ESMO Open最新文献

{"title":"Global inequalities in the burden of cancer in adolescents and young women from 1990 to 2021: findings from the Global Burden of Disease Study 2021","authors":"J. Hou , Z. Han , M. Chang , Z. Xu","doi":"10.1016/j.esmoop.2025.104153","DOIUrl":"10.1016/j.esmoop.2025.104153","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104153"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Vienna CATScore for predicting cancer-associated venous thromboembolism: an external validation across multiple time points","authors":"C. Englisch ,&nbsp;S. Nopp ,&nbsp;F. Moik ,&nbsp;A.M. Starzer ,&nbsp;P. Quehenberger ,&nbsp;M. Preusser ,&nbsp;A.S. Berghoff ,&nbsp;C. Ay ,&nbsp;I. Pabinger","doi":"10.1016/j.esmoop.2024.104130","DOIUrl":"10.1016/j.esmoop.2024.104130","url":null,"abstract":"<div><h3>Background</h3><div>Patients with cancer undergoing systemic therapies have a high risk for venous thromboembolism (VTE). Risk assessment models were developed to select high-risk subgroups that might benefit from primary thromboprophylaxis, yet currently available models reportedly underperform in contemporary cancer treatment populations and risk models across multiple time points throughout therapy are not available.</div></div><div><h3>Patients and methods</h3><div>We, therefore, aimed to validate the Vienna CATScore, a nomogram-based model including tumor type and continuous D-dimer levels, in a prospective cohort study of patients initiating contemporary systemic anticancer therapies. The validity of the model was tested at study inclusion, 3 weeks, and 3 months after start of therapy.</div></div><div><h3>Results</h3><div>Overall, 598 patients were included [49% women, median age 62 years (interquartile range 53-70 years)]. Most patients had stage IV disease (68.2%). The 6-month cumulative incidence of VTE was 9.2% [95% confidence interval (CI) 6.8% to 11.5%]. The Vienna CATScore demonstrated good discriminatory ability (c-statistics: 0.69, 95% CI 0.61-0.76) at study baseline and across all evaluated time points (c-statistics: 0.68, 95% CI 0.63-0.73). Applying a 6-month predicted VTE risk threshold of 8%, the CATScore effectively distinguished between low- and high-risk groups at study inclusion (7.1% versus 15.1% observed VTE risk, <em>P</em> = 0.004) and across all three time points (6.3% versus 13.6% observed VTE risk, <em>P</em> &lt; 0.001). Assuming a 50% risk reduction with thromboprophylaxis, this threshold resulted in a number needed to treat (NNT) of 13 and 15, respectively, in the high-risk group, while the NNT was 28 and 32, respectively, in the low-risk group.</div></div><div><h3>Conclusions</h3><div>This external validation of the Vienna CATScore confirms its effectiveness in predicting VTE risk in the initial months of state-of-the-art systemic anticancer therapies and across multiple time points.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104130"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization of HER2-negative breast cancers reveals a distinct patient subgroup with 17q12 deletion and heterozygous loss of ERBB2","authors":"X. Qiu ,&nbsp;P. Tarantino ,&nbsp;R. Li ,&nbsp;A. Grinshpun ,&nbsp;H. Gupta ,&nbsp;M.E. Hughes ,&nbsp;G. Kirkner ,&nbsp;L. Scholl ,&nbsp;B.E. Johnson ,&nbsp;M. Meyerson ,&nbsp;A.D. Cherniack ,&nbsp;Y. Jiang ,&nbsp;N. Zhou ,&nbsp;N.U. Lin ,&nbsp;H.W. Long ,&nbsp;S.M. Tolaney ,&nbsp;R. Jeselsohn","doi":"10.1016/j.esmoop.2024.104111","DOIUrl":"10.1016/j.esmoop.2024.104111","url":null,"abstract":"<div><h3>Background</h3><div>The approval of trastuzumab deruxtecan has prompted the subgrouping of human epidermal growth factor receptor 2-negative (HER2−) breast cancers (BCs) to HER2 0 and HER2 low on the basis of immunohistochemistry, although the biological significance of these subgroups remains uncertain. This study is aimed to better understand the molecular and genetic differences among HER2− tumors stratified by quantitative levels of HER2.</div></div><div><h3>Patients and methods</h3><div>We analyzed the transcriptomic and genomic data from the Molecular Taxonomy of BC International Consortium (discovery cohort) and The Cancer Genome Atlas (independent validation cohort). HER2− BCs, including hormone receptor positive and triple negative, were divided into three subgroups based on <em>ERBB2</em> messenger RNA (mRNA) levels: minimal, moderate and enhanced.