Nature Reviews Clinical Oncology最新文献

{"title":"Immunotherapy for advanced-stage squamous cell lung cancer: the state of the art and outstanding questions","authors":"Yibei Wang, Mohammed Safi, Fred R. Hirsch, Shun Lu, Solange Peters, Ramaswamy Govindan, Rafael Rosell, Keunchil Park, Jianjun J. Zhang","doi":"10.1038/s41571-024-00979-8","DOIUrl":"https://doi.org/10.1038/s41571-024-00979-8","url":null,"abstract":"<p>Immune-checkpoint inhibitors (ICIs) have transformed the treatment paradigm for advanced-stage squamous non-small-cell lung cancer (LUSC), a histological subtype associated with inferior outcomes compared with lung adenocarcinoma. However, only a subset of patients derive durable clinical benefit. In the first-line setting, multiple ICI regimens are available, including anti-PD-(L)1 antibodies as monotherapy, in combination with chemotherapy, or with an anti-CTLA4 antibody with or without chemotherapy. Several important questions persist regarding the optimal regimen for individual patients, particularly how to identify patients who might benefit from adding chemotherapy and/or anti-CTLA4 antibodies to anti-PD-(L)1 antibodies. An urgent need exists for predictive biomarkers beyond PD-L1 to better guide precision oncology approaches. Deeper knowledge of the underlying molecular biology of LUSC and its implications for response to ICIs will be important in this regard. Integration of this knowledge into multi-omics methods coupled with artificial intelligence might enable the development of more robust biomarkers. Finally, several novel therapeutic strategies, including novel ICIs, bispecific antibodies and personalized cancer vaccines, are emerging. Addressing these unresolved questions through innovative clinical trials and translational research will be crucial to further improving the outcomes of patients with LUSC. In this Review, we provide a comprehensive overview of current immunotherapeutic approaches, unresolved challenges and emerging strategies for patients with LUSC.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"12 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment advances across the cervical cancer spectrum","authors":"Alex A. Francoeur, Bradley J. Monk, Krishnansu S. Tewari","doi":"10.1038/s41571-024-00977-w","DOIUrl":"https://doi.org/10.1038/s41571-024-00977-w","url":null,"abstract":"<p>Cervical cancer is preventable with screening and vaccination approaches; however, access to these preventative measures is limited both nationally and globally and thus many women will still develop cervical cancer. Novel treatments and practice-changing research have improved cervical cancer outcomes over the past few decades. In this Review, we discuss clinical trials that have refined or redefined the treatment of cervical cancers across the early stage, locally advanced, persistent, recurrent and/or metastatic disease settings. Advances for patients with early stage disease have been achieved through trials evaluating less extensive and fertility-preserving surgeries, different surgical approaches (open versus minimally invasive), and sentinel versus full pelvic lymph node dissection. We also discuss results from trials testing the use of neoadjuvant, induction and adjuvant chemotherapy as well as immune-checkpoint inhibitors in patients with locally advanced disease. Finally, we review the progress made with systemic chemotherapy and novel therapeutics, including anti-angiogenic agents, immune-checkpoint inhibitors and antibody–drug conjugates, in the setting of metastatic and/or recurrent cervical cancer. The advances highlighted in this manuscript have reduced morbidity and improved overall survival for patients with this challenging-to-treat disease, while also inspiring additional research and trials in the field.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"27 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Women with clinically node negative breast cancer can safely avoid axillary surgery","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00982-z","DOIUrl":"https://doi.org/10.1038/s41571-024-00982-z","url":null,"abstract":"<p>Axillary nodal status provides important information on the prognosis of women with invasive breast cancer. However, the required sentinel lymph node biopsy sampling procedure and the associated risks of surgical complications have raised questions regarding the necessity of this procedure in women undergoing breast-conserving surgery for early stage disease. Now, data from INSEMA, a prospective, randomized, non-inferiority trial, confirm that this procedure can safely be avoided.</p><p>A total of 5,154 women with node-negative (on ultrasonography) T1 or T2 breast cancer were randomly assigned (1:4) to breast-conserving surgery without, versus with, axillary surgery. Invasive-disease-free survival (iDFS) was the primary end point.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"27 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imlunestrant shows efficacy both with and without abemaciclib","authors":"David Killock","doi":"10.1038/s41571-024-00983-y","DOIUrl":"https://doi.org/10.1038/s41571-024-00983-y","url":null,"abstract":"<p>Various endocrine therapies and CDK4/6 inhibitors have improved the treatment of ER⁺HER2⁻breast cancer, although resistance remains common and often involves <i>ESR1</i> (encoding ERα) mutations. Now, data from the phase III EMBER-3 trial demonstrate that the next-generation, brain-penetrant, oral selective ER degrader imlunestrant delays disease progression in previously treated patients with <i>ESR1</i> mutations, and regardless of <i>ESR1</i> status when combined with abemaciclib.