Featured
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Review Article |
Targeting cuproplasia and cuproptosis in cancer
Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.
- Daolin Tang
- , Guido Kroemer
- & Rui Kang
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Comment |
Optimizing the FDA’s Project Optimus: opportunities and challenges
Through Project Optimus, the FDA calls for radical changes in the design of early phase trials to identify the optimal doses of oncology drugs to achieve maximal efficacy with better tolerability and patient acceptability. Herein, we discuss approaches that will enable the implementation of this initiative as well as some concerns that the draft guidance has raised in the oncology community.
- Simon Rodney
- & Udai Banerji
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News & Views |
Chemotherapy in EGFR-mutated NSCLC: optimizing combinations with TKIs and amivantamab
Recent results from the FLAURA2 and MARIPOSA-2 trials underline the continued role of chemotherapy in the treatment of patients with EGFR-mutated non-small-cell lung cancer in the era of targeted therapies. Herein, we argue that the most appropriate and rational sequence and/or combination of therapies remains a matter of discussion.
- Rafael Rosell
- & María González-Cao
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Research Highlight |
From CHRYSALIS to PAPILLON: the metamorphosis of amivantamab into frontline therapy for NSCLC
- David Killock
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Review Article |
Molecular tumour boards — current and future considerations for precision oncology
According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.
- Apostolia M. Tsimberidou
- , Michael Kahle
- & Funda Meric-Bernstam
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Review Article |
Biomarkers for immunotherapy of hepatocellular carcinoma
The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.
- Tim F. Greten
- , Augusto Villanueva
- & Xin W. Wang
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Review Article |
Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy
Immune-checkpoint inhibitors (ICIs) and other immunotherapies have revolutionized the treatment of patients with cancer. Nonetheless, most patients do not derive durable benefit, indicating a need for biomarkers to guide treatment selection. In this Review, the authors describe the role of antigen presentation in response to ICIs and other immunotherapies, with a focus on the role of molecular and/or genomic alterations affecting antigen presentation.
- Kailin Yang
- , Ahmed Halima
- & Timothy A. Chan
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Review Article |
The roles and implications of RNA m6A modification in cancer
Dysregulation of N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNA, is common in various cancer types. The authors of this Review provide an overview of the mechanisms of m6A-dependent RNA regulation, summarize current knowledge of their pathological effects and potential utility as biomarkers in cancer, and describe ongoing efforts to develop small-molecule inhibitors of oncogenic m6A modifiers.
- Xiaolan Deng
- , Ying Qing
- & Jianjun Chen
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Review Article |
Rare molecular subtypes of lung cancer
Lung cancers harbouring ‘rare’ alterations (defined as those with a prevalence of <5% of oncogene-driven lung cancers) can be detected in around a third of all oncogene-driven lung cancers and are diagnosed in thousands of patients each year. Advances in our understanding of tumour biology, diagnosis and the development of novel therapies are enabling increasing use of specific therapies targeting these alterations. In this Review, the authors provide an overview of the epidemiology, diagnosis, prognosis and treatment of patients with lung cancers harbouring these rare alterations. The importance of expedited drug approval pathways and cooperation between multiple stakeholders is also emphasized.
- Guilherme Harada
- , Soo-Ryum Yang
- & Alexander Drilon
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Research Highlight |
Early MRD predicts disease recurrence and benefit from adjuvant chemotherapy in CRC
- David Killock
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News & Views |
Novel assessment of epigenetic imprinting biomarkers for the diagnosis of thyroid nodules
Caring for individuals with thyroid nodules requires accurate estimation of their risk of thyroid cancer; however, available diagnostic tools offer only imprecise estimates. Novel biomarkers might help to clarify thyroid cancer risk and facilitate more-accurate diagnostic decision-making, although limitations in this area continue to exist.
- Naykky Singh Ospina
- & Juan P. Brito
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Review Article |
The emerging roles of γδ T cells in cancer immunotherapy
γδ T cells are lymphocytes with properties of both typical αβ T cell and natural killer cells, notable tissue tropisms, and MHC-independent antitumour functions that make them attractive agents for cancer immunotherapy. In this Review, the authors provide an overview of human γδ T cell subsets, discuss the antitumour and pro-tumour activities of these cells and their prognostic value in patients with cancer, and describe the current landscape of γδ T cell-based immunotherapies.