</div></div><div><h3>Results</h3><div>We observed significant differences in mutational and transcriptional profiles across the subgroups. Tumors with enhanced <em>ERBB2</em> mRNA expression had a higher prevalence of <em>PIK3CA</em> mutations and increased estrogen receptor signaling, while tumors with minimal <em>ERBB2</em> mRNA expression displayed higher expression of proliferation and immune-related genes. We identified a distinct subgroup of BCs characterized by a large deletion of chromosome 17q12 (17q12del) with heterozygous loss of <em>ERBB2</em>, very low <em>ERBB2</em> mRNA and HER2 protein expression. This subgroup was also enriched for heterozygous losses of <em>TP53</em> and other tumor suppressor genes. Analysis of two large real-world cohorts of patients with HER2− metastatic BC (Dana-Farber Cancer Institute cohort <em>n</em> = 1063 and Memorial Sloan Kettering MetTropism cohort <em>n</em> = 1018) showed that patients with 17q12del and heterozygous loss of ERBB2 had poorer overall survival (OS).</div></div><div><h3>Conclusions</h3><div>We identified a biologically and clinically distinct subgroup of BCs characterized by a 17q12del with a heterozygous loss of <em>ERBB2</em> and low <em>ERBB2</em> mRNA and HER2 protein expression. In two large real-world cohorts of patients with HER2− metastatic BC, this subgroup was associated with poor OS, highlighting its clinical significance.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104111"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High expression level of ERBB2 and efficacy of trastuzumab deruxtecan in desmoplastic small round cell tumour: a monocentric case series report","authors":"M. Brahmi ,&nbsp;H. Vanacker ,&nbsp;A. Dufresne ,&nbsp;V. Isnardi ,&nbsp;M. Dupont ,&nbsp;A. Meurgey ,&nbsp;M. Karanian ,&nbsp;P. Meeus ,&nbsp;M.-P. Sunyach ,&nbsp;F. Tirode ,&nbsp;J.-Y. Blay","doi":"10.1016/j.esmoop.2025.104133","DOIUrl":"10.1016/j.esmoop.2025.104133","url":null,"abstract":"<div><h3>Background</h3><div>Desmoplastic small round cell tumours (DSRCTs) represent an ultra-rare subtype of soft tissue sarcoma characterized by a recurrent <em>EWSR1::WT1</em> oncogenic translocation. Considered as an extremely aggressive cancer, the prognosis remains poor with a median overall survival not exceeding 24-36 months and a 5-year survival &lt;10%.</div></div><div><h3>Patients and methods</h3><div>We analysed <em>ERBB2/</em>human epidermal growth factor receptor 2 (<em>HER2</em>) expression levels in a series of 13 DSRCT patients, using whole-exome RNA sequencing on formalin-fixed paraffin-embedded samples from a local biopathological database. In addition, a retrospective case series describes the clinical outcome of three successive DSRCT patients treated with trastuzumab deruxtecan (T-DXd).</div></div><div><h3>Results</h3><div>The gene expression analysis demonstrated a consistent high RNA expression level of <em>ERBB2</em> in DSRCT, with elevated levels [&gt;5 log2(transcripts per million + 1)] across all samples of the cohort and the expression level was the highest compared with all other sarcoma subtypes. In addition to these results, T-DXd showed a marked activity in all three DSRCT patients who presented with metastatic disease refractory to previous standard chemotherapy. So far, the treatment has been overall well tolerated and is currently pursued in the three patients (duration of response &gt;3 months for all three), which warrants additional investigation.</div></div><div><h3>Conclusions</h3><div>This case series presents a major information, suggesting that HER2 is a therapeutic target in DSRCT and T-DXd might represent a novel therapeutic option. Those results require to be rapidly shared with the scientific community and confirmed in a prospective clinical trial in this context of very poor prognosis disease and urgent unmet need.