Reviews & Analysis

The paradigm of precision medicine implies that breast cancer treatment should be tailored based on inherent risk of recurrence and/or individual sensitivity to various chemotherapies. A recent trial of olaparib in women with a BRCA1/2 mutation provides supporting evidence for this paradigm and suggests that the identification of genetic variants at the time of diagnosis might benefit an increasing number of patients.

The blood–brain barrier regulates the movement of various substances between the blood and the brain and therefore has a crucial role in ensuring normal brain function. In both primary brain tumours and brain metastases, the blood–brain barrier is modified to the blood–tumour barrier (BTB), resulting in altered permeability; however, the BTB continues to restrict the penetration of many therapeutic agents into intracranial tumours. Here, Patricia Steeg describes the current knowledge of BTB structure and function and discusses how this knowledge can be translated into improvements in cancer therapy and patient outcomes.

Artificial intelligence and machine learning have the potential to make cancer care more accessible, efficient, cost-effective and personalized. However, meticulously planned prospective deployment strategies are required to validate the performance of these technologies in real-world clinical settings and overcome the human trust barrier.

Chimeric antigen receptor (CAR) T cell therapies are generating substantial excitement and have been approved for the treatment of various haematological malignancies. All approved CARs consist of an extracellular antigen-binding domain linked to an intracellular region containing a costimulatory domain and a T cell activation domain. A key question is whether the CD28-derived and 4-1BB-derived costimulatory domains used in current commercial CAR T cell products are associated with different cellular and clinical effects. Herein, Cappell and Kochenderfer provide an overview of CD28 and 4-1BB costimulatory pathways and compare the outcomes observed in preclinical and clinical studies with CARs incorporating either costimulatory domain.

Advances in cancer immunotherapy have led to clinical trials of immunotherapy-based neoadjuvant treatments for early stage non-small-cell lung cancer. Evidence for priming of the immune system using both preoperative short-course radiotherapy and immunotherapy in this setting has now emerged from a randomized phase II study incorporating pathological and immunological end points.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy endemic to southern China, southeast Asia and north Africa. The authors of this Review present a comprehensive overview of advances from the past three decades on the pathogenic role of EBV, and the genomic, epigenomic and immune landscape of NPC, which have led to the development of new biomarkers, therapeutic targets and improved treatment approaches for patients with NPC.

Immune-checkpoint inhibitors (ICIs) are now standard-of-care therapies for patients with advanced-stage non-small-cell lung cancer (NSCLC) without a targetable driver alteration. Various ICIs or combination regimens have been approved in this setting, relative to chemotherapy, although no prospective data are available comparing the various ICI-based approaches. Here, the authors provide guidance on selecting the optimal ICI-based therapy and highlight several future research directions that will probably further improve the outcomes of patients with advanced-stage NSCLC.

Hotspot genetic alterations that confer the enzymes isocitrate dehydrogenase (IDH) 1 and 2 with neomorphic activity to produce the oncometabolite D-2-hydroxyglutarate are common in several cancer types, including acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and glioma. Herein, Pirozzi and Yan describe the current understanding of the biological, pathogenetic and prognostic implications of IDH mutations in these cancers. They also review the available preclinical and clinical data on the various therapeutic strategies that are being pursued for IDH-mutant cancers and discuss whether treatment approaches will converge or be context dependent.

Despite being the most common primary bone cancer in children and young adults, osteosarcoma is a rare cancer, a fact that has complicated efforts to improve patient outcomes. Moreover, the molecular biology of disease is highly heterogeneous and most of the recurrent genetic alterations occur in tumour-suppressor genes that are challenging therapeutic targets. Herein, Gill and Gorlick discuss the new biological discoveries, technologies, and therapeutic agents and approaches that, through collaborative efforts, are poised to generate advances in the treatment of osteosarcoma after more than four decades of stagnation.

Patients with primary central nervous system (CNS) malignancies largely do not derive benefit from immune-checkpoint inhibitors. Paradoxically, a subset of those with CNS metastases from tumours located outside of the CNS will respond to the same approach. In this Perspective, the authors explore the key differences in the immune cell composition of primary CNS malignancies and brain metastases and provide guidance on potential alternative immunotherapies that might be effective in patients with these historically difficult-to-treat malignancies.

Assuming that the latest incidence trends continue for the major cancer types, the incidence of all cancers combined will double by 2070 relative to 2020, with the greatest increases predicted in lower-resource settings. The authors of this Perspective discuss how population-level approaches with amenable goals should be considered an integral part of cancer control.

Whole-genome sequencing of samples from patients with myeloid malignancies can enable more accurate risk stratification than is possible with conventional cytogenetics. Research by Duncavage et al. demonstrates that such an approach can now be delivered within several days using a highly streamlined and automated workflow.

Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies.

Advances in sequencing technology have rapidly improved our understanding of the biology of acute myeloid leukaemia and led to the development of several novel targeted therapies. In this Review, the authors summarize the landscape of novel targeted therapies for patients with acute myeloid leukaemia and provide guidance on future research directions.

Immune responses against tumour antigens that do not arise from cancer cell-specific mutations can result in autoimmune reactions against the tissue of origin of the tumour. Despite their undesirable effects, these symptoms can have prognostic value and correlate with favourable disease outcomes. The authors of this Perspective discuss the importance of such beneficial autoimmunity in patients with advanced-stage disease and in cancer immunosurveillance.

The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers.

The Kerala Oral Cancer Screening Trial did not demonstrate an overall cancer-related mortality benefit. Herein, we discuss the important lessons learnt from a recent reanalysis of data from this trial in an attempt to demonstrate the advantages of using a novel risk-based approach to cancer screening.

Various cancers can disseminate to the bone, including the most common malignancies in men and women, prostate and breast cancer, respectively. Herein, the authors review the roles of the bone microenvironment in skeletal metastasis, highlighting the biology and clinical relevance of circulating tumour cells and disseminated tumour cells. Notably, bone metastases are associated with considerable morbidity and a poor prognosis, and the authors also discuss established and future therapeutic approaches for targeting components of the bone microenvironment to prevent or treat skeletal metastases.

Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.

Anti-angiogenic therapy has the capacity to ameliorate antitumour immunity and, thus, some combinations of anti-angiogenics and immunotherapies have been approved and a number of them are being tested. The authors of this Perspective describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as a vascular counterpart of immune checkpoints.