Review Articles

  • Review Article |

    With the development of novel targeted therapies for patients with colorectal cancer, comes a wealth of new, and increasingly complex information on biomarkers. In this Review, the authors describe this increased complexity, with a focus on interactions between more than one biomarker and the implications of these interactions for patient management.

    • Anita Sveen
    • , Scott Kopetz
    •  & Ragnhild A. Lothe
  • Review Article |

    In this Review, the authors present current insights into the genetic aetiology and pathogenesis of chronic lymphocytic leukaemia, highlighting the effect of recurrent lesions on progression, and discuss their clinical implications for management and development of novel therapeutic paradigmns.

    • Francesc Bosch
    •  & Riccardo Dalla-Favera
  • Review Article |

    Despite their promise, immunotherapy–radiotherapy combinations could be limited by the patient-specific nature of radiation-induced immune responses. This Review discusses methods of assessing the immune response to radiotherapy and approaches to predict the synergy between immunotherapy and radiotherapy for personalized medicine.

    • Clemens Grassberger
    • , Susannah G. Ellsworth
    • , Moses Q. Wilks
    • , Florence K. Keane
    •  & Jay S. Loeffler
  • Review Article |

    The authors of this Review discuss treatments currently available for patients with head and neck squamous cell carcinomas (focusing in those of the oral cavity, oropharynx, hypopharynx and larynx). Advances in surgical and non-surgical approaches (mainly combinations of radiotherapy and chemotherapy) are discussed, including the first immunotherapeutic agents approved for these malignancies.

    • John D. Cramer
    • , Barbara Burtness
    • , Quynh Thu Le
    •  & Robert L. Ferris
  • Review Article |

    Neutrophils accumulate in the circulation of patients with cancer, and the neutrophil-to-lymphocyte ratio is a widely used biomarker. However, the effects of neutrophils on tumour development and progression, and the efficacy of therapies, remain relatively unknown. In this Review, the authors draw on data from animal models and patients with cancer to provide an overview of the effects of neutrophils in cancer.

    • Merav E. Shaul
    •  & Zvi G. Fridlender
  • Review Article |

    Approximately 50% of patients with diffuse large B cell lymphoma (DLBCL) are cured with chemotherapy. However, patients with relapsed and/or refractory DLBCL have few other treatment options. In this Review, the authors describe emerging data on genetically targeted therapies for patients with DLBCL and how these might improve patient outcomes.

    • Yi Miao
    • , L. Jeffrey Medeiros
    • , Yong Li
    • , Jianyong Li
    •  & Ken H. Young
  • Review Article |

    Immune-checkpoint inhibitors (ICIs) have dramatically improved the survival of patients with certain forms of cancer; however, these agents also have adverse effects that are often quite different to those of more traditional cancer therapies. In this Review, the authors describe the epidemiology, treatment and management of the various immune-related adverse events that can occur in patients receiving ICIs.

    • Filipe Martins
    • , Latifyan Sofiya
    • , Gerasimos P. Sykiotis
    • , Faiza Lamine
    • , Michel Maillard
    • , Montserrat Fraga
    • , Keyvan Shabafrouz
    • , Camillo Ribi
    • , Anne Cairoli
    • , Yan Guex-Crosier
    • , Thierry Kuntzer
    • , Olivier Michielin
    • , Solange Peters
    • , Georges Coukos
    • , Francois Spertini
    • , John A. Thompson
    •  & Michel Obeid
  • Review Article |

    The therapeutic options currently available for patients with metastatic renal cell carcinoma (RCC) include immune-checkpoint inhibitors, novel targeted agents and combination strategies, and thus optimal patient selection and treatment sequencing are important. The authors review relevant aspects of the molecular biology of metastatic RCC, with an emphasis on biomarkers, and suggest tailored algorithms to individualize and guide treatment approaches

    • Ritesh R. Kotecha
    • , Robert J. Motzer
    •  & Martin H. Voss
  • Review Article |

    The metabolic conditions in tumours can result in phenotypic reprogramming of non-tumour cells, including immune cells, in the tumour microenvironment. This Review provides an overview of the pathways of cancer metabolism that intersect with immunometabolism, typically resulting in immunosuppression, with a focus on how these metabolic pathways could be targeted in order to enhance anticancer immunity and immunotherapy.