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104133"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atezolizumab plus bevacizumab as first-line treatment of unresectable hepatocellular carcinoma: interim analysis results from the phase IIIb AMETHISTA trial","authors":"F. Piscaglia ,&nbsp;G. Masi ,&nbsp;E. Martinelli ,&nbsp;G. Cabibbo ,&nbsp;M. Di Maio ,&nbsp;A. Gasbarrini ,&nbsp;M. Iavarone ,&nbsp;L. Antonuzzo ,&nbsp;V. Mazzaferro ,&nbsp;A. Ballestrero ,&nbsp;C. Garufi ,&nbsp;F. Bergamo ,&nbsp;C. Celsa ,&nbsp;D. Marino ,&nbsp;F. Tovoli ,&nbsp;F.R. Ponziani ,&nbsp;T. Pressiani ,&nbsp;C. Astolfi ,&nbsp;G.C. Gazzoli ,&nbsp;F. Ciardiello ,&nbsp;L. Rimassa","doi":"10.1016/j.esmoop.2024.104110","DOIUrl":"10.1016/j.esmoop.2024.104110","url":null,"abstract":"<div><h3>Background</h3><div>The treatment of advanced hepatocellular carcinoma (HCC) with atezolizumab and bevacizumab led to significant improvements in overall survival (OS), progression-free survival (PFS), and response rate compared with sorafenib in the phase III IMbrave150 trial. The etiology of background liver disease can differ between Eastern and Western populations, leading to a potentially different impact of systemic therapies; therefore the unequal representation must be considered in the IMbrave150 trial. To provide further data on the safety and effectiveness of atezolizumab and bevacizumab, the phase IIIb AMETHISTA (Atezolizumab plus bevacizumab in METastatic HCC Italian Safety TriAl) ran in a Western (Italian) population of patients with advanced HCC. The results of the interim analysis are presented in this paper.</div></div><div><h3>Methods</h3><div>AMETHISTA is a multicenter, phase IIIb, single-arm study evaluating the safety and effectiveness of atezolizumab and bevacizumab in an Italian population of patients with systemic treatment-naive HCC (ClinicalTrials.gov: <span><span>NCT04487067</span><svg><path></path></svg></span>). The primary objective was safety (incidence of grade 3-5 bleeding/hemorrhages). The main secondary objective was effectiveness.</div></div><div><h3>Results</h3><div>A total of 152 patients were enrolled and 149 were treated. At the cut-off date, the median observation time was 13.4 months (interquartile range 8.3-15.5 months). The incidence of grade 3-5 bleeding/hemorrhages was 11.4%. Besides, results of other safety endpoints were consistent with the safety profile of atezolizumab plus bevacizumab, and the underlying disease, without any new safety observation. The median OS was 18.2 months (95% confidence interval 15.4 months to not evaluable); the median PFS was 8.5 months (95% confidence interval 7.5-11.2 months).</div></div><div><h3>Conclusion</h3><div>Results from the interim analysis are consistent with data from the IMbrave150 trial, and further confirm first-line atezolizumab plus bevacizumab as a standard of care for patients with systemic treatment-naive advanced and unresectable HCC.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104110"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health networking on cancer in the European Union: a ‘green paper’ by the EU Joint Action on Networks of Expertise (JANE)","authors":"P.G. Casali ,&nbsp;H. Antoine-Poirel ,&nbsp;S. Berrocoso ,&nbsp;J.-Y. Blay ,&nbsp;T. Dubois ,&nbsp;A. Ferrari ,&nbsp;A. Fullaondo ,&nbsp;E. Hovig ,&nbsp;P. Jagodzińska-Mucha ,&nbsp;I. Ługowska ,&nbsp;S. Kaasa ,&nbsp;D. Nicoară ,&nbsp;V. Pletsa ,&nbsp;S. Provenzano ,&nbsp;M. Santoro ,&nbsp;M. Šekerija ,&nbsp;W. Van Hoof ,&nbsp;M. Vyas ,&nbsp;A. Trama ,&nbsp;Malvika Vyas","doi":"10.1016/j.esmoop.2024.104126","DOIUrl":"10.1016/j.esmoop.2024.104126","url":null,"abstract":"<div><div>Health networking is in principle a formidable instrument to address many challenges posed by cancer, one of the two most common and most lethal non-communicable chronic diseases. The European Union (EU)’s Beating Cancer Plan foresaw the addition of new health networks to the four already existing European Reference Networks on rare cancers: the Network of Comprehensive Cancer Centres and several networks of expertise (NoEs), which will be shortly deployed on items as complex and poor-prognosis cancers, palliative care, survivorship, personalised primary and secondary prevention, omic technologies, hi-tech medical resources, and cancers in adolescents and young adults. The community of experts of the EU Joint Action, due to build such NoEs, has drafted this ‘green paper’, incorporating 13 open questions, in an effort to foster discussion on some open questions about health networking on cancer in the EU. These affect highly diverse issues such as the following: how gaps in research into the instrument of health networking may be filled; which items lend themselves more to health networking in the EU; what degree of cooperation and harmonisation should be required of EU member states to best exploit health networking and give rise