Reviews & Analysis

International treatment guidelines for chronic myeloid leukaemia incorporate recommendations for attempting discontinuation of treatment with tyrosine-kinase inhibitors (TKIs) with the aim of a treatment-free remission (TFR). The authors of this Review discuss how results of clinical studies of TFR can guide routine practice, address the development of predictors of outcome after TKI discontinuation and present strategies that warrant further consideration to enable more patients to enter TFR.

Effective anticancer therapies typically activate antitumour immunity, predominately mediated by T cells in the tumour microenvironment. Here, we discuss the roles of B cells and tertiary lymphoid structures in the context of chemotherapy-induced complement activation, which results in the induction of a B cell subset that modulates T cell function.

Evidence of quality of life improvements in patients with advanced-stage cancer has spurred a move towards early integration of palliative care into the outpatient setting. As discussed herein, meaningful and sustained improvements in timely access to palliative care requires commitments to funding, encouraging integration and routinizing referral across care settings. More palliative medicine training positions as well as broader education of clinicians and the public about the benefits of palliative care throughout the disease course are also needed.

Despite improvements in diagnostic strategies, cancer of unknown primary — metastatic cancer in patients in whom the primary tumour remains undetected — continues to account for around 1–2% of all cancers. In this Review, Rassy and Pavlidis discuss insights into the biology of CUP and shifts in the clinical management of this enigmatic disease entity in the era of precision medicine.

Haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for several haematological malignancies. Improvements in HSCT methodologies have considerably reduced treatment-related morbidity and mortality, thus broadening eligibility and placing increased emphasis on the prevention of disease relapse. In this Review, the authors discuss approaches to dissecting the biology of HSCT and exploiting the biological insights to enhance the graft-versus-tumour response, in particular with adoptive cell therapies and other immune-directed therapies, whilst minimizing graft-versus-host disease.

Alternative splicing enables the regulated generation of multiple mRNA and protein products from a single gene. This Review outlines the splicing process and its alterations in cancer before highlighting related opportunities for the development of innovative therapeutic approaches.

Mutations in genes encoding subunits of the SWI/SNF chromatin-remodelling complexes occur in almost 25% of all cancers. Herein, Mittal and Roberts discuss the mechanisms by which these mutations might promote cancer and describe the associated vulnerabilities that provide opportunities for targeted therapy or immunotherapy with immune-checkpoint inhibitors.

The treatment of immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors has mostly been based on adapting therapeutic approaches used in the management of primary autoimmune diseases. The authors of this Review provide an overview of the different cellular and soluble immune factors involved in the pathogenesis of irAEs in order to help clinicians deliver personalized immunopathologically guided treatment to manage these adverse events.

The use of bispecific antibodies to engage cells of the immune system that are cytotoxic to cancer cells is a major focus of cancer immunotherapy, with approvals for the treatment of acute lymphoblastic leukaemia. Here, the authors review the clinical results obtained with bispecific antibodies to date. They also discuss the challenges associated with this therapeutic approach and the proposed solutions aimed at preventing or minimizing toxicities, countering immune escape and broadening the indications for these treatments.

The authors of this Review present the main pathways that regulate apoptosis as well as other signalling pathways that interact with them, highlighting actionable molecular targets for anticancer therapy. They also provide an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents.

The identification of individuals carrying cancer susceptibility genetic variants could be improved by peridiagnostic cancer genetic testing and cascade testing of the relatives of patients diagnosed with cancer. Herein we discuss two studies that highlight the importance of active involvement of the medical team, both in informing the relatives and offering pre-test telephone genetic counselling.

Lineage plasticity is a source of intratumoural heterogeneity and enables tumour adaptation to an adverse tumour microenvironment, eventually leading to therapeutic resistance. The authors of this Review provide an overview of the impact of lineage plasticity on cancer progression and therapy resistance, with a focus on neuroendocrine transformation in lung and prostate tumours, and discuss emerging management strategies and open questions in the field.

Cancer cells, like non-malignant cells, are dependent on folate uptake for growth. However, cancer cells are much more reliant on folate receptors (FRs) and particularly FRα for folate uptake than non-malignant cells. In this Review, the authors describe the available data on the role of FRα as a biomarker and as a target of imaging probes, and of targeted therapies in patients with solid tumours.

The survival outcomes of the FLAURA trial support osimertinib as the new first-line standard of care for patients with EGFR-mutated advanced-stage non-small-cell lung cancer in health-care systems that can afford its cost. However, the low crossover rate is a flaw of this study. Knowledge of mechanisms of resistance to provide tailored treatment is the new challenge preventing a continued paradigm shift in this disease.

Advances in imaging and biomarker discovery have led to a revolution in prostate cancer diagnosis, and nontargeted prostate biopsies should become obsolete. The authors of this Perspective article describe the current diagnostic pathway and discuss how advances in prebiopsy multiparametric MRI and the discovery of novel tumour markers should lead to a new diagnostic pathway.

T_RM cells have a role in peripheral immune surveillance in several organs. The presence of T_RM cells in the immune infiltrate is also associated with improved outcomes in patients with several solid tumour types, and these cells might have a role in the response to immune checkpoint inhibitors. In this Review, the authors describe the available date on the role of T_RM cells in patients with breast cancer

Developing novel technologies to discriminate malignant tissue from nonmalignant structures and thereby facilitate safe, complete tumour resection is a major priority for advancing oncological neurosurgery. Herein, we discuss a recently reported innovation involving stimulated Raman spectroscopy of intraoperative tissue samples and data interpretation with artificial intelligence, as well as the implications of this approach for neurosurgical oncology.

Brain metastases are a frequent manifestation of several common solid tumour types, including lung cancer, breast cancer and melanoma. Although the presence of brain-metastatic disease continues to be associated with poor outcomes, advances in surgery, radiotherapy and systemic therapies that can permeate the blood–brain barrier are beginning to improve patient outcomes. In this Review, the authors provide an overview of contemporary advances in the management of brain metastases over the past decade.

Surgery remains a key pillar of cancer therapy, particular for those with curable, localized disease. The immediate perioperative period (days before and after surgery) is associated with various psychological and physiological stresses and associated factors, including inflammatory mediators, that might promote cancer progression and thus determine long-term outcomes. Herein, the authors present the hypothesis and supporting evidence that the use of certain types of immunotherapy, together with interventions to abrogate stress–inflammatory responses, in conjunction with surgery might improve the overall success of cancer treatment.

Patients with small-cell lung cancer (SCLC) have historically received chemotherapy, typically with poor survival outcomes. In the past few years, the combination of immune-checkpoint inhibitors (ICIs) with chemotherapy has provided a more effective alternative to chemotherapy alone. Nonetheless, durations of survival are often short, and no robust biomarkers of response are available. In this Review, the authors provide a summary of the efficacy and safety of ICIs in patients with SCLC, and also highlight potential novel immunotherapeutic approaches that are currently in the early stages of investigation.