Cancer 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 |

    The discovery of ERBB2 as a gene frequently amplified and/or overexpressed in breast cancers and of its product HER2 as a biomarker has spurred the development of various targeted therapies. As a result, the prognosis of patients with advanced-stage HER2-positive breast cancer has greatly improved in the past decades. The authors of this Review describe the development of the current treatment landscape for these patients and discuss how to address resistance to further improve outcomes.

    • Antonio Marra
    • , Sarat Chandarlapaty
    •  & Shanu Modi

  • Review Article |

    Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.

    • Sebastian Klobuch
    • , Tom T. P. Seijkens
    •  & John B. A. G. Haanen

  • Review Article |

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that accumulate in the tumour microenvironment, where they exert various immunosuppressive mechanisms as well as a variety of other tumour-promoting effects. Herein, the authors provide an overview of MDSC generation and their accumulation in tumours, describe the interplay between MDSCs and various other cell types found in tumours, and review the mechanisms by which MDSCs promote tumour development and progression, metastasis, and resistance to treatment. They also discuss the effects of established treatment modalities on MDSCs as well as implications for the development of novel therapeutic strategies targeting these cells.

    • Samantha A. Lasser
    • , Feyza G. Ozbay Kurt
    •  & Viktor Umansky

  • News & Views |

    Recent results from the phase III PHILA trial demonstrate a benefit in terms of progression-free survival derived from the addition of pyrotinib to first-line chemotherapy plus trastuzumab in patients with metastatic HER2-positive breast cancer. Dual HER2 blockade with pyrotinib and trastuzumab is an effective therapeutic strategy but might increase the risk of gastrointestinal toxicity; therefore, the risk-to-benefit ratio should be carefully evaluated.

    • Pier Paolo M. Berton Giachetti
    •  & Giuseppe Curigliano

  • Review Article |

    p53, encoded by TP53, the commonest mutated gene in cancer, is an appealing target for systemic anticancer therapies including those designed to restore p53 function. Thus far, and despite promising preclinical data and several clinical trials, no p53-restoring systemic therapy has been approved for therapeutic use. Despite this limited success, several research efforts are ongoing. In this Review, the authors summarize the role of p53 in cancer with a focus on the complexity of p53 function and how this relates to clinical attempts to restore at least some of these functions.

    • Amos Tuval
    • , Charlotte Strandgren
    •  & Klas G. Wiman

  • Review Article |

    Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy have become the standard-of-care therapy for patients with advanced-stage hormone receptor-positive breast cancer. However, this success has created several challenges, such as the need to better understand resistance to these agents and develop novel therapies accordingly. Here, the authors provide an update on the clinical activity of the established CDK4/6 inhibitors along with a summary of ongoing research efforts attempting to address the new challenges created by the success of these agents.

    • Laura Morrison
    • , Sibylle Loibl
    •  & Nicholas C. Turner

  • News & Views |

    Recent results from the FLAURA2 and MARIPOSA-2 trials underline the continued role of chemotherapy in the treatment of patients with EGFR-mutated non-small-cell lung cancer in the era of targeted therapies. Herein, we argue that the most appropriate and rational sequence and/or combination of therapies remains a matter of discussion.

    • Rafael Rosell
    •  & María González-Cao

  • Perspective |

    The current standard-of-care adjuvant treatment for patients with colorectal cancer is chemotherapy selected on the basis of conventional histopathological staging criteria; however, the clinical benefit from these regimens is limited. The authors of this Perspective discuss strategies to minimize toxicity and monitor efficacy of these regimens, and propose new tools for disease staging that could enable more personalized treatment decisions.

    • Li Yang
    • , Jinlin Yang
    •  & David J. Kerr

  • News & Views |

    Neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy with pelvic lymphadenectomy is the current standard therapy for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). A phase II trial testing treatment intensification by adding the immune-checkpoint inhibitor nivolumab to chemotherapy has yielded promising complete response rates, which suggests that bladder-preserving treatment could become attainable in selected patients. This trial heralds a new era in demonstrating the feasibility of bladder preservation for selected patients with MIBC.