to European networks of national/regional networks; how the idea of subsidiarity may be best interpreted to support health networking in the context of EU treaties, which basically do not include health; how health networks should be funded and with what degree of cooperation between the EU and national levels; whether EU health networks should be shaped as legal entities or could give rise to secondary legal entities, also with a view to fundraising; how health networks should be best shaped to advance cancer research and how the EU regulatory system should be updated to exploit such impulse to health networks, in view of the EU General Data Protection Regulation and the new EU Health Data Space; how artificial intelligence can be exploited today within health networks and to what extent it will be able to overcome challenges such as the current lack of interoperability of electronic health records and the language barrier across the EU; and how health networks should involve patients and their groups, with regard to their formal role within EU health networks as well as their ability to have a say in items such as production of clinical practice guidelines, the design of investigator-driven clinical trials, EU regulatory decisions on medicines and devices, health service data governance, and identification of unmet needs.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104126"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment with infliximab and tacrolimus in steroid-refractory pneumonitis secondary to anti-HER2 therapy","authors":"O. Fakih ,&nbsp;E. Ahmed ,&nbsp;M. Paravasthu ,&nbsp;J. Pearson ,&nbsp;L.G. Spencer ,&nbsp;C. Palmieri","doi":"10.1016/j.esmoop.2024.104128","DOIUrl":"10.1016/j.esmoop.2024.104128","url":null,"abstract":"","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104128"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study","authors":"G. Ku ,&nbsp;G.M. Haag ,&nbsp;H. Park ,&nbsp;V.K. Lam ,&nbsp;T.J. George ,&nbsp;S.S. Kim ,&nbsp;M. Gutierrez ,&nbsp;V. Shankaran ,&nbsp;S. Stein ,&nbsp;C.S. Denlinger ,&nbsp;E. Elimova ,&nbsp;A. Nagrial ,&nbsp;A.R. He ,&nbsp;M.B. Sawyer ,&nbsp;H.H. Yoon ,&nbsp;R. Geva ,&nbsp;J. Starr ,&nbsp;G. Curigliano ,&nbsp;T. Golan ,&nbsp;R. von Moos ,&nbsp;M. Di Bartolomeo","doi":"10.1016/j.esmoop.2024.104107","DOIUrl":"10.1016/j.esmoop.2024.104107","url":null,"abstract":"<div><h3>Background</h3><div>Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC.</div></div><div><h3>Patients and methods</h3><div>Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety.</div></div><div><h3>Results</h3><div>Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported.</div></div><div><h3>Conclusions</h3><div>While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104107"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Progressive natural killer cell dysfunction in advanced-stage clear-cell renal cell carcinoma and association with clinical outcomes","authors":"W. Xu ,&nbsp;G. Birch ,&nbsp;A. Meliki ,&nbsp;V. Moritz ,&nbsp;M. Bharadwaj ,&nbsp;N.R. Schindler ,&nbsp;C. Labaki ,&nbsp;R.M. Saliby ,&nbsp;K. Dinh ,&nbsp;J.T. Horst ,&nbsp;M. Sun ,&nbsp;S. Kashima ,&nbsp;M. Hugaboom ,&nbsp;A. Dighe ,&nbsp;M. Machaalani ,&nbsp;G.-S.M. Lee ,&nbsp;M. Hurwitz ,&nbsp;B.A. McGregor ,&nbsp;M.S. Hirsch ,&nbsp;S.A. Shukla ,&nbsp;D.A. Braun","doi":"10.1016/j.esmoop.2024.104105","DOIUrl":"10.1016/j.esmoop.2024.104105","url":null,"abstract":"<div><h3>Background</h3><div>Natural killer (NK) cells are important contributors to antitumor immunity in clear-cell renal cell carcinoma (ccRCC). However, their phenotype, function, and association with clinical outcomes in ccRCC remain poorly understood.</div></div><div><h3>Materials and methods</h3><div>We analyzed single-cell RNA sequencing data from 13 primary tumors, 1 localized tumor extension, and 1 metastasis from ccRCC patients at different clinical stages. For each primary tumor specimen, paired normal kidneys were also analyzed. Differential gene expression analysis was carried out to investigate NK cell phenotypes and to derive a gene expression signature. Gene signatures from NK cell subclusters of interest were used to interrogate bulk transcriptomic datasets and expression with clinical outcomes. Finally, tumor-infiltrating NK cell function (cytokine production and cytotoxicity) was assessed by isolation of live NK cells from ccRCC tissue, co-culture with K562 target cells, and measurement of cytokine production (interferon-γ) and cytotoxicity (CD107a) markers by flow cytometry.