Perspectives

The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.

The current standard-of-care adjuvant treatment for patients with colorectal cancer is chemotherapy selected on the basis of conventional histopathological staging criteria; however, the clinical benefit from these regimens is limited. The authors of this Perspective discuss strategies to minimize toxicity and monitor efficacy of these regimens, and propose new tools for disease staging that could enable more personalized treatment decisions.

Despite some success in patients with certain B cell malignancies and relapsed and/or refractory multiple myeloma, studies testing chimeric antigen receptor (CAR) T cells in patients with advanced-stage solid tumours have been largely unsuccessful, with a few notable exceptions. In this Perspective, the author provides some possible reasons for the failures of most CAR T cell-based approaches and suggests strategies that might address some of these challenges.

The use of composite end points in clinical trials can expedite drug development and approval, and thus improve patient access to novel treatments, but are often vaguely and heterogeneously defined, with considerable inter-study variation in the component events that are included. The different component events can vary in clinical significance and be differentially affected by treatment but, nevertheless, are rarely reported separately. In this Perspective, Walia et al. define composite outcomes that are commonly used in oncology, discuss the advantages and challenges of using composite end points, and advocate for transparent reporting including a full breakdown of the component events to facilitate accurate interpretation of trial results and the true benefit of an intervention.

Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.

The authors of this Perspective propose that, with further improvement in detection efficiency, circulating tumour cells (CTCs), which are released early during cancer development, have the potential to be used for the early detection of clinically relevant, aggressive cancers. Thus, use of CTCs as diagnostic biomarkers might improve outcomes by enabling the identification of cancers at a stage at which they are more amenable to treatment while avoiding overtreatment of patients with indolent tumours.

FLASH radiotherapy involves delivering ultra-high dose rates of radiation, which enables sustained tumour control with reduced toxicity to surrounding tissues. The authors of this Perspective describe the principles underlying FLASH radiotherapy, present the available evidence from preclinical studies testing this modality and discuss the challenges for its application in routine clinical practice.

Glioblastoma, the most common form of brain cancer in adults, has a dismal prognosis and has proven recalcitrant to novel targeted therapies and immunotherapies. Extrachromosomal DNAs (ecDNAs) harbouring oncogenes are increasingly recognized as important drivers of tumour development, evolution and resistance to treatment, particularly in patients with glioblastoma. In this Perspective, the authors summarize key reasons for the failed clinical translation of new therapies for glioblastoma, highlighting the important contributions of ecDNAs. They then focus on the opportunities and challenges of utilizing ecDNAs to improve the likelihood of success in the development of precision medicines for this disease.

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.

In this Perspective, Nathan Cherny appraises the FDA approvals of therapeutic agents granted for use in adult patients with solid tumours during the 5 years 2017–2021 against the aspirations of the Cancer Moonshot, in terms of sheer number of approvals, the strength of the supporting evidence and the magnitude of clinical benefit. He also outlines areas where improvements are needed to more confidently ensure that the clinical benefits of approved treatments justify the associated risks.

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’.

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.

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.

Patients with primary central nervous system (CNS) malignancies largely do not derive benefit from immune-checkpoint inhibitors. Paradoxically, a subset of those with CNS metastases from tumours located outside of the CNS will respond to the same approach. In this Perspective, the authors explore the key differences in the immune cell composition of primary CNS malignancies and brain metastases and provide guidance on potential alternative immunotherapies that might be effective in patients with these historically difficult-to-treat malignancies.

Assuming that the latest incidence trends continue for the major cancer types, the incidence of all cancers combined will double by 2070 relative to 2020, with the greatest increases predicted in lower-resource settings. The authors of this Perspective discuss how population-level approaches with amenable goals should be considered an integral part of cancer control.

Immune responses against tumour antigens that do not arise from cancer cell-specific mutations can result in autoimmune reactions against the tissue of origin of the tumour. Despite their undesirable effects, these symptoms can have prognostic value and correlate with favourable disease outcomes. The authors of this Perspective discuss the importance of such beneficial autoimmunity in patients with advanced-stage disease and in cancer immunosurveillance.

Anti-angiogenic therapy has the capacity to ameliorate antitumour immunity and, thus, some combinations of anti-angiogenics and immunotherapies have been approved and a number of them are being tested. The authors of this Perspective describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as a vascular counterpart of immune checkpoints.

In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.

Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

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.