    • Jakob Klemm
    • , Ekaterina Laukhtina
    •  & Shahrokh F. Shariat

  • Review Article |

    Patients with advanced-stage urothelial cancer (aUC) continue to have poor long-term survival outcomes. However, developments in the past 5 years, most notably the availability of maintenance therapy with the anti-PD-1 antibody avelumab, are beginning to change this issue. In this Review, the authors provide an overview of the treatment of patients with aUC, including considerations of the various promising new therapeutic modalities and how they might improve clinical outcomes.

    • Rosa Nadal
    • , Begoña P. Valderrama
    •  & Joaquim Bellmunt

  • Review Article |

    Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.

    • Venkateswar Addala
    • , Felicity Newell
    •  & Nicola Waddell

  • Perspective |

    Despite some success in patients with certain B cell malignancies and relapsed and/or refractory multiple myeloma, studies testing chimeric antigen receptor (CAR) T cells in patients with advanced-stage solid tumours have been largely unsuccessful, with a few notable exceptions. In this Perspective, the author provides some possible reasons for the failures of most CAR T cell-based approaches and suggests strategies that might address some of these challenges.

    • Steven M. Albelda

  • Review Article |

    Hepatocellular carcinoma (HCC) is among the most common causes of cancer-related death globally, and despite improvements in prevention and treatment strategies, continued increases in HCC incidence and mortality are predicted. Cirrhosis remains the major risk factor for HCC, although the underlying aetiology is shifting from virus-related to non-viral liver diseases. In this Review, the authors discuss the changing trends in HCC epidemiology and their implications for screening, prevention and therapy, including opportunities to further improve the management of patients with, or at high risk of, HCC.

    • Amit G. Singal
    • , Fasiha Kanwal
    •  & Josep M. Llovet

  • News & Views |

    PRO-TECT is a randomized trial that innovatively integrated financial toxicity screening into a pre-existing digital symptom-monitoring programme, enabling longitudinal detection of financial toxicity. Such a strategy provides an unobtrusive and cost-effective method for early detection and mitigation of financial toxicity by aligning the needs of patients and carers with the resources available in community clinical practices.

    • Christopher T. Su
    •  & Veena Shankaran

  • Comment |

    Projected increases of cancer-attributable health-care costs, accompanied by staff shortages, will impose future economic and operational challenges on national health-care systems. Herein, we highlight a series of clinical and health economic rationales in support of publicly funded clinical trial teams that conduct real-world dose-reduction trials aiming for adjustment of cancer drug label doses to reduce not only the financial burden on payers, but also the toxicity burden on patients.

    • Kim Theilgaard-Mönch
    •  & Lars Holger Ehlers

  • Review Article |

    According to the precision oncology paradigm, cancer therapies are increasingly being matched to specific sensitizing alterations using a biomarker-directed approach. However, the criteria for determining the actionability of molecular alterations and selecting matched treatments evolve over time. Molecular tumour boards (MTBs) have emerged as means to capitalize on the collective knowledge of various experts to interpret molecular-profiling data and to eliminate subjectivity in treatment selection. This Review describes the components, processes and increasingly important role of MTBs in optimizing the implementation of precision oncology in both clinical trials and clinical practice, as well as current and future considerations for ensuring the sustainability of MTBs and expanding their outreach to underserved populations.

    • Apostolia M. Tsimberidou
    • , Michael Kahle
    •  & Funda Meric-Bernstam

  • Perspective |

    The use of composite end points in clinical trials can expedite drug development and approval, and thus improve patient access to novel treatments, but are often vaguely and heterogeneously defined, with considerable inter-study variation in the component events that are included. The different component events can vary in clinical significance and be differentially affected by treatment but, nevertheless, are rarely reported separately. In this Perspective, Walia et al. define composite outcomes that are commonly used in oncology, discuss the advantages and challenges of using composite end points, and advocate for transparent reporting including a full breakdown of the component events to facilitate accurate interpretation of trial results and the true benefit of an intervention.

