Metastasis articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Despite improved outcomes owing to advances in systemic targeted therapies, patients with brain metastases from oncogene-driven non-small-cell lung cancer continue to have a poor prognosis. This situation largely reflects the limited central nervous system (CNS) penetrance of most targeted therapies, a limitation that is beginning to be addressed with the development of later-generation agents. In this Review, the authors describe the CNS activity of targeted therapies for patients with oncogene-driven non-small-cell lung cancers, including discussions of novel agents with improved CNS penetrance and the potential of intrathecal administration for patients with leptomeningeal disease.

    • Kelsey Pan
    • , Kyle Concannon
    •  & Xiuning Le

  • Perspective |

    The authors of this Perspective propose that, with further improvement in detection efficiency, circulating tumour cells (CTCs), which are released early during cancer development, have the potential to be used for the early detection of clinically relevant, aggressive cancers. Thus, use of CTCs as diagnostic biomarkers might improve outcomes by enabling the identification of cancers at a stage at which they are more amenable to treatment while avoiding overtreatment of patients with indolent tumours.

    • Rachel Lawrence
    • , Melissa Watters
    •  & Yong-Jie Lu

  • Review Article |

    The oligometastatic state is generally considered to constitute an intermediate point along the spectrum of cancer dissemination at which the metastatic burden is limited and local ablative therapies can result in meaningful clinical benefit, and possibly even cure. In this Review, Katipally et al. reframe the oligometastatic phenotype as a dynamic state that expands beyond merely the number or size of metastases. They highlight important risk factors defining the metastatic spectrum that can inform both staging and therapy, and identify themes in the literature that might guide strategies to optimally combine metastasis-directed local therapies with modern systemic treatments.

    • Rohan R. Katipally
    • , Sean P. Pitroda
    •  & Ralph R. Weichselbaum

  • Review Article |

    Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.

    • Alissa J. Cooper
    • , Lecia V. Sequist
    •  & Jessica J. Lin

  • Review Article |

    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

  • News & Views |

    SABR-COMET was the first randomized controlled trial to demonstrate an overall survival benefit with the use of stereotactic ablative body radiotherapy (SABR) for the treatment of oligometastatic cancer. Considering the recently reported long-term follow-up data from SABR-COMET, we review the outcomes and limitations of this study in the context of other emerging information on therapy for oligometastatic disease.

    • Tyler P. Robin
    •  & Jeffrey R. Olsen

  • Review Article |

    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.

    • John H. Suh
    • , Rupesh Kotecha
    •  & Eric L. Chang

  • Review Article |

    Systemic hormone therapies and chemotherapy are the cornerstones of treatment for patients with de novo metastatic prostate cancer, with a currently limited role for local treatments. Herein, the authors outline the pathobiological and immunological rationale for local cytoreductive treatment of the primary tumour and/or metastases in patients with this disease. They also review the preclinical and clinical evidence for the use of radical prostatectomy, prostate radiotherapy, minimally invasive ablative therapies, and metastasis-directed therapy (predominantly with stereotactic ablative radiotherapy) in this population.

    • Martin J. Connor
    • , Taimur T. Shah
    •  & Hashim U. Ahmed

  • News & Views |

    In the past few years, efforts have been made to combine two approaches — immune-checkpoint inhibition and locally ablative radiation therapy — to treat patients with metastatic non-small-cell lung cancer. Herein we discuss the implications of two studies that support the existence of a systemic therapy augmented by radiotherapy (STAR) effect in this setting.

    • Jordan A. Torok
    •  & Joseph K. Salama

  • Perspective |

    The oligometastatic paradigm challenges the prevailing view of metastasis as a disseminated process and proposes the existence of a spectrum of biological virulence within metastatic lesions. The authors present evidence for this heterogeneity and discuss how it affects the staging and treatment of patients with metastatic cancer.

    • Sean P. Pitroda
    •  & Ralph R. Weichselbaum

  • Consensus Statement
    | Open Access

    Most cancer-related deaths are attributable to metastasis, but few treatments are specifically designed to disrupt this process. In this Position Paper, representatives of the joint Cancer Research UK and Cancer Therapeutics CRC Australia Metastasis Working Group describe the challenges associated with discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer and provide guidance on how these challenges might be overcome.