- Sofia Mensurado
- , Rafael Blanco-Domínguez
- & Bruno Silva-Santos
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Review Article |
Criteria for the translation of radiomics into clinically useful tests
Despite a considerable increase in research output over the past decades, the translation of radiomic research into clinically useful tests has been limited. In this Review, the authors provide 16 key criteria to guide the clinical translation of radiomics with the hope of accelerating the use of this technology to improve patient outcomes.
- Erich P. Huang
- , James P. B. O’Connor
- & Lalitha K. Shankar
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News & Views |
BFAST but be smart: bTMB remains an exploratory biomarker in NSCLC
A high tumour mutational burden (≥10 mutations per megabase) is a companion biomarker in the histology-agnostic approval of pembrolizumab for treatment-refractory advanced-stage solid tumours, and continues to be an exploratory predictive biomarker for immune-checkpoint inhibitors in non-small-cell lung cancer. Herein, we discuss recent results from the first phase III trial evaluating blood-based tumour mutational burden in patients with treatment-naive advanced-stage non-small-cell lung cancer.
- So Yeon Kim
- & Roy S. Herbst
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News & Views |
Personalizing the approach to neoadjuvant therapy: a promising path to improving outcomes of resectable melanoma
Clinical trials of neoadjuvant therapy for melanoma have expanded rapidly over the past several years. Preliminary data demonstrate the prognostic value of pathological response, which might have clinical implications for refining the roles of surgery and adjuvant therapy. These clinical questions are under active investigation across many ongoing clinical trials.
- Giorgos C. Karakousis
- & Tara C. Mitchell
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Review Article |
Circulating tumour DNA — looking beyond the blood
Advances in circulating tumour DNA (ctDNA) detection and analysis are beginning to be implemented in clinical practice. Nonetheless, much of this development has thus far focused on plasma ctDNA. Theoretically, all bodily fluids, including urine, cerebrospinal fluid, saliva, pleural fluid and others, can also contain measurable ctDNA and can provide several advantages over the reliance on plasma ctDNA. In this Review, Tivey et al. describe the potential roles of ctDNA obtained from non-plasma sources in optimizing the outcomes of patients with cancer.
- Ann Tivey
- , Matt Church
- & Natalie Cook
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Perspective |
Nano-omics: nanotechnology-based multidimensional harvesting of the blood-circulating cancerome
Liquid biopsy assays of diverse cancer-associated molecular alterations in blood, including genomic, epigenomic, transcriptomic, proteomic and metabolomics changes, offer considerable opportunities for early detection of cancer as well as improved management of the disease. In this Perspective, the authors review key advances in liquid biopsy-based multi-omics approaches for biomarker discovery. They also introduce the ‘nano-omics’ paradigm, whereby nanotechnology tools are used to capture and enrich various cancer-derived analytes from biofluids for subsequent omics analyses, with the aim of developing novel biomarker panels for early cancer detection.
- Lois Gardner
- , Kostas Kostarelos
- & Marilena Hadjidemetriou
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News & Views |
Gut microbes as biomarkers of ICI response — sharpening the focus
Two recent large-cohort studies reinforce the potential predictive capability of gut microbiota for immune-checkpoint inhibitor response and toxicities in patients with melanoma. However, additional investigations are required to understand the mechanistic underpinnings of this complex multifaceted relationship, and how it can be exploited for personalized cancer care.
- Neal Bhutiani
- & Jennifer A. Wargo
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Review Article |
B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome
The tumour microenvironment includes various diverse immune cell types, each of which might influence tumour progression and response to treatment, particularly with immunotherapies. These cell types include different subtypes of B lymphocytes, which are often associated with tertiary lymphoid structures (TLS) and can have pro-tumour or anti-tumour effects, either through their classical function in antibody production and antigen presentation or other mechanisms. Herein, Fridman et al. discuss the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation, the potential of B cells and TLS as prognostic and/or predictive biomarkers, and novel approaches aiming to enhance the development of TLS and anti-tumour B cells for cancer therapy.
