a combined therapeutic strategy that reduces co-option in mice.
- Kyrre E Emblem
- & Rakesh K Jain
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Technical Report |
Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles
Fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq) enables accurate detection of histone marks on chromatin extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples.
- Paloma Cejas
- , Lewyn Li
- & Henry W Long
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Resource |
The prognostic landscape of genes and infiltrating immune cells across human cancers
A searchable pan-cancer resource generated using data from nearly 18,000 human tumors reveals links between tumor infiltration by particular leukocyte subsets, tumor expression of particular gene signatures, and patient prognosis.
- Andrew J Gentles
- , Aaron M Newman
- & Ash A Alizadeh
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Technical Report |
An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage
Aaron Newman and his colleagues introduce a next-generation sequencing–based approach for the cost-effective detection and quantitation of tumor-derived circulating DNA in both early- and advanced-stage tumors and with high levels of sensitivity and specificity. CAPP-Seq (cancer personalized profiling by deep sequencing) can simultaneously detect multiple mutations and mutation types, including rearrangements. Here, utility is demonstrated for non–small-cell lung cancer.
- Aaron M Newman
- , Scott V Bratman
- & Maximilian Diehn
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Technical Report |
Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy
- Kyrre E Emblem
- , Kim Mouridsen
- & A Gregory Sorensen
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Article |
LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker
The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis.
- Dahu Chen
- , Yutong Sun
- & Li Ma
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Brief Communication |
Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer
By modeling acquired resistance to the EGFR antibody cetuximab in metastatic colorectal cancer, the authors identify a new mutation in the ectodomain of the receptor. The mutation is present in patient tumors after cetuximab therapy, confirming that it represents a clinically-relevant mechanism for therapy resistance. Moreover, the mutation does not affect the response to other EGFR antibodies, suggesting that if independently confirmed it may be a useful indicator to tailor anti-EGFR therapy.
- Clara Montagut
- , Alba Dalmases
- & Joan Albanell
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Letter |
A MEK-independent role for CRAF in mitosis and tumor progression
Raf kinase activity is deregulated in cancers and is thought to promote tumor growth by inducing proliferation signaling through MEK/Erk. This report identifies a new role for c-Raf independent of MEK/Erk and relying on phosphorylation of Ser338. Phospho–C-Raf interacts with the mitotic kinases Aurora-A and Plk1, activating the latter to promote mitotic progression and increase cell division, and this pathway is a crucial mediator for the protumorigenic effect of c-Raf in vivo.
- Ainhoa Mielgo
- , Laetitia Seguin
- & David A Cheresh
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Between Bedside and Bench |
miRNAs in the spotlight: Understanding cancer gene dependency
- Carlo M Croce
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News & Views |
A CUE hints at tumor resistance
Some individuals with estrogen receptor–α (ER-α)-positive breast cancer do not respond to tamoxifen treatment. Increased expression of the ubiquitin ligase CUEDC2 may contribute to this endocrine resistance by reducing theamounts of ER-α (pages 708–714).
- Christoforos Thomas
- & Jan-Ake Gustafsson
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News & Views |
A new treasure in the breast cancer gene hunt
A new potential breast cancer oncogene, ZNF703, has been identified in the chromosomal region 8p12 in humans, which is commonly amplified in an aggressive subtype of breast cancer. ZNF703 is a transcriptional repressor and regulates many genes that are involved in multiple aspects of the cancer phenotype, such as increased proliferation, invasion and an altered balance of progenitor stem cells.
- Paul Spellman
- & Joe Gray
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Review Article |
Cancer epigenetics reaches mainstream oncology
- Manuel Rodríguez-Paredes
- & Manel Esteller
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A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma
Biomarkers still off the mark for detecting breast cancer