Reviews & Analysis

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.

New epidemiological data from the American Cancer Society indicate a continued decline in overall cancer mortality in the USA but also reveal alarming countertrends. Rising advanced-stage presentation of prostate cancer, an accelerating incidence of early-onset colorectal cancer, and widening disparities in uterine and lung cancer outcomes underscore that the next frontier in oncology is equitable delivery, not just biological discovery.

First-line therapy for chronic lymphocytic leukaemia (CLL) is rapidly evolving, with a recent phase III trial showing that fixed-duration therapy with BCL-2 inhibitor-based doublet regimens is non-inferior to continuous BTK inhibitor therapy. Novel approaches to further improve outcomes with time-limited regimens include measurable residual disease-guided and three-drug approaches.

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.

Novel immunotherapy combinations are now available for second or later-line therapy for follicular lymphoma. The addition of tafasitamab, an anti-CD19 antibody, or epcoritamab, a CD20 × CD3 bispecific antibody, to lenalidomide–rituximab (R²) has demonstrated promising efficacy. Herein, I compare recent phase III trials testing each combination and discuss their practical implications.

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.

RNA sequencing (RNA-seq) is increasingly being integrated into molecular tumour profiling but remains underutilized for clinical decision-making. This Perspective presents a framework for assessing the therapeutic, diagnostic and prognostic actionability of RNA-seq findings as well as an ‘actionable transcriptome’ list to help guide the application of RNA-seq findings in oncology practice.

Despite radical cystectomy, residual urothelial cancer cells can persist undetected in patients with muscle-invasive bladder cancer, silently seeding future relapse. New data from the phase III IMvigor011 trial demonstrate that circulating tumour DNA (ctDNA) can be used to effectively stratify patients by recurrence risk, enabling adjuvant atezolizumab to be delivered selectively to those who are likely to benefit. This precision ctDNA-guided strategy might fundamentally reshape postoperative management through alignment of treatment intensity with molecular risk.