    • Anushka Walia
    • , Jordan Tuia
    •  & Vinay Prasad

  • News & Views |

    Epstein–Barr virus (EBV)-based biomarkers are used for nasopharyngeal carcinoma (NPC) screening in endemic regions. A recent prospective study describes the use of a new serological biomarker, antibodies targeting the EBV protein BNLF2b, for NPC screening in >20,000 participants. This biomarker yielded both higher sensitivity and specificity for NPC detection in the screening cohort compared with the conventionally used antibodies. Herein, we highlight the key findings of this study and discuss the implications of these results.

    • W. K. Jacky Lam
    •  & Anthony T. C. Chan

  • Review Article |

    Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

    • Ana C. Veneziani
    • , Eduardo Gonzalez-Ochoa
    •  & Amit M. Oza

  • Perspective |

    Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.

    • Yi Pu
    • , Lu Li
    •  & Shensi Shen

  • Comment |

    In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

    • Edward R. Scheffer Cliff
    • , Talal Hilal
    •  & Aaron S. Kesselheim

  • Review Article |

    The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.

    • Tim F. Greten
    • , Augusto Villanueva
    •  & Xin W. Wang

  • News & Views |

    Following the recent FDA Accelerated Approval of enfortumab vedotin (EV) plus pembrolizumab for patients with advanced-stage urothelial carcinoma who are cisplatin-ineligible, herein we highlight key clinical outcomes with this combination based on results from Cohort K of the pivotal phase Ib/II EV-103 trial. We also discuss treatment sequencing, de-escalation strategies and toxicity management as EV–pembrolizumab becomes widely used in clinical practice.

    • Pooja Ghatalia
    •  & Elizabeth R. Plimack

  • Review Article |

    The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) have diverse cancer-promoting functions in malignant cells as well as immune cells and other cell types in the tumour microenvironment, presenting an attractive opportunity for both direct and immune-mediated therapeutic activity manifest through inhibition of a single target. Accordingly, a variety of agents designed to selectively target TAM RTKs are entering clinical testing. This Review provides an essential guide to the TAM RTKs for clinicians. The authors comprehensively review the various roles of TAM RTKs in cancer, the evidence supporting their potential as therapeutic targets, and the translational development of TAM-targeted agents as cancer treatments.

    • Deborah DeRyckere
    • , Justus M. Huelse
    •  & Douglas K. Graham

  • 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

  • Review Article |

    In oncology, mRNA–lipid nanoparticles (LNPs) have been used either to achieve intratumoural expression of immune-stimulating cytokine combinations or as cancer vaccines, and new strategies are in development to enable the selective delivery of payloads into cancer cells previously considered unreachable. The authors of this Review present various approaches for delivering mRNA–LNPs to tumours and discuss improvements that will improve the selective targeting of cancer cells with mRNA–LNPs.

    • Edo Kon
    • , Nitay Ad-El
    •  & Dan Peer

  • Review Article |

    Advances over the past decade have established a prominent role of the gut microbiota in the modulation of immune homeostasis and function, including in patients with cancer receiving immune-checkpoint inhibitors. In this Review, the authors summarize current knowledge of the role of the microbiota in this context, describe several methods of modulating the microbiota clinically to improve patient outcomes, and highlight important future directions in this expanding area of research.

    • Rebecca C. Simpson
    • , Erin R. Shanahan
    •  & Georgina V. Long

  • Review Article |

    Advances in the treatment of childhood cancers have substantially improved cure rates, although the gains in survival are offset by an elevated burden of morbidities and an excess risk of early death owing predominantly to the adverse effects of therapy. In this Review, the authors summarize the evolution of paediatric cancer therapies over the past five decades as well as the associated landscape of treatment-related late and/or long-term health conditions experienced by childhood cancer survivors. In addition, they discuss strategies that are being explored to reduce the overall burden and consequences of these morbidities with the ultimate aim of improving not only the quantity but also the quality of life-years gained for this large, medically vulnerable population.

    • Matthew J. Ehrhardt
    • , Kevin R. Krull
    •  & Melissa M. Hudson

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