    • Xiaoyun Li
    • , Mathias Wenes
    • , Pedro Romero
    • , Stanley Ching-Cheng Huang
    • , Sarah-Maria Fendt
    •  & Ping-Chih Ho
  • Review Article |

    Immunotherapy with immune-checkpoint inhibitors (ICIs) is a new pillar in the treatment of cancer but can a have range of immune-related adverse effects, including some rare neurological toxicities that constitute paraneoplastic neurological syndromes (PNSs). In this Review, the authors provide an overview of PNSs, the associations of these conditions with ICI therapy and recommendations for the prevention and management of ICI-associated PNSs.

    • Francesc Graus
    •  & Josep Dalmau
  • Review Article |

    The development of chimeric antigen receptor (CAR) T cell therapy is an important advance in the treatment of cancer. Herein, the authors outline the key limitations of CAR T cell therapy, with a focus on mechanisms of resistance, and discuss strategies to improve the efficacy and broaden the applicability of this promising therapeutic approach.

    • Nirali N. Shah
    •  & Terry J. Fry
  • Review Article |

    Patients with lymphoma typically receive chemotherapy as the first-line treatment. However, patients who fail to respond or develop relapsed disease often have poor outcomes. In this Review, the authors summarize the available data on therapeutics designed to modulate epigenetic changes, including DNA methylation and histone acetylation, in patients with lymphoma and describe the most promising directions of future research.

    • David Sermer
    • , Laura Pasqualucci
    • , Hans-Guido Wendel
    • , Ari Melnick
    •  & Anas Younes
  • Review Article |

    Despite much hope, anti-angiogenic agents have largely failed to achieve the promise demonstrated in preclinical models. In this Review, the authors discuss an alternative hypothesis — vessel co-option — that might explain many of these failures and describe the evidence for a role of this largely overlooked aspect of tumour biology.

    • Elizabeth A. Kuczynski
    • , Peter B. Vermeulen
    • , Francesco Pezzella
    • , Robert S. Kerbel
    •  & Andrew R. Reynolds
  • Review Article |

    In this Review, Pantel and Alix-Panabières provide an overview of approaches for the detection and characterization of minimal residual disease (MRD) using circulating tumour cells and circulating tumour DNA. They also discuss the clinical implications of such liquid biopsy approaches to MRD monitoring for the management of patients with cancer.

    • Klaus Pantel
    •  & Catherine Alix-Panabières
  • Review Article |

    The majority of genetically targeted approaches to cancer therapy focus on somatic mutations. However, evidence is accumulating in support of a role for germline genetic alterations in determining responsiveness to treatment. In this Review, the authors summarize the therapeutic potential of knowledge of the germline genome in patients with cancer.

    • Subotheni Thavaneswaran
    • , Emma Rath
    • , Kathy Tucker
    • , Anthony M. Joshua
    • , Dominique Hess
    • , Mark Pinese
    • , Mandy L. Ballinger
    •  & David M. Thomas
  • Review Article |

    The advent of effective molecularly targeted treatments and immunotherapies for non-small-cell lung cancer (NSCLC) has greatly improved patient outcomes. Whereas most patients selected for treatment with molecularly targeted drugs derive benefits from these agents, benefit from immunotherapy is more difficult to predict. Herein, Camidge and colleagues compare and contrast predictive biomarkers for immunotherapy and targeted therapy of NSCLC to highlight considerations for biomarker development.

    • D. Ross Camidge
    • , Robert C. Doebele
    •  & Keith M. Kerr
  • Review Article |

    The development of more-targeted cancer therapies has not been matched by more-targeted imaging methods. This discrepancy has, in some scenarios, resulted in inaccurate assessments of the effects of novel therapies. In this Review, the authors describe potential novel imaging approaches that could be adopted to enable improvements in imaging-based monitoring of treatment responses and resistance.

    • Mirjam Gerwing
    • , Ken Herrmann
    • , Anne Helfen
    • , Christoph Schliemann
    • , Wolfgang E. Berdel
    • , Michel Eisenblätter
    •  & Moritz Wildgruber
  • Review Article |

    Regulatory T (Treg) cells are implicated in cancer immune evasion and escape and thus contribute to tumour development and progression. In this Review, the authors provide an overview of the phenotypes and roles of Treg cells in the context of cancer and outline potential strategies to target this cell type in anticancer immunotherapy.

    • Yosuke Togashi
    • , Kohei Shitara
    •  & Hiroyoshi Nishikawa
  • Review Article |

    In the past few years, the use of data from the real world has garnered increasing interest; however, studies using real-world data (RWD) should not be used as substitutes for clinical trials. The authors of this Review explore the quality of RWD, provide a framework for the use of RWD and draw attention to the methodological pitfalls inherent to using RWD.

