Tumour heterogeneity articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.

    • Kyoji Tsuchikama
    • , Yasuaki Anami
    •  & Chisato M. Yamazaki

  • Review Article |

    Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits.

    • Lorenzo Galluzzi
    • , Molykutty J. Aryankalayil
    •  & Silvia C. Formenti

  • Review Article |

    Advances in surgical technique and chemotherapy regimens have improved the survival outcomes of patients with pancreatic cancer, although these remain dismal relative to most other solid tumours. Attempts to further improve outcomes have led to increasing research interest in neoadjuvant therapy, which is beginning to improve the outcomes of certain subgroups of patients. In this Review, the authors provide an overview of the various neoadjuvant therapy approaches for patients with pancreatic cancer, including discussions of several promising future research directions

    • Christoph Springfeld
    • , Cristina R. Ferrone
    •  & John Neoptolemos

  • News & Views |

    New genetic analyses demonstrate that the presence of low-frequency subclonal populations, including high-risk subclones, at diagnosis in multiple myeloma can contribute to disease relapse and poor clinical outcomes. Thus, sensitive detection approaches are required to detect these subclones at diagnosis together with innovative treatment strategies to eradicate low-frequency, high-risk subclones and prevent them from becoming dominant.

    • Eileen M. Boyle
    •  & Faith E. Davies

  • 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 |

    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

  • Perspective |

    The availability of ever more sensitive cell sorting and sequencing technologies has enabled the interrogation of tumour cell biology at the highest possible level of resolution — analysis of a single cell. In this Perspective, the authors describe the application of such approaches to the analysis of single tumour-associated immune cells and their potential for improving the outcomes in patients receiving anti-cancer immunotherapies.

    • Satyen H. Gohil
    • , J. Bryan Iorgulescu
    •  & Kenneth J. Livak

  • Review Article |

    Despite several major therapeutic advances, multiple myeloma (MM) remains largely incurable, indicating a need for novel therapies. Thus, considerable research interest exists in chimeric antigen receptor (CAR) T cells targeting BCMA, which is almost universally expressed on MM cells. In this Review, the authors describe the clinical experience with anti-BCMA CAR T cells and discuss several new directions of future research that might prolong the responses of patients receiving these therapies.

    • Lekha Mikkilineni
    •  & James N. Kochenderfer

  • Review Article |

    The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.

    • Lorenzo Galluzzi
    • , Juliette Humeau
    •  & Guido Kroemer

  • 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

  • News & Views |

    Recent genomic and transcriptomic analyses of diffuse large B cell lymphoma (DLBCL) have provided important new insights into the heterogeneous biology of this disease. The findings provide opportunities to improve treatment strategies, although considerable work is needed to establish and optimize the clinical applicability and utility of molecular classifications of DLBCL.

    • Sydney Dubois
    •  & Fabrice Jardin

  • 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

  • News & Views |

    The biological complexity of triple-negative breast cancers (TNBCs) and the lack of highly recurrent targetable genetic alterations pose major challenges for the implementation of targeted therapies for this disease. A recent multiomic in silico study has identified genetic drivers of five different TNBC molecular subtypes, providing new opportunities for precision medicine approaches.

    • Fresia Pareja
    •  & Jorge S. Reis-Filho

  • Review Article |

    The onset of acquired resistance to treatment is virtually inevitable in patients with solid tumours. In this Review, the authors describe the role of tumour heterogeneity in the development of acquired resistance, potential treatment strategies that take into account the heterogeneity of patient's tumours, and how a better understanding of tumour heterogeneity might improve the outcomes of patients.

    • Ibiayi Dagogo-Jack
    •  & Alice T. Shaw

  • Comment |

    Few clinical trials incorporate studies of evolutionary cancer biology, despite the frequent emergence of acquired resistance to anticancer therapies. This problem motivated the first CRUK Marshall Symposium on Cancer Evolution in May 2017, which provided a forum for evolutionary and ecological theorists, cancer biologists, and clinicians to consider how evolutionary biology might inform improvements in cancer medicine. Herein, we discuss the key themes and opportunities for the future.

    • Erik Sahai
    •  & Charles Swanton

  • Review Article |

    The development of predictive biomarkers is complex and the non-systematic approach to biomarker development in HER2-positive breast cancer challenges the way translational research is performed. Women with very favourable prognostic features will likely prefer shorter courses of treatment and might enquire about the possibility to forego aggressive chemotherapy. Considering these legitimate needs, Gingras et al. review the results of more than a decade of translational research efforts in this disease.

    • Isabelle Gingras
    • , Géraldine Gebhart
    •  & Martine Piccart-Gebhart

  • Review Article |

    Recent advances in molecular biology and our understanding of the development of colorectal cancer (CRC) has enabled the more-precise use of innovative targeted therapies for this disease. In particular, large databases to capture and store genomic information on causative genes frequently deregulated in CRC, the use of gene-expression profiling to differentiate the subtypes of CRC into prognostic and predictive groups, and results from next-generation sequencing analyses have led to an appreciation of the extensive intratumour heterogeneity of this disease. The authors highlight these advances, place them into clinical context, and present other novel targets and therapeutic opportunities on the horizon.