</p><p>In EMBER-3, patients with progression of ER⁺ HER2⁻ breast cancer during or ≤1 year after completing (neo)adjuvant therapy with an aromatase inhibitor, or during first-line treatment for advanced-stage disease, were randomly assigned to receive imlunestrant (<i>n</i> = 331), standard endocrine therapy (exemestane or fulvestrant; <i>n</i> = 330), or imlunestrant–abemaciclib (<i>n</i> = 213). The majority of patients (59.8%) had also received a prior CDK4/6 inhibitor, most for advanced-stage disease. The primary end points were progression-free survival (PFS) with imlunestrant versus standard therapy among patients with <i>ESR1</i> mutations and among all patients, and with imlunestrant–abemaciclib versus imlunestrant among all patients.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"5 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"cfDNA screening for fetal aneuploidy facilitates maternal cancer detection","authors":"David Killock","doi":"10.1038/s41571-024-00981-0","DOIUrl":"https://doi.org/10.1038/s41571-024-00981-0","url":null,"abstract":"<p>Sequencing of plasma cell-free DNA (cfDNA) is commonly performed during pregnancy to screen for fetal aneuploidy. Now, data from the ongoing prospective IDENTIFY study demonstrate that this strategy also enables prompt detection of occult maternal cancers.</p><p>IDENTIFY is enrolling individuals with unusual or nonreportable cfDNA fetal aneuploidy-screening results but without perceived signs or symptoms of cancer to undergo further standardized genome-wide cfDNA sequencing and a uniform cancer-screening protocol. The primary outcome is the presence of cancer after initial screening using this protocol including rapid whole-body MRI, various blood tests (including serum tumour markers), faecal occult blood test (FOBT), family and medical history, and physical examination.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"81 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adding blinatumomab to chemotherapy reduces recurrence risk in standard-risk paediatric B-ALL","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00980-1","DOIUrl":"https://doi.org/10.1038/s41571-024-00980-1","url":null,"abstract":"<p>Despite considerable progress, B-cell acute lymphoblastic leukaemia (B-ALL) remains a major cause of cancer-related death in children. Now, data from the phase III AALL1731 trial demonstrate that adding the CD19 × CD3 bispecific T cell engager blinatumomab to chemotherapy significantly improves the outcomes of patients with standard-risk B-ALL with an average or high risk of disease relapse.</p><p>In this trial, 1,440 children (1–10 years of age) with standard-risk B-ALL with an average (<i>n</i> = 835) or high (<i>n</i> = 605) risk of relapse, based on cytogenetic features and minimal residual disease (MRD) status on completion of induction therapy, were randomly assigned (1:1) to receive two cycles of post-induction (for average-risk patients) or post-consolidation (for high-risk patients) chemotherapy with versus without blinatumomab. Disease-free survival (DFS) was the primary endpoint.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"11 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ipilimumab plus nivolumab efficacious in patients with dMMR/MSI-H disease","authors":"Peter Sidaway","doi":"10.1038/s41571-024-00978-9","DOIUrl":"https://doi.org/10.1038/s41571-024-00978-9","url":null,"abstract":"<p>The combination of the anti-PD-1 antibody nivolumab plus the anti-CTLA4 antibody ipilimumab showed promising efficacy outcomes as first-line therapy in 45 patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) as part of the single-arm, phase II CheckMate 142 trial. Now, data from the phase III CheckMate 8HW trial confirm the efficacy of this combination in this setting.</p><p>A total of 303 patients who had not received systemic therapy for unresectable or metastatic dMMR/MSI-H CRC were randomly assigned (2:1) to receive either ipilimumab plus nivolumab or investigator’s choice of chemotherapy, with or without targeted therapy. Patients were also randomly assigned to a nivolumab monotherapy arm, although data from this arm were not reported at this cutoff. Progression-free survival (PFS) in those with centrally confirmed dMMR/MSI-H status (255 patients) was the primary end point.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"90 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell dynamics with neoadjuvant immunotherapy in head and neck cancer","authors":"Maryann Zhao, Jonathan D. Schoenfeld, Ann Marie Egloff, Glenn J. Hanna, Robert I. Haddad, Douglas R. Adkins, Ravindra Uppaluri","doi":"10.1038/s41571-024-00969-w","DOIUrl":"https://doi.org/10.1038/s41571-024-00969-w","url":null,"abstract":"<p>Immune-checkpoint inhibitors (ICIs) are being tested as neoadjuvant therapies in various solid tumours, including in patients with head and neck squamous cell carcinoma (HNSCC), with promising results. Key findings thus far include that this approach is well-tolerated with favourable clinical outcomes including promising pathological response rates in initial studies. Pathological responses are likely to be increased by combining other agents with anti-PD-(L)1 antibodies. Comparisons of