Reviews & Analysis

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.

Clinical trials of neoadjuvant therapy for melanoma have expanded rapidly over the past several years. Preliminary data demonstrate the prognostic value of pathological response, which might have clinical implications for refining the roles of surgery and adjuvant therapy. These clinical questions are under active investigation across many ongoing clinical trials.

The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.

The development of covalent, allele-specific inhibitors of KRAS^G12C represents a major breakthrough in precision oncology. Herein we discuss recent data from the phase II KRYSTAL-1 trial of adagrasib in KRAS^G12C-mutated non-small-cell lung cancer (NSCLC). This trial showed responses in a subset of patients, including among those with brain metastases, and offers exploratory insights into potential biomarkers of response.

Data on a new treatment approach utilizing bispecific monoclonal antibodies targetting B-cell maturation antigen (BCMA) were recently published, yielding very encouraging results in the setting of relapsed and/or refractory multiple myeloma (RRMM). How to safely and effectively deliver this treatment to patients and where it fits in the RRMM treatment paradigm are important questions for the future.

Advances in circulating tumour DNA (ctDNA) detection and analysis are beginning to be implemented in clinical practice. Nonetheless, much of this development has thus far focused on plasma ctDNA. Theoretically, all bodily fluids, including urine, cerebrospinal fluid, saliva, pleural fluid and others, can also contain measurable ctDNA and can provide several advantages over the reliance on plasma ctDNA. In this Review, Tivey et al. describe the potential roles of ctDNA obtained from non-plasma sources in optimizing the outcomes of patients with cancer.

The oligometastatic state is generally considered to constitute an intermediate point along the spectrum of cancer dissemination at which the metastatic burden is limited and local ablative therapies can result in meaningful clinical benefit, and possibly even cure. In this Review, Katipally et al. reframe the oligometastatic phenotype as a dynamic state that expands beyond merely the number or size of metastases. They highlight important risk factors defining the metastatic spectrum that can inform both staging and therapy, and identify themes in the literature that might guide strategies to optimally combine metastasis-directed local therapies with modern systemic treatments.

Tracking circulating tumour DNA (ctDNA) after surgery holds promise for patient management and therapeutic intervention in non-small-cell lung cancer (NSCLC). A study published by Zhang and colleagues tracks ctDNA from 261 patients with stages I–III NSCLC and suggests that the likelihood of disease relapse decreases for high-risk stage II/III patients after 18 months without ctDNA detection.

After a frustratingly slow pace of development of new effective treatments for mesothelioma, single or dual therapy with immune-checkpoint inhibitors has substantially improved overall survival over previous standard-of-care therapies in various disease settings. The authors of this Review summarize the current evidence on immunotherapies for mesothelioma, focusing on strategies evaluated in randomized clinical trials and emerging predictors of response, and discuss future treatment opportunities.

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.

Radiotheranostics enables the clinician to image and then target lesions using the same probe. Despite this appealing potential, interest in the field of radiotheranostics has long been constrained by a lack of expertise, high infrastructure costs and the availability of non-radioactive alternative approaches. Nonetheless, several recent successes have led to renewed research interest. In this Review, the authors summarize the current challenges and opportunities in this rapidly emerging area.