Reviews & Analysis

Although radiotherapy affects multiple cellular pathways, treatments are generally planned with the assumption that all tumours respond similarly to radiation. The authors of this Review summarize the effect of various pathways activated by radiotherapy on tumour responses to radiotherapy and present the current knowledge on genomic classifiers designed to inform treatment decisions.

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.

PADA-1 is the first trial to demonstrate benefit from a treatment-switching strategy guided by active monitoring of ESR1 mutations in plasma circulating tumour DNA (ctDNA) from patients with breast cancer. The results of this trial raise important questions about the specific treatment approach tested, and the feasibility of trials incorporating longitudinal ctDNA analyses to anticipate resistance and guide treatment.

The first phase III trial to test perioperative immune-checkpoint inhibitor therapy for high-risk renal cell carcinoma yielded highly promising results, leading to regulatory approvals of adjuvant pembrolizumab. However, subsequent phase III trials, including the IMmotion010 trial of adjuvant atezolizumab, did not demonstrate similar benefits. Although molecular biomarkers are urgently needed to better delineate responder subgroups, the unique design of each trial might partially explain some of the patterns identified.

Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.

CAR T cell therapy has altered the natural history of relapsed and/or refractory diffuse large B cell lymphoma (DLBCL). However, the availability of multiple products has created provider uncertainty regarding treatment selection and the need to balance toxicity and efficacy. In a retrospective analysis, the authors suggest that axicabtagene ciloleucel might be superior to tisagenlecleucel. However, several questions remain unresolved.

In the past decade, oncologists worldwide have seen unprecedented advances in drug development and approvals but have also become increasingly cognizant of the rising costs of and increasing inequities in access to these therapies. These trends have resulted in the current problematic situation in which dramatic disparities in outcomes exist among patients with cancer worldwide owing, in part, to the lack of access to drugs that provide clinically meaningful benefits. In this Viewpoint, we have asked six oncologists working in different countries to describe how they perceive this issue in their region and propose potential solutions.

Neuroendocrine neoplasms (NENs), which can develop in almost any organ and range from indolent neuroendocrine tumours (NETs) to rapidly progressive and fatal neuroendocrine carcinomas (NECs), have historically been approached in a siloed manner according to their specific tissue of origin. However, NETs and NECs across different sites of origin often share genomic and phenotypic characteristics. In this Review, the authors discuss both the clinical and biological commonalities as well as key organ-specific differences of NENs, with a focus on those of the gastrointestinal system and lung. Moreover, they advocate for a cross-cutting, tissue-agnostic approach to drug development for these rare tumours that might enable advances in one disease entity to accelerate research in others, ultimately improving patient care.

Owing to several limitations, including elimination by the immune system and a lack of tumour specificity, systemically administered synthetic nanoparticles are used for a limited range of cancer indications. In this Review, the authors describe the potential of cellular nanoparticles (comprising a cell membrane coating around a synthetic core) to overcome these issues as well as their application in drug delivery, phototherapy and immunotherapy.

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.

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.

Systemic therapies for early-stage disease have been tested in clinical trials for decades. The authors of this Review provide an overview of the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era, focusing on design, end points and biomarkers that, together, could enable the delivery of more personalized treatment.

Either alone or in combination, chemotherapy remains the mainstay treatment for most human malignancies. This treatment modality is associated with a high burden of chemotherapy-associated adverse events (CAAEs) that greatly affect patients because of their considerable morbidity, mortality and costs. Kuderer et al. discuss the pathophysiology, management and risk factors of the most common acute CAAEs with a major effect on survival, quality of life, function and/or continuation of optimal therapy.

T cells are key effectors of immunotherapies that have revolutionized the treatment of cancer; however, chronic exposure to tumour-associated antigens can result in progressive loss of T cell effector functions and self-renewal capacity, a state termed ‘T cell exhaustion’ that is believed to limit the efficacy of immunotherapy. This Review synthesizes the new immunobiological insights that present a more nuanced view beyond T cell exhaustion being entirely undesirable and indicate that this hypofunctional state might be as much a reflection as it is the cause of poor tumour control. Hence, the authors describe how, in certain contexts, interruption of this programme could impair T cell persistence and discuss interventions to mitigate the development of T cell exhaustion that might ultimately improve clinical outcomes.

A high serum lactate dehydrogenase (LDH) level is generally associated with an inferior outcome in patients with most tumour types. LDH is also known to have immunosuppressive and/or tumour-promoting effects, suggesting a potentially broader role for this enzyme in clinical oncology. In this Review, the authors provide a holistic overview of the current role of LDH in both cancer biology and oncology, and highlight possible areas of future research interest, including the development of novel therapies targeting LDH.

Clinical research needs support from preclinical models that consider the biology and genetics of human cancers during treatment, such as patient-derived xenograft (PDX) models. The authors of this Review discuss how PDX models have been used in the past decade for precision oncology and present emerging approaches that could broaden the application of these models.

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.

Peritoneal surface malignancies (PSMs) typically have a poor prognosis, although considerable advances in the understanding and management of these malignancies have been made over the past decade. This Review comprehensively describes the improvements in knowledge of the biology, assessment and classification, perioperative and surgical management, systemic treatment and pre-emptive management of PSMs. The authors also outline future directions for research in this field.

The incidence of early-onset forms of many cancers (defined as cancers diagnosed in individuals <50 years of age) has increased in a number of countries over the past several decades. The underlying reasons for this apparent increase probably include greater use of screening programmes, but also changing patterns in early-life exposures. In this Review, the authors describe the emerging global increase in the incidence of early-onset cancers and suggest changes that might address this situation.

The entry of cells into senescence can act as a barrier to tumorigenesis; however, in certain contexts senescent malignant and non-malignant cells can acquire pro-tumorigenic properties. The authors of this Review discuss the cell-intrinsic and cell-extrinsic mechanisms involved in both the antitumorigenic and tumour-promoting roles of senescent cells, and describe the potential of various senolytic and senomorphic therapeutic approaches in oncology.