    • Christopher M. Booth
    • , Safiya Karim
    •  & William J. Mackillop
  • Review Article |

    CRISPR systems have enabled important advances in cancer research by accelerating the development of study models or as a tool in genetic screening studies to discover and validate therapeutic targets. The authors of this Review discuss these applications and new potential uses, such as cancer detection and development of anticancer therapies.

    • Hao Yin
    • , Wen Xue
    •  & Daniel G. Anderson
  • Review Article |

    Women with early-stage oestrogen receptor (ER)-positive (ER+) breast cancer remain at risk of distant recurrence for at least 15 years after discontinuation of 5 years of standard endocrine therapy. The authors of this Review discuss the epidemiology and mechanisms underlying late recurrence and examine several models used for risk prognostication and for estimating the presence of minimal residual disease.

    • Juliet Richman
    •  & Mitch Dowsett
  • Review Article |

    Herein, advances in our understanding of the genomic landscape of childhood acute lymphoblastic leukaemia (ALL), encompassing both somatic and germline alterations, are reviewed. The clinical implications of these alterations, particularly those in the germ line, are discussed with regard to susceptibility to ALL, treatment responses and therapy-related toxicities.

    • Ching-Hon Pui
    • , Kim E. Nichols
    •  & Jun J. Yang
  • Review Article |

    The mechanisms of resistance to immunotherapy seem to broadly overlap with the immunoediting process whereby cancers evade detection by the immune system. The authors of this Review discuss these interactions as well as the strategies that can be used to overcome therapeutic resistance

    • Jake S. O’Donnell
    • , Michele W. L. Teng
    •  & Mark J. Smyth
  • Review Article |

    Patients with cancer might be at a higher risk of nonmedical opioid use than was previously thought; however, opioid analgesics remain the gold standard to treat cancer-related pain. The authors of this Review examine the role of opioids in cancer-related pain, the risk of substance use disorder and methods to achieve the right balance between both to ensure safe opioid use.

    • Joseph Arthur
    •  & Eduardo Bruera
  • Review Article |

    Broad population screening of asymptomatic individuals for cancers of the prostate or thyroid has resulted in overdiagnosis and overtreatment. Herein, the authors describe the epidemiology, pathology, and screening guidelines for the management of patients with those cancers, and discuss existing international active surveillance protocols.

    • Lisa M. Lowenstein
    • , Spyridon P. Basourakos
    • , Michelle D. Williams
    • , Patricia Troncoso
    • , Justin R. Gregg
    • , Timothy C. Thompson
    •  & Jeri Kim
  • Review Article |

    FGFR alterations can be detected in a small subset of many different cancer types. Inspired by the successes with other targeted therapies, preliminary attempts to target FGFR-altered cancers have been hampered by low response rates and acquired resistance. In this Review, the author describes the development of FGFR inhibitors thus far, and provides guidance on future research priorities.

    • Masaru Katoh
  • Review Article |

    A deterioration of disease can occur upon treatment with anti-PD-1/PD-L1 monoclonal antibodies; this paradoxical phenomenon is defined as hyperprogression. The authors discuss the pathophysiological hypotheses that might explain hyperprogressive disease and the resulting challenges for patient management, with a focus in clinical decisions involving immune-checkpoint inhibitors.

    • Stéphane Champiat
    • , Roberto Ferrara
    • , Christophe Massard
    • , Benjamin Besse
    • , Aurélien Marabelle
    • , Jean-Charles Soria
    •  & Charles Ferté
  • Review Article |

    Inhibition of poly(ADP-ribose) polymerase (PARP) is the paradigmatic example of synthetic lethal therapy and is predicated on exploiting DNA repair deficiencies that are a hallmark of cancer. In this Review, the authors review the progress made to date with PARP inhibitors and describe the expanding landscape of novel anticancer therapies targeting the DNA damage response. Potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.

    • Patrick G. Pilié
    • , Chad Tang
    • , Gordon B. Mills
    •  & Timothy A. Yap
  • Review Article |

    Successful surgical resection offers patients with pancreatic cancer the best chance of survival. However, many patients do not have surgically resectable disease. In this Review, the authors describe recent improvements in pancreatic cancer surgery, which have increased survival and also enabled more patients to undergo surgery.