</div></div><div><h3>Results</h3><div>Single-cell transcriptomic data were analyzed from 13 patients with ccRCC (tumor/normal kidney), resulting in 21 139 NK cells. Clustering analysis revealed six NK cell subsets. Bright-like NK cells were significantly enriched in advanced ccRCC compared with localized ccRCC and normal kidney, expressed markers of tissue residency (<em>ZNF683</em>/Hobit, <em>ITGA1</em>/CD49a, <em>CD9</em>, <em>ITGAE</em>/CD103), and had decreased expression of cytotoxicity genes (<em>GZMB</em>/Granzyme-B, <em>PRF1</em>/perforin). In independent cohorts (The Cancer Genome Atlas ccRCC cohort, CheckMate 025), a gene expression score representing this dysfunctional NK cell phenotype was enriched in advanced ccRCC and was associated with worse overall survival. Functional interrogation of tumor-infiltrating NK cells from ccRCC confirmed that tumor-resident CD49a+CD9+ NK cells had impaired cytotoxicity compared with CD49a−CD9− NK cells.</div></div><div><h3>Conclusions</h3><div>A dysfunctional, tumor-resident NK cell phenotype was enriched among patients with metastatic disease and associated with worse survival in patients with advanced ccRCC across multiple patient cohorts. Restoration of NK cell function (via cytokine stimulation or NK cell engineering) could provide a novel avenue for therapeutic intervention against ccRCC.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104105"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors associated with first-to-second-line attrition among patients with metastatic breast cancer in the real world","authors":"E. Blondeaux ,&nbsp;L. Boni ,&nbsp;G. Chilà ,&nbsp;A. Dri ,&nbsp;R. Caputo ,&nbsp;F. Poggio ,&nbsp;A. Fabi ,&nbsp;G. Arpino ,&nbsp;F. Pravisano ,&nbsp;E. Geuna ,&nbsp;V. Delucchi ,&nbsp;T. Ruelle ,&nbsp;I. Giannubilo ,&nbsp;M. De Laurentiis ,&nbsp;F. Puglisi ,&nbsp;C. Bighin ,&nbsp;M. Lambertini ,&nbsp;F. Montemurro ,&nbsp;L. Del Mastro","doi":"10.1016/j.esmoop.2024.104125","DOIUrl":"10.1016/j.esmoop.2024.104125","url":null,"abstract":"<div><h3>Background</h3><div>Estimating patient attrition across lines of treatment (i.e. the probability that upon treatment failure the patient will not be able to receive a subsequent treatment) may be a valuable tool for optimizing treatment sequencing. We sought to describe the first-to-second-line attrition rate and factors associated with attrition in a real-world cohort of patients with metastatic breast cancer.</div></div><div><h3>Methods</h3><div>The Gruppo Italiano Mammella (GIM)14/BIO-META (NCT02284581) is an ongoing, ambispective observational multicenter study enrolling patients with metastatic breast cancer receiving first-line therapy. In patients experiencing disease progression, attrition was defined as no further anticancer treatment and death within 6 months from the end of first-line therapy. The attrition rate from the first-to-second line was studied by descriptive analyses and univariate and multivariable logistic models were used to explore potentially predictive factors.</div></div><div><h3>Results</h3><div>From January 2000 to December 2021, 3109 patients with metastatic breast cancer were enrolled in the GIM14/BIO-META study. Among them, 2498 patients experienced first-line treatment failure. Overall, first-to-second line attrition was 9.0% (95% confidence interval 7.9% to 10.1%), with similar attrition for patients with hormone receptor-positive/HER2-negative (8.5%) and HER2-positive (7.1%) breast cancer. Patients with triple-negative disease experienced the highest attrition (13.0%). Age, menopausal status, disease-free interval from primary tumor diagnosis, type of metastatic spread, and tumor subtype independently predicted first-to-second-line attrition.</div></div><div><h3>Conclusions</h3><div>These findings could inform treatment decisions and guide clinical research on treatment sequencing. For instance, patients with the lowest risk of attrition may be the ideal candidates for trials exploring de-escalated first-line regimens, followed by more aggressive treatments upon progression.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 2","pages":"Article 104125"},"PeriodicalIF":7.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}