    • Robin L. Anderson
    • , Theo Balasas
    •  & James W. A. Ritchie

  • 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

  • Opinion |

    The aberrant tumour vasculature and the associated angiogenic factors have been implicated in tumour immune evasion and progression. Herein, the authors provide their perspectives on how normalization of the tumour microenvironment using antiangiogenic agents could potentially increase the effectiveness of immunotherapies and improve the outcomes of patients with cancer. The authors also highlight important considerations for future research in this area.

    • Dai Fukumura
    • , Jonas Kloepper
    •  & Rakesh K. Jain

  • Review Article |

    The combination of immunotherapies with other therapeutic modalities, including anti-angiogenic agents, is currently under investigation to improve the outcomes of patients receiving immunotherapies. In this article, the authors review the effects mediated by anti-angiogenic agents that might increase the efficacy of immunotherapies and discuss the possibility that immunotherapies might increase the efficacy of anti-angiogenic agents and/or promote changes in the tumour vasculature.

    • Kabir A. Khan
    •  & Robert S. Kerbel

  • Review Article |

    Despite the achievement of locoregional control, a third of patients undergoing surgery for cancer will have disease recurrence. In this Review, the authors describe the potential to optimize the outcomes of patients with cancer by minimizing inflammation and activation of the sympathetic nervous system in the perioperative period, which is often achievable with simple and cost-effective changes in patient-management strategies.

    • Jonathan G. Hiller
    • , Nicholas J. Perry
    •  & Erica K. Sloan

  • Comment |

    We posit that disseminating tumour cells detected in the bone marrow or in the circulation are either cancer stem cells with full metastatic potential, tumour-bulk cells, or dormant cancer cells. This model has both therapeutic and diagnostic implications, raising concern over inadequate treatment as well as the possibility of overtreatment resulting from overdiagnosis.

    • Klaus Pantel
    •  & Daniel F. Hayes

  • Comment |

    Patients with resectable solid tumours can harbour minimal residual disease (MRD) after initial treatment, which is a potential source for subsequent metastatic relapse. The interaction between disseminated tumour cells (DTCs) and the new microenvironment in which they reside determines whether DTCs remain dormant or progress into overt metastases. We highlight the promise of liquid biopsies to inform on MRD.

    • Klaus Pantel
    •  & Catherine Alix-Panabières

  • Review Article |

    According to the cancer stem cell (CSC) paradigm, a minor subpopulation of cancer cells with stem-cell properties predominantly underlies tumour progression, therapy resistance, and disease recurrence. Notably, epithelial-to-mesenchymal transition (EMT) is implicated in these processes, and CSCs typically show markers of EMT-programme activation. Herein, the authors outline our current understanding of the links between the EMT programme, the CSC phenotype, metastasis, and drug resistance, and discuss the potential for therapeutic targeting of these facets of tumour biology.

    • Tsukasa Shibue
    •  & Robert A. Weinberg

  • Review Article |

    After curative treatment, 30% of patients with stage I–III and up to 65% of patients with stage IV colorectal cancer (CRC) develop recurrent disease. Thus, surveillance for disease recurrence is clearly needed in these patients, but controversy surrounds the optimal follow-up approaches. Herein, the current evidence relating to surveillance strategies for patients with CRC is comprehensively reviewed, and the future development of patient-centred programmes is discussed.

    • Eric P. van der Stok
    • , Manon C. W. Spaander
    •  & Ernst J. Kuipers

  • Review Article |

    Emerging evidence suggests that the prolonged therapeutic use of androgen receptor (AR)-targeting agents in patients with prostate cancer induces histological dedifferentiation and lineage alterations. Roubaud and colleagues propose that AR suppression creates a checkpoint by which potent therapies exert a selective pressure on prostate cancer cells, favouring dedifferentiated and/or treatment-resistant cell lineages. The authors present a new clinical trial strategy in which rapid drug cycling is used to delay the onset of resistance and treatment-induced lineage crisis in patients with prostate cancer.

    • Guilhem Roubaud
    • , Bobby C. Liaw
    •  & David J. Mulholland

  • News & Views |

    Most patients with cancer who develop brain metastases have a very poor prognosis, especially those with brain metastases from non-small-cell lung cancer. The short life-expectancy of these patients, which is typically measured in weeks or a few months, raises an important question: do they benefit from whole-brain radiotherapy, or are they appropriately treated with best supportive care alone? A recent randomized trial sought to answer this question.