- Wolf H. Fridman
- , Maxime Meylan
- & Catherine Sautès-Fridman
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News & Views |
Improving breast cancer risk prediction with epigenetic risk factors
Over the past decade, iterative improvements to models predicting breast cancer risk have primarily come from new information about genetic risk factors and improvements to mammogram-based risk scores. Epigenetic risk factors offer some potential to further improve risk stratification. However, the recently developed DNA methylation score (the WID-BC index) is not yet convincing for predicting breast cancer risk.
- Melissa C. Southey
- & Pierre-Antoine Dugué
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Review Article |
The emerging roles of circRNAs in cancer and oncology
Circular RNAs (circRNAs) are a novel class of primarily non-coding RNAs with increasingly recognized roles in cancer development and progression through diverse mechanisms of action. Herein, the authors review the current understanding of circRNA biogenesis, regulation, physiological functions and pathophysiological roles in cancer. They also discuss the clinical potential of circRNAs as biomarkers, therapeutic agents and drug targets in oncology as well as research controversies, technical issues and biological knowledge gaps that need to be addressed before this promise can be realized.
- Lasse S. Kristensen
- , Theresa Jakobsen
- & Jørgen Kjems
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Review Article |
Treatment landscape of triple-negative breast cancer — expanded options, evolving needs
In the past few years, advances in omics technologies have led to a better understanding of the heterogeneity of triple-negative breast cancers (TNBCs) and their microenvironment, supporting a view of this breast cancer subtype as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. The authors of this Review describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can provide improved opportunities for tailoring treatment.
- Giampaolo Bianchini
- , Carmine De Angelis
- & Luca Gianni
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Perspective |
Predicting cancer outcomes with radiomics and artificial intelligence in radiology
Prognostication of outcome across multiple cancers and prediction of response to various treatment modalities are among the next generation of challenges that artificial intelligence (AI) tools can solve using radiology images. The authors of this Perspective describe the evolution of AI-based approaches in oncology imaging and address the path to their adoption as decision-support tools in the clinic.
- Kaustav Bera
- , Nathaniel Braman
- & Anant Madabhushi
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News & Views |
Immunotherapy biomarkers: the long and winding road
A recent meta-analysis examined and validated biomarkers of response to immune-checkpoint inhibitors (ICIs). Herein, we discuss the findings of this analysis, which are consistent with previously identified determinants of ICI efficacy and demonstrate that some genetic variables influence response across multiple cancer types.
- Tyler J. Alban
- & Timothy A. Chan
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Perspective |
Liquid biopsy enters the clinic — implementation issues and future challenges
Liquid biopsy assays have the potential to revolutionize the diagnosis and management of cancer, and rapid progress is being made in the clinical translation of such assays. This Perspective outlines notable advances in the use of liquid biopsy technologies in the management of solid tumours, as well as future research avenues, clinical trial methodologies and implementation logistics for the eventual integration of liquid biopsy into the clinical workflow.
- Michail Ignatiadis
- , George W. Sledge
- & Stefanie S. Jeffrey
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Review Article |
Advances in the development of personalized neoantigen-based therapeutic cancer vaccines
Personalized neoantigen-based therapeutic vaccines hold promise as cancer immunotherapies. This Review provides an overview of the complex personalized neoantigen vaccine production process, vaccine-induced T cell responses and strategies to enhance these responses. Completed and ongoing clinical studies testing such vaccines are discussed, and considerations for future clinical investigation of this novel, individualized form of immunotherapy are outlined.
- Eryn Blass
- & Patrick A. Ott
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News & Views |
Dissecting the immunogenomic biology of cancer for biomarker development
Studies have identified multiple molecular properties with a biological rationale supporting a role in mediating selective responses to immune-checkpoint inhibitors (ICIs), including loss-of-function mutations in mSWI/SNF chromatin regulators; however, their clinical biomarker relevance is uncertain. Herein, we evaluate emerging concepts, challenges and considerations around translating biology into biomarkers for ICIs in solid tumours setting.
- Eliezer M. Van Allen
- & Toni K. Choueiri
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Perspective |
Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy
The availability of ever more sensitive cell sorting and sequencing technologies has enabled the interrogation of tumour cell biology at the highest possible level of resolution — analysis of a single cell. In this Perspective, the authors describe the application of such approaches to the analysis of single tumour-associated immune cells and their potential for improving the outcomes in patients receiving anti-cancer immunotherapies.