    • Oliver Strobel
    • , John Neoptolemos
    • , Dirk Jäger
    •  & Markus W. Büchler
  • Review Article |

    TRK fusion proteins are pathognomonic in certain rare tumour types and present in a small subset of diverse cancer types, including some common cancers; TRK inhibitors have promising efficacy in the treatment of these cancers, in a histology-agnostic manner. In this Review, the biology of TRK signalling and TRK fusions, strategies to target these drivers, the unique safety profile of TRK inhibitors and mechanisms of and strategies to overcome acquired resistance to these agents are discussed.

    • Emiliano Cocco
    • , Maurizio Scaltriti
    •  & Alexander Drilon
  • Review Article |

    Effective therapeutic strategies to target RAS-mutant cancers have proved elusive, but in the past few years, several promising strategies have been tested in clinical trials. The authors describe historical and ongoing therapeutic approaches based on the direct or indirect targeting of RAS.

    • Meagan B. Ryan
    •  & Ryan B. Corcoran
  • Review Article |

    Intriguing evidence suggests that expression of RANK or RANKL by various cells of the tumour microenvironment modulates the anticancer immune response. Herein, the authors review this evidence, discuss the current preclinical and clinical data supporting a potential of RANKL inhibition to improve anticancer immunotherapy and describe hypothetical immune-related mechanisms of action.

    • Elizabeth Ahern
    • , Mark J. Smyth
    • , William C. Dougall
    •  & Michele W. L. Teng
  • Review Article |

    Improvements in the management of patients with early stage breast cancer have been achieved through intense therapeutic escalation but also with de-escalation of systemic therapies. The authors of this Review summarize key trials using both approaches and highlight the need to use therapeutic escalation for patients who would benefit from that approach and de-escalation for patients with a favourable prognosis.

    • Noam F. Pondé
    • , Dimitrios Zardavas
    •  & Martine Piccart
  • Review Article |

    Androgen receptor (AR) splice variants (AR-Vs) are truncated isoforms of the AR, of which a subset remain constitutively active in the absence of circulating androgens. AR-Vs have been proposed to contribute to therapeutic resistance. The authors of this Review outline the current understanding of the role of the spliceosome in prostate cancer progression and explore the therapeutic utility of manipulating alternative splicing.

    • Alec Paschalis
    • , Adam Sharp
    • , Jonathan C. Welti
    • , Antje Neeb
    • , Ganesh V. Raj
    • , Jun Luo
    • , Stephen R. Plymate
    •  & Johann. S. de Bono
  • Review Article |

    The clinical management of patients with non-small-cell lung carcinoma has greatly evolved owing to the development of tyrosine-kinase inhibitors (TKIs) targeted against the driver mutations of this disease. The authors of this Review describe the existing evidence on the sequential administration of TKIs and the use of next-generation TKIs upfront.

    • Gonzalo Recondo
    • , Francesco Facchinetti
    • , Ken A. Olaussen
    • , Benjamin Besse
    •  & Luc Friboulet
  • Review Article |

    Molecular profiling studies are providing novel insights into the biology of hepatocellular carcinoma, although these remain to be translated into novel effective therapies. Nevertheless, therapeutic advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.

    • Josep M. Llovet
    • , Robert Montal
    • , Daniela Sia
    •  & Richard S. Finn
  • Review Article |

    The majority of patients receiving immunotherapy do not respond to treatment but might still have adverse events. Furthermore, some patients with an initial response will develop acquired resistance to treatment. In this Review, the authors describe the role of circulating tumour DNA in the management of patients receiving immunotherapy.

    • Luc Cabel
    • , Charlotte Proudhon
    • , Emanuela Romano
    • , Nicolas Girard
    • , Olivier Lantz
    • , Marc-Henri Stern
    • , Jean-Yves Pierga
    •  & François-Clément Bidard
  • Review Article |

    Following the success of poly(ADP-ribose) PARP inhibitors in patients with BRCA1/2 mutations, considerable research interest has emerged in the discovery of alternative forms of synthetic lethality. In this Review, the authors summarize the potential of various novel forms of synthetic lethality to further improve the treatment of patients with cancer.

    • Alan Ashworth
    •  & Christopher J. Lord
  • Review Article |

    The combination of radiotherapy and immune-checkpoint inhibition (ICI) has generated considerable excitement among oncologists, and numerous clinical trials are currently exploring the efficacy of this approach; however, the safety and tolerability of this combination remains incompletely understood. In this Review, the authors describe the available data on safety considerations in patients receiving radiotherapy in combination with ICI.

