Review Articles

The development of immune checkpoint inhibitors and novel targeted therapies and the incorporation of these agents into first-line therapy for biomarker-selected patients with metastatic gastric cancer has improved outcomes. Nonetheless, many challenges remain, including both primary and acquired resistance as well as a lack of relevant biomarkers in certain subgroups. In this Review, the authors describe the current approach to first-line therapy for patients with metastatic gastric cancer as well as emerging approaches that might improve the standard of care in the coming years.

Glucagon-like peptide 1 receptor agonists (GLP1RAs) are widely used by individuals with type 2 diabetes mellitus (T2DM) and/or obesity. Both of these conditions are also associated with an increased risk of certain cancers, and this risk might be ameliorated following intentional weight loss, which can consistently be achieved with GLP1RAs. Conversely, several reports have suggested an increased risk of certain cancers, such as medullary or non-medullary thyroid cancer and pancreatic cancer among those receiving GLP1RAs. In this Review, the authors evaluate these competing risks and the underlying evidence as well as highlighting areas in which evidence is limited and more research will be needed in order to definitively understand the implications of GLP1RAs for cancer risk.

Cholangiocarcinomas, comprising intrahepatic, extrahepatic and perihilar subtypes as well as gallbladder cancer, are a heterogeneous group of malignancies that necessitates a personalized approach to both surgery and systemic therapy. In this Review, the authors describe progress in the development of personalized perioperative therapy strategies as well as the most promising future research directions in this diverse and often difficult-to-treat group of cancers.

Despite substantial interest in exploiting ferroptosis — an iron-mediated, lipid peroxidation-driven form of cell death — for cancer therapy, progress towards clinical translation has been limited. This comprehensive Review describes the major barriers that have restricted ferroptosis-based therapeutic development as well as emerging opportunities presented by new ferroptosis-inducing agents, biomarker-guided patient selection and rational combination treatments.

Effective early detection and intervention strategies for lung cancer are urgently needed. The authors of this Review summarize the current state of lung cancer screening and provide future directions for optimal implementation, including biomarker development. They also discuss precancer interception strategies that could transform both lung cancer prevention and early intervention.

Analysis of tumour tissue to guide the clinical management of patients with cancer poses several challenges. This Review outlines the potential of liquid biopsy-based analysis of circulating tumour DNA (ctDNA) to address these limitations and thereby improve precision medicine in the context of metastatic colorectal cancer, as well as opportunities to refine the management of locoregional disease using recurrence risk-tailored approaches predicated on ctDNA-based evaluation of minimal residual disease status.

Adjuvant therapy with anti-PD-L1 antibodies and other immune-checkpoint inhibitors (ICIs) is an established standard of care for many patients with surgically resected solid tumours. Nonetheless, the activity of ICIs and ICI-containing combinations in the metastatic setting as well as the emergence of effective neoadjuvant and perioperative approaches involving these agents is challenging the use of adjuvant therapy. In this Review, the authors consider the role of adjuvant therapy in patients with resected solid tumours, including the potential for personalization based on recurrence risk and/or the presence of specific biomarkers.

Platelets can promote cancer progression through either direct and indirect mechanisms, and they can also suppress tumour progression in certain contexts. The authors of this Review discuss how insights on these properties have been leveraged to develop cancer therapies in which platelets are engineered to act as targeted delivery vehicles or as active effector cells, outlining opportunities and challenges for clinical translation.

Premenopausal women aged <40 years diagnosed with oestrogen receptor-positive early-stage breast cancer have disproportionately poorer outcomes relative to older women. The authors of this Review propose a biology-driven approach to challenge the conventional sequencing of chemotherapy and endocrine therapy in this population.

This Review outlines the fundamental role of chimeric antigen receptor (CAR) T cell therapy for children, adolescents and young adults (CAYAs) with relapsed and/or refractory B cell acute lymphoblastic leukaemia, emphasizing the crucial need to further exploit CAR T cells and other immunotherapies to improve survival with broadened access across disease states. Opportunities and challenges for expanding CAR T cell therapy to other haematological and non-haematological malignancies in CAYAs are also discussed.

Increased understanding of the biology of smouldering multiple myeloma (SMM) is being leveraged to improve the management of this clinically heterogeneous precursor of MM. This Review describes the current diagnostic work-up, risk stratification and management of SMM, highlighting early intervention approaches for high-risk SMM that might provide the best opportunity to convert MM into a curative disease and discussing persistent challenges in this field.

Despite well-established roles of microRNAs (miRNAs) as tumour suppressors or oncogenes, miRNA-based diagnostics, prognostic tools and treatments have yet to be incorporated into routine oncology practice. In this Review, the authors discuss innovative approaches to address challenges in the clinical translation of miRNA-based diagnostics and treatments by integrating fundamental miRNA biology, multiomics and artificial intelligence-driven analyses.

Cancer screening aims to identify either pre-malignant conditions or earlier-stage disease in non-symptomatic individuals. The authors of this Review recapitulate the general principles of cancer screening, discussing the current screening practices for several cancer types as well as advances in cancer detection that might hold promise for screening an increasing number of cancers in the future.

Treatment selection based on the presence of one or more specific biomarkers has the potential to optimize treatment outcomes; nonetheless, most patients lack a specific biomarker that is predictive of benefit from one or more targeted treatment approaches. In this Review, the authors describe the potential of computational analysis approaches to enable the discovery of more complex predictive biomarkers based on comprehensive analysis of large clinical and preclinical datasets and thus address this unmet need.

The management of localized bladder cancers is rapidly evolving. In this Review, the authors discuss diagnostic innovations, refinements in surgical approaches and novel intravesical or systemic treatments such as immunotherapies and antibody–drug conjugates, as well as future directions including bladder-sparing approaches for muscle-invasive disease and novel biomarkers for personalized treatment and follow-up.

Despite the availability of various novel therapies, the global incidence of acute myeloid leukaemia (AML) has continued to increase. Owing to a combination of population ageing and more effective diagnosis, AML remains much more common in economically developed countries. Conversely, AML is less common in the economically developing world, albeit often with worse outcomes owing to a lack of access to effective therapies. In this Review, the authors describe these global trends as well as their underlying reasons, including the changing landscape of risk factors, demographic disparities and differing treatment outcomes.

Despite advances in the treatment of many advanced-stage solid tumours, the outcomes of patients with central nervous system tumours have not improved substantially for several decades, largely owing to a lack of novel therapies. In this Review, the authors describe the clinical experience with chimeric antigen receptor T cells both in adults and children with these historically difficult to treat malignancies, including some promising signals of efficacy.

The identification of prognostic and predictive biomarkers for immune checkpoint inhibitors, antibody–drug conjugates and targeted therapies for urothelial carcinoma is currently an active area of research. In this setting, circulating tumour DNA is emerging as a minimally invasive biomarker with utility for monitoring clinical responses. The authors of this Review discuss biomarkers that could have clinical utility in patients with this malignancy

Advances in the management of hormone-sensitive prostate cancer have been achieved through intensification of therapy, although careful patient selection is required. In this Review, the authors discuss personalized treatment strategies for both non-metastatic and metastatic hormone-sensitive prostate cancer, as well as emerging novel therapies and key principles for toxicity mitigation.

Third-generation EGFR tyrosine kinase inhibitors such as osimertinib have substantially improved clinical outcomes in advanced-stage EGFR-mutant non-small-cell lung cancer, but resistance remains inevitable. In this Review, the authors discuss biomarker-directed and biomarker-unselected approaches to overcome established resistance to osimertinib, as well as pre-emptive upfront strategies to delay or prevent the occurrence of osimertinib resistance.