Reviews & Analysis

Cerebrospinal fluid liquid biopsies can enable the characterization and monitoring of medulloblastoma. The analysis of copy-number variations in circulating tumour DNA present in these samples can be used as a biomarker to determine the presence of measurable residual disease, and facilitate the optimal treatment and clinical management of patients with medulloblastoma.

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.

Patients receiving cytotoxic therapies for cancer have an increased risk of cognitive and functional decline that is usually associated with ageing. In this Review, the authors describe how cancer therapies can enhance physiological ageing processes and highlight the potential for interventions that could potentially ameliorate these long-term adverse events in patients receiving active treatment for cancer and in cancer survivors.

In oncology, a definition of drug value that patients, payers, regulators and clinicians agree upon on does not exist. The authors of this Perspective discuss different approaches to measuring value, such as assessments of benefit–risk balance and cost-effectiveness, individual attitudes to risk, and use of scales developed to measure value objectively. They also explain how regulators can help to inform different decision makers.

Targeted therapies have improved the outcomes of many patients with cancer, although many more lack targetable alterations or do not derive clinical benefit for other reasons. Radiotherapy can also provide benefit to many patients, although radioresistance often limits the effectiveness of this intervention. Here, the authors describe the potential for radiotherapy to promote non-oncogene dependence on targetable signalling pathways, thus extending the benefits of both targeted therapy and radiotherapy to greater numbers of patients.

Immunotherapy is revolutionizing the treatment of many cancers and hepatocellular carcinoma (HCC) is no exception. This Review describes the heterogeneous immune microenvironments of HCC as well as their links with the various aetiologies underlying this malignancy and with response or resistance to immunotherapies. In addition, the authors provide an overview of the current landscape of clinical trials evaluating immunotherapies across all stages of HCC.

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.

Efforts are being made to incorporate immune-checkpoint inhibitors into therapy for early stage non-small-cell lung cancer. The IMpower010 trial of adjuvant atezolizumab has recently become the first study to demonstrate that this strategy can improve disease-free survival in a subset of patients. This trial opens a new area of research in the quest for the optimal perioperative strategy to increase overall survival.

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.

A high tumour burden has long been associated with inferior outcomes on traditional cancer therapies and emerging evidence suggests that tumour burden is particularly relevant for patients receiving immune-checkpoint inhibitors. Here, the authors summarize the available clinical and preclinical evidence for the role of tumour burden in determining the outcomes of patients receiving immune-checkpoint inhibitors and highlight areas that are likely to be of future research interest in this emerging area.

Chimeric antigen receptor (CAR) T cells have remarkable efficacy in patients with B cell acute lymphoblastic leukaemia (ALL), but have not been successful to date in patients with T cell ALL (T-ALL). Now, data from Pan and colleagues demonstrate the safety and impressive short-term efficacy of allogeneic donor-derived anti-CD7 CAR T cells in an early-phase clinical trial involving patients with relapsed and/or refractory T-ALL.

Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage cancers, although the majority of patients will not respond to these agents. Here, the authors describe the potential of targeting emerging immunomodulatory pathways, with a focus on alternative immune checkpoints and tumour metabolism as approaches that might enable further improvements in the outcomes of patients with cancer, either as monotherapies or in combination with existing agents.

EGFR exon 19 deletions and exon 21 mutations, and HER2 amplification and/or overexpression, are predictive of response to matched molecularly targeted therapies that have greatly improved patient outcomes. However, insertion mutations in exon 20 of either EGFR or HER2 generally do not confer sensitivity to these therapies. In this Review, the authors discuss the prevalence of EGFR and HER2 exon 20 insertions across cancers, their biology and detection, and associated responses to current molecularly targeted therapies and immunotherapies. In addition, they focus on new therapeutic strategies that are being developed to target tumours driven by these non-classic EGFR and HER2 alterations.

Two recent studies addressed the functional properties and clinical significance of tumour antigen-specific effector T cells in human melanomas and lung carcinomas using single-cell strategies. Herein, we discuss their findings, which expand our understanding of T cell alterations in the tumour microenvironment and demonstrate that CD8⁺ T cell exhaustion is mediated by exposure to tumour cell-specific antigens and is associated with a tissue-resident memory phenotype.

The MYC proto-oncogenes are among the most commonly activated proteins in human cancer, yet the clinical efficacy of MYC-targeted agents remains to be demonstrated. The authors of this Review describe how activation of the MYC pathway affects cancer cells as well as the tumour microenvironment and propose strategies for the therapeutic targeting of MYC-driven cancers.

Fluorescence-guided surgery (FGS) using tumour-targeted imaging agents has emerged over the past decade as a method of intraoperative cancer detection; however, the clinical implementation of tumour-targeted FGS remains in the early stages. The authors of this Review discuss how target selection, imaging agents and detection systems could enable real-time intraoperative visualization to benefit patients with cancer.

Cancer-associated fibroblasts (CAFs) are inherently linked with cancers and have long been considered attractive therapeutic targets. However, the existence of several CAF subpopulations with substantial phenotypic and functional heterogeneity and plasticity is increasingly recognized. This Review provides an overview of the heterogeneity of CAFs and its implications with regard to the tumour-promoting and tumour-restraining roles of these cells as well as their clinical relevance in terms of prognostic value and therapeutic potential. The authors also provide insights and perspectives on future research and clinical studies involving CAFs.

Patients with early-stage rectal cancer might potentially benefit from treatment with an organ-sparing approach, which preserves quality of life owing to avoidance of the need for permanent colostomy. Trials conducted to investigate this have so far been hampered by considerable inter-trial heterogeneity in several key features. In this Consensus Statement, the authors provide guidance on the optimal end points, response assessment time points, follow-up procedures and quality of life measures in an attempt to improve the comparability of clinical research in this area.

Hypoxia is a common feature of tumours, contributes to many of the hallmarks of cancer and influences responses to anticancer therapies. Thus, strategies to eliminate and/or exploit tumour hypoxia have long been explored, although with limited success to date. Herein, the authors describe new insights into hypoxia biology, discuss the implications of these advances for novel hypoxia-directed therapeutic strategies, and review the progress made with longstanding methods for targeting hypoxic tumours.

Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for patients with several forms of cancer, predominantly those harbouring loss-of-function BRCA1/2 mutations or other homologous recombination defects. Nonetheless, most patients receiving PARP inhibitors will ultimately develop resistance to PARP inhibitors, resulting in disease progression. In this Review, the authors describe the mechanisms of resistance to PARP inhibitors and discuss the potential treatment strategies that might overcome these effects.