Reviews & Analysis

Chimeric antigen receptor T cells have revolutionized the treatment of patients with certain haematological malignancies. Nonetheless, an optimal approach to lymphodepleting chemotherapy and/or bridging therapies has yet to be defined in patients receiving these agents. In this Review, the authors describe the various lymphodepletion and/or bridging therapy strategies used, and highlight the need for prospective comparisons in order to determine the safest and most effective approach.

Vaccination against COVID-19 confers robust protection from severe disease. However, the extent to which this applies to patients with cancer remains uncertain given that these patients were excluded from most of the pivotal studies. In this Review, the authors provide an overview of the efficacy and immunogenicity of COVID-19 vaccines in patients with cancer, and discuss alternatives to vaccination for those who might be unable to develop a proficient immune response following vaccination.

Gastrointestinal stromal tumour (GIST) is the most common form of sarcoma and has become a paradigm of precision medicine owing to the fact that almost all patients harbour one of several known molecule drivers, most of which can be targeted therapeutically. Nevertheless, novel therapeutic strategies are required to overcome the intrinsic resistance of certain subtypes of GIST to existing treatments as well as the acquired resistance that eventually arises in initially sensitive subtypes. This Review describes the biology of GIST, the evolution of the current treatments for this cancer, and the emerging therapeutic agents and approaches that might overcome the remaining clinical challenges.

Patients with pancreatic ductal adenocarcinoma (PDAC) usually have a dismal prognosis, and even after curative resection most patients will have disease relapse and ultimately die. Nonetheless, adjuvant chemotherapy has considerably improved the outcomes of patients who are able to undergo surgery. The PREOPANC trial provides some evidence supporting the use of neoadjuvant therapy for patients with borderline resectable PDACs but not, as claimed, for those with resectable tumours.

Surgical quality remains a priority for patients with cancer, payers and policymakers. Whether the risk-standardized mortality rate (RSMR) is a better metric than surgical volume to inform the regionalization of cancer surgery remains controversial. In particular, RSMR has been criticized on both theoretical and methodological grounds. Novel alternative means that incorporate surgical volume, as well as evidence-based process measures, are needed.

Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies.

The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in most developed countries. In this Review, the authors provide an overview of the epidemiology, molecular biology and treatment of HPV-positive OPSCC, including discussions of the role of treatment de-escalation and emerging novel therapies.

Immune-checkpoint inhibitors (ICIs) have dramatically improved the outcomes of patients with advanced-stage solid tumours, including the potential for long-term remission in a subset. However, long-term follow-up data reveal a risk of chronic toxicities from these agents, which can have important quality-of-life implications. In this Review, the authors describe the current level of evidence of chronic toxicities of ICIs and their implications for patients

Immune-checkpoint inhibitors are associated with a unique spectrum of organ-specific inflammatory toxicities known as immune-related adverse events (irAEs). In the past few years, aggregate clinical data, real-world data and multi-omics data have been used to investigate the underlying mechanisms and clinical presentations of irAEs. The authors of this Perspective summarize the knowledge on irAEs that has been obtained from different sources of ‘big data’.

Multiple myeloma and its precursor stages, monoclonal gammopathy of undetermined significance and smouldering multiple myeloma, have a considerable degree of genetic heterogeneity. The authors of this Review discuss how single-cell studies in these individuals are enabling the mutational and phenotypic characterization of cells within the bone marrow tumour, immune microenvironment and peripheral blood to eventually guide early diagnosis, risk stratification and treatment strategies.

A variety of cytokines have diverse antitumour and/or pro-tumour activities and, accordingly, alterations in cytokine networks contribute to cancer development and progression. Therefore, cytokines and their receptors have long been investigated as therapeutic agents or targets in oncology, although with mostly disappointing results. Herein, Propper and Balkwill discuss the lessons learnt from initial clinical trials of monotherapy approaches as well as subsequent strategies to better leverage cytokines and cytokine antagonists in the treatment of solid tumours.

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.