- Satyen H. Gohil
- , J. Bryan Iorgulescu
- & Kenneth J. Livak
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News & Views |
Translating noninvasive molecular responses into clinical reality for cancer immunotherapy
Noninvasive liquid biopsy assays integrating tumour and immune biomarkers are a promising tool to enhance clinical decision-making in immuno-oncology. Here, we discuss how circulating tumour DNA dynamics, in conjunction with pre-treatment tumour and immune features, can predict clinical response to immune-checkpoint inhibitors alongside the challenges in making their use a clinical reality.
- Joseph C. Murray
- & Valsamo Anagnostou
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Review Article |
Lung cancer LDCT screening and mortality reduction — evidence, pitfalls and future perspectives
Despite the introduction of novel therapies, lung cancer remains the leading cause of cancer-related mortality worldwide. Randomized controlled trials of low-dose CT-based lung cancer screening in high-risk populations have shown a reduction in mortality. The authors of this Review discuss these studies and present the Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL), a framework to define the scope of future implementation research on lung cancer screening.
- Matthijs Oudkerk
- , ShiYuan Liu
- & John K. Field
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Review Article |
Tumour budding in solid cancers
Tumour budding is hypothesized to reflect the invasive and metastatic capacities of cancers and is accordingly associated with unfavourable patient outcomes. Herein, Lugli and colleagues describe the pathobiological characteristics of this phenomenon, including its associations with epithelial–mesenchymal transition and features of the tumour microenvironment, and review the evidence demonstrating the value of tumour budding as a prognostic biomarker across various solid cancers.
- Alessandro Lugli
- , Inti Zlobec
- & Iris D. Nagtegaal
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News & Views |
Towards multi-cancer screening using liquid biopsies
Cell-free DNA and proteins are secreted into the bloodstream by multiple types of cancer. In a recently published prospective study involving 10,006 women, such markers were used in a cancer screening approach that incorporated PET–CT as a confirmatory test. Herein, we discuss the implications of these results.
- Y. M. Dennis Lo
- & W. K. Jacky Lam
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Review Article |
The adenosine pathway in immuno-oncology
Signalling induced by extracellular adenosine (eADO) can suppress antitumour immunity through multiple mechanisms. Herein, the authors review the pathophysiological functions of eADO in cancer and the related prognostic implications. They discuss the associated opportunities for eADO pathway-targeted immunotherapy, highlighting potential limitations and the scope for combination and biomarker-based strategies. The data emerging from oncology clinical trials of the diverse range of therapies that have been developed to target the eADO signalling pathway are also described.
- Bertrand Allard
- , David Allard
- & John Stagg
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News & Views |
Microbial DNA signature in plasma enables cancer diagnosis
Bacteria within tumours affect progression and response to therapy; in addition, bacterial DNA can be detected in cell-free plasma. Herein, we discuss evidence showing that intratumoural bacteria are characteristic for each tumour type, and that detection of cell-free bacterial DNA in blood could provide an accurate and non-invasive test for cancer diagnosis.
- Amiran Dzutsev
- & Giorgio Trinchieri
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Review Article |
Treatment-free remission in patients with chronic myeloid leukaemia
International treatment guidelines for chronic myeloid leukaemia incorporate recommendations for attempting discontinuation of treatment with tyrosine-kinase inhibitors (TKIs) with the aim of a treatment-free remission (TFR). The authors of this Review discuss how results of clinical studies of TFR can guide routine practice, address the development of predictors of outcome after TKI discontinuation and present strategies that warrant further consideration to enable more patients to enter TFR.
- David M. Ross
- & Timothy P. Hughes
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Review Article |
Progress in refining the clinical management of cancer of unknown primary in the molecular era
Despite improvements in diagnostic strategies, cancer of unknown primary — metastatic cancer in patients in whom the primary tumour remains undetected — continues to account for around 1–2% of all cancers. In this Review, Rassy and Pavlidis discuss insights into the biology of CUP and shifts in the clinical management of this enigmatic disease entity in the era of precision medicine.
- Elie Rassy
- & Nicholas Pavlidis
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