Perspectives

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.

The incidence of early-onset colorectal cancer (CRC) is increasing worldwide for reasons that are currently unclear. Herein, the authors review the current epidemiological, clinical, pathological and molecular understanding of early-onset CRC that occurs in patients ≥50 years of age, drawing contrasts with later-onset CRC. They also discuss future research strategies for improved understanding, prevention, early detection and clinical management of early-onset CRC.

Genotyping is recommended for all patients with metastatic non-squamous non-small-cell lung cancers (NSCLC), both to enable patients to receive targeted therapies and to avoid therapies they are unlikely to benefit from. However, obtaining tumour biopsy material for genotyping is often challenging and is unfeasible in some patients, indicating the need to incorporate liquid biopsy approaches. In this Perspective, the authors provide guidance on how analysis of ctDNA from liquid biopsy samples in patients with metastatic NSCLC prior to first-line therapy has the potential to extend the benefits of genotyping to virtually all patients.

The possible uses of artificial intelligence (AI) in radiation oncology are diverse and wide ranging. Herein, the authors discuss the potential applications of AI at each step of the radiation oncology workflow, which might improve the efficiency and overall quality of radiation therapy for patients with cancer. The authors also describe the associated challenges and provide their perspective on how AI platforms might change the roles of radiation oncology medical professionals.

The availability and subsequent successes of immune-checkpoint inhibitors (ICIs) in patients with metastatic melanoma, and to a lesser extent in those with several other forms of cancer, have made long-term treatment-free remissions a realistic possibility for a subset of patients. In this Perspective, the authors describe available data on long-term remission from patients with melanoma and other solid tumours and provide early recommendations regarding the circumstances in which ICIs can be safely discontinued.

Monitoring both cancer incidence and death rates is important for guiding health policy and the direction of future research. In this Perspective, the authors describe changes in cancer incidence and death rates in the USA, highlighting the effects of specific policies and research developments, and providing insight into unmet needs that should be addressed by future health policies.

Advances in imaging and biomarker discovery have led to a revolution in prostate cancer diagnosis, and nontargeted prostate biopsies should become obsolete. The authors of this Perspective article describe the current diagnostic pathway and discuss how advances in prebiopsy multiparametric MRI and the discovery of novel tumour markers should lead to a new diagnostic pathway.

Surgery remains a key pillar of cancer therapy, particular for those with curable, localized disease. The immediate perioperative period (days before and after surgery) is associated with various psychological and physiological stresses and associated factors, including inflammatory mediators, that might promote cancer progression and thus determine long-term outcomes. Herein, the authors present the hypothesis and supporting evidence that the use of certain types of immunotherapy, together with interventions to abrogate stress–inflammatory responses, in conjunction with surgery might improve the overall success of cancer treatment.

An immunosuppressive tumour microenvironment is one of the main reasons why patients with solid tumours fail to respond to immune-checkpoint inhibition. In this Perspective, the authors describe the potential of nanomedicines to normalize the tumour microenvironment, thus overcoming this immunosuppressive barrier and enabling greater numbers of patients to respond to immune-checkpoint inhibition.

A systems biology-based approach incorporating multiscale, longitudinal measurements (from single-cell analyses to whole-body monitoring) would help to decipher the complexity of cancer and would facilitate the development of personalized therapies. The authors of this Perspective discuss how systems biology-based approaches can provide data for early detection of disease transitions, prediction of therapeutic responses and clinical outcomes, and for the design of personalized treatments.

Oncology phase I trials have been traditionally referred to as ‘toxicity trials’. The distinction of clinical trials into three phases has been challenged in the past few years, leading to the current situation in which response rates are increasingly reported from phase I trials. The authors dissect the ethical dilemmas surrounding the therapeutic intent of phase I trials and provide evidence of contemporary phase I trials as a therapeutic option for patients with cancer.

The authors of this Perspective critically evaluate various artificial intelligence (AI)-based computational approaches used for digital pathology and provide a broad framework to incorporate these tools into clinical oncology, discussing challenges such as the need for well-curated validation datasets, regulatory approval and fair reimbursement strategies.

The oligometastatic paradigm challenges the prevailing view of metastasis as a disseminated process and proposes the existence of a spectrum of biological virulence within metastatic lesions. The authors present evidence for this heterogeneity and discuss how it affects the staging and treatment of patients with metastatic cancer.

Historically, academic surgeons, so-called surgeon scientists, have been at the forefront of cancer research. However, the role of the surgeon scientist is changing, and concerns have been raised about declines in the number of surgeons performing basic science research alongside clinical activity. Herein, the multifactorial drivers of these changes are discussed and strategies to increase surgical engagement in oncology research are described.

Precision medicine approaches to the treatment of cancer are largely reliant on genomic analysis alone. In this Perspective the authors provide a rationale for the incorporation of analysis of the proteome, which is a rich source of biological heterogeneity, into the treatment and management of patients with cancer.

Integrating molecular nuclear imaging in clinical research has great potential to improve anticancer therapy, particularly through the development of imaging biomarkers. Herein, the multistage process of developing novel molecular imaging biomarkers is discussed, highlighting both the challenges that have restricted the use of molecular imaging in clinical oncology research and future opportunities in this area.

Many clinical trials are testing the safety and/or efficacy of combining radiotherapy with immunotherapy, nearly all using a single-site irradiation (or ‘abscopal’) approach, but emerging evidence suggests that this approach likely produces suboptimal results. The authors of this Perspective provide a biological rationale supporting the abandonment of the abscopal approach, and instead advocate exploring comprehensive irradiation of multiple/all lesions.

With the expansion of the precision medicine paradigm, seamless trial approaches to drug development hold great promise for accelerating the accessibility of novel therapeutic agents but are also accompanied by important trade-offs. The authors describe several opportunities to improve the efficiency of drug development in oncology, as well as new mechanisms to obtain information about anticancer therapies throughout their life cycle.

Liquid biopsy approaches hold great promise in early cancer diagnosis or minimal residual disease monitoring for cancer recurrence. Herein, the authors evaluate contemporary next-generation sequencing approaches to circulating tumour DNA detection in these contexts, with a focus on studies in patients with non-small-cell lung cancer. They discuss the feasibility of introducing these strategies into the clinic, highlighting the technical and analytical challenges, as well as possible solutions.

Despite extensive research efforts, very few DNA methylation-based biomarkers have been implemented clinically. In this Perspective, the authors describe the importance of considering the genomic locations examined in determining the diagnostic or prognostic relevance of putative DNA methylation-based biomarkers.