baseline biopsy samples with post-treatment surgical specimens have enabled correlative studies utilizing multiomic and immunogenomic methods. Data from these studies suggest that pretreatment intratumoural tissue-resident memory CD8⁺ T cells are key drivers of tumour regression and give rise to both local and systemic antitumour immune responses. Analyses of systemic responses have defined a PD-1⁺KLRG1⁻ circulating CD8⁺ T cell subpopulation that is highly predictive of response, and revealed the interrelationships between intratumoural clones and circulating CD8⁺ T cells. Lastly, interrogation of T cell populations within lymph nodes is beginning to delineate the immune crosstalk between the primary tumour and tumour-draining lymph nodes and how this relationship might be disrupted with tumour infiltration of the latter. In this Review, we examine data from trials testing neoadjuvant ICIs in patients with HNSCC, focusing on human papillomavirus-unrelated disease, and highlight correlative immunogenomic findings from these trials.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"48 10 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptomeningeal metastatic disease: new frontiers and future directions","authors":"Ahmad Ozair, Hannah Wilding, Debarati Bhanja, Nicholas Mikolajewicz, Michael Glantz, Stuart A. Grossman, Arjun Sahgal, Emilie Le Rhun, Michael Weller, Tobias Weiss, Tracy T. Batchelor, Patrick Y. Wen, Daphne A. Haas-Kogan, Mustafa Khasraw, Roberta Rudà, Riccardo Soffietti, Philipp Vollmuth, Vivek Subbiah, Chetan Bettegowda, Lily C. Pham, Graeme F. Woodworth, Manmeet S. Ahluwalia, Alireza Mansouri","doi":"10.1038/s41571-024-00970-3","DOIUrl":"https://doi.org/10.1038/s41571-024-00970-3","url":null,"abstract":"<p>Leptomeningeal metastatic disease (LMD), encompassing entities of ‘meningeal carcinomatosis’, neoplastic meningitis’ and ‘leukaemic/lymphomatous meningitis’, arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients. Underdiagnosis and misdiagnosis are common, response assessment remains challenging, and the prognosis associated with this disease of whole neuroaxis remains extremely poor. The dearth of effective therapies is further challenged by the difficulties in studying this dynamic disease state. In this Review, a multidisciplinary group of experts describe the emerging evidence and areas of active investigation in LMD and provide directed recommendations for future research. Drawing upon paradigm-changing advances in mechanistic science, computational approaches, and trial design, the authors discuss domain-specific and cross-disciplinary strategies for optimizing the clinical and translational research landscape for LMD. Advances in diagnostics, multi-agent intrathecal therapies, cell-based therapies, immunotherapies, proton craniospinal irradiation and ongoing clinical trials offer hope for improving outcomes for patients with LMD.</p>","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"83 1","pages":""},"PeriodicalIF":78.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic lethal strategies for the development of cancer therapeutics","authors":"Natalie Y. L. Ngoi,&nbsp;David Gallo,&nbsp;Carlos Torrado,&nbsp;Mirella Nardo,&nbsp;Daniel Durocher,&nbsp;Timothy A. Yap","doi":"10.1038/s41571-024-00966-z","DOIUrl":"10.1038/s41571-024-00966-z","url":null,"abstract":"Synthetic lethality is a genetic phenomenon whereby the simultaneous presence of two different genetic alterations impairs cellular viability. Importantly, targeting synthetic lethal interactions offers potential therapeutic strategies for cancers with alterations in pathways that might otherwise be considered undruggable. High-throughput screening methods based on modern CRISPR–Cas9 technologies have emerged and become crucial for identifying novel synthetic lethal interactions with the potential for translation into biologically rational cancer therapeutic strategies as well as associated predictive biomarkers of response capable of guiding patient selection. Spurred by the clinical success of PARP inhibitors in patients with BRCA-mutant cancers, novel agents targeting multiple synthetic lethal interactions within DNA damage response pathways are in clinical development, and rational strategies targeting synthetic lethal interactions spanning alterations in epigenetic, metabolic and proliferative pathways have also emerged and are in late preclinical and/or early clinical testing. In this Review, we provide a comprehensive overview of established and emerging technologies for synthetic lethal drug discovery and development and discuss promising therapeutic strategies targeting such interactions. The experience with PARP inhibitors provides evidence of the clinical utility of synthetic lethality, whereby the simultaneous presence of two specific alterations is required for antitumour activity. In this Review, the authors describe attempts to identify novel synthetic lethal interactions, including the role of emerging technologies in identifying new synthetic lethal relationships as well as novel agents that are currently being tested in clinical trials that might extend the clinical relevance of synthetic lethality beyond PARP inhibitors.","PeriodicalId":19079,"journal":{"name":"Nature Reviews Clinical Oncology","volume":"22 1","pages":"46-64"},"PeriodicalIF":81.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41571-024-00966-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}