    • Dirk Rades
    •  & Steven E. Schild

  • Review Article |

    To form metastases, cancer cells must leave the immunosuppressive tumour microenvironment and traffic, predominantly in the circulation, to new tissue sites, where they must then expand. During this process, the tumour cells are open to attack by the immune system. This Review highlights the possible mechanisms used by circulating tumour cells in the blood and disseminated tumour cells in other tissues to evade, escape, or subvert the immune system in order to survive and form metastatic lesions.

    • Malte Mohme
    • , Sabine Riethdorf
    •  & Klaus Pantel

  • Review Article |

    Distant metastasis remains a common cause of death in patients with solid tumours, even after treatment with surgery, radiotherapy and/or chemotherapy. Treatment itself can sometimes cause or promote metastasis by increasing the number of circulating tumour cells. The authors of this article discuss preclinical and clinical data concerning cancer treatments, circulating tumour cell mobilization and other factors that might promote metastasis.

    • Olga A. Martin
    • , Robin L. Anderson
    •  & Michael P. MacManus

  • News & Views |

    In three practice guidelines from ASCO, experts provide evidence-based recommendations that address overarching clinical questions for the management of patients with pancreatic cancer. These guidelines offer improved strategies for interdisciplinary patient management and highlight the need for further research in several areas.

    • Oliver Strobel
    •  & Markus W. Büchler

  • News & Views |

    The results of a number of studies have demonstrated the promise of adding intrahepatic arterial selective internal radiotherapy (SIRT) to chemotherapy for patients with liver metastases from colorectal cancer; however, the frequent progression of extrahepatic metastases observed in patients treated with SIRT in the SIRFLOX trial call the potential overall benefit of this approach into question.

    • Josep Tabernero
    •  & Ramon Salazar

  • Review Article |

    The routes and timing of metastatic dissemination during cancer progression remain shrouded in mystery. However, phylogenetic studies are beginning to shed new light on this process and various models have been proposed. In this Review, Kamila Naxerova and Rakesh Jain discuss the hypothesized trajectories of metastasis, and examine the extent to which the current phylogenetic evidence support these models. In addition, the experimental techniques of lineage tracing, their strengths and weaknesses, and future directions for studies using such methods are discussed.

    • Kamila Naxerova
    •  & Rakesh K. Jain

  • Opinion |

    Patients with oligometastases who develop a small number of metastatic lesions might achieve long-term survival with the use of ablative surgery or stereotactic radiotherapy. More patients are receiving aggressive treatment for oligometastatic disease, yet long-term survival might not be due to the treatments themselves, but rather to the selection of patients with slow-growing indolent disease. The authors examine the key evidence supporting or refuting the existence of an oligometastatic state and its appropriate treatment.

    • David A. Palma
    • , Joseph K. Salama
    •  & Ralph Weichselbaum

  • Review Article |

    Around 20% of patients with colorectal cancer (CRC) have synchronous hepatic metastases at the time of presentation, highlighting the need for appropriate diagnostic and staging assessments. Furthermore, various approaches to the therapeutic management of such patients are available, and the treatment strategy used is influenced by clinical presentation. Herein, these aspects of the management of patients with CRC and synchronous liver metastases are comprehensively reviewed, focusing on the integration of surgical approaches within a multidisciplinary framework.

    • Ajith K. Siriwardena
    • , James M. Mason
    •  & Santhalingam Jegatheeswaran

  • Review Article |

    Brain metastasis is an important complication associated with a number of common primary cancers, including lung and breast cancers, and melanoma, and has major effects on patient morbidity and mortality. This Review discusses the advances in our understanding of the molecular biology of brain metastases, and how this knowledge has influenced the imaging, surgical, radiological and pharmaceutical approaches involved in the management of brain metastasis.

    • Taofeek K. Owonikoko
    • , Jack Arbiser
    •  & Jeffrey J. Olson

  • Review Article |

    Advances in single-cell molecular analysis are enhancing our ability to explore the mechanisms of metastasis. In this Review, the authors describe how circulating tumour cells (CTCs), captured from a minimally invasive blood test—and readily amenable to serial sampling—have the potential to inform intratumour heterogeneity and tumour evolution.

    • Matthew G. Krebs
    • , Robert L. Metcalf
    •  & Caroline Dive

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