Browse Articles

Patients with HER2⁺ breast cancer often respond to trastuzumab, although acquired resistance is common and can involve a range of mechanisms. reflecting the highly heterogeneous biology of this breast cancer subtype. In this Review, the authors describe the role of dual HER2 blockade, involving the co-administration of two HER2-targeted therapies (including monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates) in patients with HER2⁺ breast cancer.

Despite recent FDA approval, the clinical utility of vorasidenib in the treatment of IDH-mutant low-grade gliomas remains unclear. Herein, we critique the pivotal trial of vorasidenib, and highlight the questionable choice of control intervention and end points, ethical concerns, as well as the uncertain efficacy observed, and argue that the approval might be premature given the high cost of this drug and lack of clear benefit over standard treatments.

Precision oncology has reached a milestone as data from two trials in which molecular profiling guided both site-specific and tumour-agnostic therapies indicate improved survival outcomes in patients with cancer of unknown primary. These findings can also be extrapolated and support the use of tissue-agnostic approaches in general, and also suggest that the tissue of origin might have a role in the agnostic classification of cancers and their response to treatment.

The development of clinically relevant artificial intelligence (AI) models has traditionally required access to extensive labelled datasets, which inevitably centre AI advances around large centres and private corporations. Data availability has also dictated the development of AI applications: most studies focus on common cancer types, and leave rare diseases behind. However, this paradigm is changing with the advent of foundation models, which enable the training of more powerful and robust AI systems using much smaller datasets.

Although ovarian cancer is considered an immunoreactive disease, moderate to no efficacy has been shown in the trials testing immune-checkpoint inhibitors in these patients performed thus far. The authors of this Review summarize these results and propose a systematic classification of ovarian cancer based on CD8⁺ T cell immunophenotypes that, integrated with genetic data, can enable the design of tailored therapeutic approaches, including adoptive cell therapy and novel immunotherapy combinations.

My close experience with cancer and interactions with other patients, caregivers and health-care providers have shaped my belief that patients must be at the centre of research and care. In this Comment, I advocate for a redirection of research efforts in order to measure patient-centred outcomes and address health disparities.

Endometrial cancer is the commonest gynaecological cancer in economically developed countries, and both the incidence and mortality continue to increase. This increasing prevalence highlights the need for novel treatment approaches that will improve patient outcomes. In this Review, the authors describe the epidemiology and standard-of-care treatment approaches for patients with endometrial cancer, as well as highlighting the importance of understanding tumour biology and incorporating this knowledge into better-informed treatment strategies for specific subgroups of patients.

Tumour mutational burden (TMB), reflecting the number of mutations present in the DNA of a tumour, is a biologically appealing biomarker of a response to immune-checkpoint inhibitors (ICIs). Nonetheless, the clinical predictive value of TMB for ICI response has thus far been mixed, with robust associations seen only for a few ICI-responsive cancer types. In this Review, the authors summarize the available data on TMB and discuss ongoing research efforts to improve the clinical utility of this biomarker.

Patients with advanced-stage hormone receptor-positive (HR⁺) breast cancer typically receive first-line treatment with anti-oestrogen-based agents, often combined with a CDK4/6 inhibitor, although resistance remains common. The authors of this Review discuss how a variety of novel endocrine therapies together with tumour molecular profiling could shape the future therapeutic landscape for these patients.

In the past 2 years, substantial improvements have been made in the management of advanced-stage EGFR-mutant non-small-cell lung cancer. Recent studies have suggested added benefit from the combination of third-generation tyrosine-kinase inhibitors with either chemotherapy or a bispecific antibody targeting EGFR and MET. Herein, we summarize these advances and their implications for clinical practice.

Several different viruses have a role in cancer pathogenesis, contributing to the development of various haematological malignancies and solid tumours via diverse, multifaceted mechanisms. However, this viral aetiology presents a unique opportunity for adoptive virus-specific T cell (VST) therapy. This Review summarizes the mechanisms of viral carcinogenesis and describes the current clinical experience with adoptive cellular immunotherapies for virus-related cancers, predominantly using non-genetically modified VSTs. The authors also discuss challenges and future directions for the ongoing clinical development of VST therapies.

Solid tumours are complex ecosystems comprising many different cell types with spatially structured arrangement. The authors of the Review describe how single-cell and spatial profiling tools have been applied to understand the cellular architecture of the tumour microenvironment. These approaches have potential to improve the way cancer is diagnosed and treated.

Anti-HER2 therapy has revolutionized the treatment of HER2-positive breast cancer. However, HER2 has emerged as a driver of various other cancers and the indications for HER2-targeted therapy have expanded to include diverse HER2-overexpressing as well as HER2-mutant tumour types beyond breast cancer, facilitated by the advent of novel agents with greater potency and distinct mechanisms of action. Some of these agents have demonstrated promising activity even against HER2-low cancers. Herein, Yoon and Oh describe the landscape of HER2 alterations and HER2-targeted drug development beyond breast cancer. They also discuss new insights into mechanisms of resistance and potential strategies by which they might be overcome.

BCMA-directed chimeric antigen receptor T cell therapies and bispecific T cell engagers are moving to earlier lines of therapy in multiple myeloma. In addition, combination therapy with the BCMA-targeting antibody–drug conjugate belantamab mafodotin at first or subsequent relapse has the potential to improve survival of patients with this disease. This increasing number of therapeutic options makes treatment selection and sequencing increasingly complex.