Reviews & Analysis

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  • 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.

    • Jamie E. Chaft
    • Andreas Rimner
    • Tina Cascone
    Review Article
  • 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.

    • Anil K. D’Cruz
    • Richa Vaish
    News & Views
  • 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.

    • Lorenz C. Hofbauer
    • Aline Bozec
    • Klaus Pantel
    Review Article
  • 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.

    • Federica Di Nicolantonio
    • Pietro Paolo Vitiello
    • Alberto Bardelli
    Review Article
  • 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.

    • Zowi R. Huinen
    • Elisabeth J. M. Huijbers
    • Arjan W. Griffioen
  • Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.

    • Yoshiaki Nakamura
    • Akihito Kawazoe
    • Kohei Shitara
    Review Article
  • In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.

    • Abhijit Pal
    • Rajiv Shinde
    • Johann de Bono
  • Antibody–drug conjugates (ADCs) were originally developed for patients with haematological malignancies. In light of the recent increase in interest in this type of therapy, this Review describes the clinical experience with two ADCs — gemtuzumab ozogamicin and inotuzumab ozogamicin — in patients with haematological malignancies and provides guidance on the future directions for the development of novel ADCs for patients with leukaemias.

    • Elias Jabbour
    • Shilpa Paul
    • Hagop Kantarjian
    Review Article
  • An unfavourable gut bacterial composition has been shown to reduce the likelihood of clinical benefit from immune-checkpoint inhibitors (ICIs). The results of two first-in-human studies of faecal microbiota transplantation in patients with melanoma refractory to anti-PD-1 antibodies validate preclinical evidence that this approach can improve the gut microbiota and overcome resistance to ICIs; however, many questions remain.

    • Arielle Elkrief
    • Bertrand Routy
    News & Views
  • A recent meta-analysis examined and validated biomarkers of response to immune-checkpoint inhibitors (ICIs). Herein, we discuss the findings of this analysis, which are consistent with previously identified determinants of ICI efficacy and demonstrate that some genetic variables influence response across multiple cancer types.

    • Tyler J. Alban
    • Timothy A. Chan
    News & Views
  • Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

    • Aakash Desai
    • Justin F. Gainor
    • Vivek Subbiah
  • ATM, BRCA1, BRCA2, CHEK2, PALB2 and TP53 are all established breast cancer susceptibility genes. Over the past 30 years, many other genes have been proposed as candidates. In these two large studies, the candidacy of several questionable genes has been largely resolved, and a final list of ten genes for breast and, importantly, ovarian cancer risk has emerged.

    • William D. Foulkes
    News & Views
  • Talimogene laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of patients with recurrent melanoma. Now, a recent study in patients with primary cutaneous B cell lymphoma confirms prior results in melanoma and reveals new mechanisms of action. Herein, we discuss these findings and their implications for expanding the role of oncolytic viruses.

    • Howard L. Kaufman
    • Dawid Maciorowski
    News & Views
  • The discovery that the anticancer activity of thalidomide and its analogues, such as lenalidomide, reflects drug-induced degradation of specific target proteins has heightened interest in novel ‘degrader’ drugs. Herein, the authors review the wide and expanding use of thalidomide analogues in the treatment of multiple cancers and outline how lessons learned from this experience, particularly with lenalidomide, can guide the clinical development of new targeted protein degradation platforms.

    • Max Jan
    • Adam S. Sperling
    • Benjamin L. Ebert
    Review Article
  • CD19-specific chimeric antigen (CAR)-modified T cells are approved for patients with advanced-stage forms of certain B cell malignancies. However, a subset of patients will have anti-CAR immune responses, leading to a lack of CAR T cell persistence and a rapid loss of any antitumour efficacy. In this Review, the authors describe the extent of anti-CAR immune responses in patients and suggest measures that could be used to better monitor for these events. Additionally, they describe novel approaches to CAR T cell therapy that might reduce the risk of such responses in the future.

    • Dimitrios L. Wagner
    • Enrico Fritsche
    • Mohamed Abou-el-Enein
    Review Article
  • The question of whether allogeneic chimeric antigen receptor (CAR) T cells could replace autologous CAR T cell therapy has garnered considerable interest, but limited data have been available for comparisons to date. Now, Benjamin et al. have reported their experience with allogeneic anti-CD19 CAR T cells in 21 paediatric and adult patients with acute lymphoblastic leukaemia.

    • Amanda M. DiNofia
    • Stephan A. Grupp
    News & Views
  • In this Consensus Statement, members from five working groups or societies provide updated comprehensive recommendations to manage toxicities from cancer immunotherapies in children, adolescents and young adults. In their recommendations, they advocate for the adoption of age-based and discipline-specific management criteria, and call for an increased inclusion of young patients with cancer in clinical trials.

    • Dristhi Ragoonanan
    • Sajad J. Khazal
    • Kris M. Mahadeo
    Consensus Statement
  • PD-L1 expression is currently the best available biomarker for the prediction of responsiveness to immune-checkpoint inhibitors. However, several immunohistochemical assays are now approved for clinical use in various settings, despite imperfect inter-assay concordance, with important implications for pathology services and, potentially, for clinical outcomes. In this Review, the authors compare the performance of the various FDA-approved PD-L1 assays, discuss the varying implications of PD-L1 expression across different tumour types and provide guidance on possible novel approaches that might optimize the clinical utility of PD-L1 as a biomarker.

    • Deborah Blythe Doroshow
    • Sheena Bhalla
    • Fred R. Hirsch
    Review Article
  • Antibody–drug conjugates (ADCs) constitute a unique class of anticancer agents with demonstrated clinical efficacy against several different cancer types. Herein, the authors discuss the design and mechanisms of action of ADCs and how these properties are reflected in the clinical activity and toxicity profiles of such agents. Potential strategies to overcome the limitations of ADCs and thereby maximize their therapeutic benefit for patients with cancer are also proposed.

    • Joshua Z. Drago
    • Shanu Modi
    • Sarat Chandarlapaty
    Review Article
  • Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation. Pharmacological agents, ionizing radiation and cytokines can induce ferroptosis and thus suppress tumour growth, but ferroptosis can also trigger inflammation-associated immunosuppression. The authors describe the key molecular mechanisms of ferroptosis, including crosstalk with tumour-associated signalling pathways, and discuss potential therapeutic applications of ferroptosis.

    • Xin Chen
    • Rui Kang
    • Daolin Tang
    Review Article