    • Cornelis J. A. Punt
    • , Miriam Koopman
    •  & Louis Vermeulen

  • Review Article |

    In the past 5 years, results from large-scale whole-exome sequencing studies have brought new insight into the clonal heterogeneity and evolution of multiple myeloma, a genetically complex disease. Herein, the authors describe the driver gene alterations and sequential acquisition of the main genomic aberrations involved in this disease, with a focus on the clonal heterogeneity of multiple myeloma and its clinical implications.

    • Salomon Manier
    • , Karma Z. Salem
    •  & Irene M. Ghobrial

  • Review Article |

    Contrary to other cancer types, histopathology remains the mainstay of diagnosis and classification of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Increasing knowledge of the molecular genetics and biology of GEP-NENs promises to improve classification of disease subtypes, and thus the management of the disease. Herein, the authors discuss the features of GEP-NENs that, as prognostic or predictive biomarkers, could form the basis for a novel, clinically useful molecular classification system.

    • Mark Kidd
    • , Irvin Modlin
    •  & Kjell Öberg

  • Review Article |

    The advent of next-generation sequencing technologies has substantially improved our understanding of prostate cancer genetics; however, this knowledge is currently not fully reflected in the form of targeted treatment strategies. In this Review, the authors summarize our current understanding of the genetic landscape of prostate cancer and the challenges to treatment posed by the presence of considerable intratumour and intertumour heterogeneity.

    • Daniel E. Spratt
    • , Zachary S. Zumsteg
    •  & Scott A. Tomlins

  • Review Article |

    Metabolic reprogramming to support tumour growth is a near universal characteristic of cancer, and thus targeting cancer metabolism has been, and continues to be, a focus for drug-development efforts. In this Review, the authors describe the various metabolic alterations and vulnerabilities of tumours that are potentially important targets for anticancer agents, highlighting both the challenges and opportunities.

    • Ubaldo E. Martinez-Outschoorn
    • , Maria Peiris-Pagés
    •  & Michael P. Lisanti

  • Review Article |

    Considerable hope, as well as a substantial degree of hype, has surrounded cancer-screening programmes, but current practices are suboptimal and are the subject of continued improvement efforts. In this Review, the authors discuss the experiences to date in screening for breast, cervical, colorectal, lung and prostate cancers, outline the lessons we have learned, and describe how this knowledge is informing improvements in cancer screening, with the hope they will eventually live up to the hype.

    • Yiwey Shieh
    • , Martin Eklund
    •  & Laura J. Esserman

  • Review Article |

    Reports of neoadjuvant therapeutic trials in breast cancer, particular those of dual-agent HER2 blockade, have described improved pathological complete response (pCR) rates and associations of this surrogate end point with prolonged survival; however, the same therapies have not been reported to improve survival in the adjuvant setting, or indeed long-term patient outcomes after neoadjuvant therapy. In this Review, the multiplex factors that might explain these apparent discrepancies, including study designs issues, and clinical and biological differences, are discussed.

    • Leticia De Mattos-Arruda
    • , Ronglai Shen
    •  & Javier Cortés

  • Review Article |

    Although dramatic changes in the delivery of radiation therapy have occurred, the impact of radiobiology on the clinic has been far less substantial. New advances are uncovering some of the mechanistic processes that underlie the differences between the tumour and host tissue characteristics. The authors of this Review focus on how these processes might be targeted to improve the outcome of radiotherapy for patients.

    • Dörthe Schaue
    •  & William H. McBride

  • Review Article |

    Hormone-receptor-positive breast cancer accounts for the majority of all breast cancers. The evolution of this disease from early stage to the metastatic setting leads to increased heterogeneity and the development of treatment resistance representing a great challenge for management decisions. In this Review, we examine the current evidence that can guide treatment decisions in patients with advanced-stage ER+ breast cancer, discuss how to tackle these therapeutic challenges and provide suggestions for the optimal management of this patient population.

    • Christopher D. Hart
    • , Ilenia Migliaccio
    •  & Angelo Di Leo

  • Review Article |

    Traditionally, intertumour heterogeneity in breast cancer has been documented in terms of different histological subtypes, treatment sensitivity profiles, and clinical outcomes among different patients. High-throughput molecular profiling studies have confirmed that spatial and temporal intratumour heterogeneity of breast cancers exist at a level beyond common expectations. In this Review, the authors describe the different levels of tumour heterogeneity, and discuss the strategies that can be adopted by clinicians to tackle treatment response and resistance issues associated with such heterogeneity for the optimal clinical management of breast malignancies.

    • Dimitrios Zardavas
    • , Alexandre Irrthum
    •  & Martine Piccart

  • 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

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