    • William L. Hwang
    • , Luke R. G. Pike
    • , Trevor J. Royce
    • , Brandon A. Mahal
    •  & Jay S. Loeffler
  • Review Article |

    Emerging evidence indicates that tumour-derived extracellular vesicles (EVs), notably exosomes, mediate intercellular communication to promote cancer development and progression. Herein, the authors discuss EV properties and physiological functions, particularly their pro-metastatic effects, and highlight the diagnostic and therapeutic potential of EVs in cancer.

    • Rong Xu
    • , Alin Rai
    • , Maoshan Chen
    • , Wittaya Suwakulsiri
    • , David W. Greening
    •  & Richard J. Simpson
  • Review Article |

    Evidence of the functional roles of non-coding RNAs in cancer is expanding, and the potential of these RNAs as diagnostic and prognostic biomarkers is increasingly recognized. Herein, the authors review the recent developments in these areas and provide compendiums of circulating microRNAs and long non-coding RNAs that have promise as diagnostic and prognostic cancer biomarkers.

    • Simone Anfossi
    • , Anna Babayan
    • , Klaus Pantel
    •  & George A. Calin
  • Review Article |

    In recent years, a number of novel agents have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). Herein, Jan A. Burger and Susan O’Brien outline the emerging paradigm of individualized therapy for patients with CLL aimed at exploiting the advantages of these novel agents but also integrating traditional therapies for selected patients.

    • Jan A. Burger
    •  & Susan O’Brien
  • Review Article |

    Patients with advanced-stage urothelial carcinoma typically receive chemotherapy and might also receive immune-checkpoint inhibitors following disease progression. However, the majority of patients will ultimately develop resistance to treatment. In this Review, the authors describe the evolutionary mechanisms of treatment resistance in patients with urothelial carcinoma.

    • Panagiotis J. Vlachostergios
    •  & Bishoy M. Faltas
  • Review Article |

    The multiple myelomas (MMs) are heterogeneous malignancies that are nearly always associated with chromosomal abnormalities, which can be considered either primary or secondary abnormalities. The classification of MM according to the underlying primary cytogenetic abnormality might enable the development of better treatment strategies. The authors describe treatment approaches that consider the current standard of care for patients with MM along with recommendations for certain subgroups of patients.

    • Shaji K. Kumar
    •  & S. Vincent Rajkumar
  • Review Article |

    Patients with sarcomas have historically been treated with surgery and/or chemotherapy, although the outcomes achieved with these approaches, especially in advanced-stage disease, are often disappointing. In this Review, the authors describe the opportunities created by selective use of targeted therapies on the basis of the biological characteristics of individual tumours.

    • Armelle Dufresne
    • , Mehdi Brahmi
    • , Marie Karanian
    •  & Jean-Yves Blay
  • Review Article |

    The tumour stroma is a component of the tumour microenvironment and has crucial roles in tumour initiation, progression, and metastasis. Most anticancer therapies target cancer cells specifically, but the tumour stroma can promote resistance to such therapies. Herein, the authors provide an overview of the complex cancer cell–tumour stroma interactions and discuss how novel treatment strategies should combine anticancer and antistromal agents.

    • Kenneth C. Valkenburg
    • , Amber E. de Groot
    •  & Kenneth J. Pienta
  • Review Article |

    Glioblastoma is a disease associated with a dismal patient prognosis, necessitating the development of novel therapies. Substantial research effort is being devoted to the development of immunotherapies for glioblastoma. Herein, the rationale and promise for this approach are discussed, together with the challenges and how they might be overcome.

    • Michael Lim
    • , Yuanxuan Xia
    • , Chetan Bettegowda
    •  & Michael Weller
  • Review Article |

    Developments in genomic sequencing technologies have enabled increasing amounts of information on the genomes of individual cancers to be revealed. At the same time, increasing numbers of therapies targeting specific genomic alterations are being made available, necessitating the use of genomics to diagnose and treat patients with cancer. In this Review, the authors describe the emerging clinical relevance of genomics in oncology, in addition to the many challenges that currently preclude routine clinical use.

    • Michael F. Berger
    •  & Elaine R. Mardis
  • Review Article |

    The PI3K–AKT–mTOR pathway has key roles in tumorigenesis and is dysregulated in most cancers. Consequently, numerous drugs that target key nodes of this pathway have been developed, although few of these agents have been approved for the treatment of cancer. Herein, the authors review the current experience with anticancer therapies that target the PI3K–AKT–mTOR pathway, discuss the challenges that have limited the clinical translation of these agents, and provide perspectives for the future development of these drugs.

    • Filip Janku
    • , Timothy A. Yap
    •  & Funda Meric-Bernstam