ESMO Open最新文献

{"title":"Laboratory Prognostic Index (LAB-PI) in diffuse large B-cell lymphoma: a single blood analysis predicts outcomes as good as IPI, NCCN-IPI, and GELTAMO-IPI☆","authors":"F. Martin-Moro ,&nbsp;L. Bento ,&nbsp;J. Marquet ,&nbsp;S.F. Browne-Arthur ,&nbsp;A. Gutierrez ,&nbsp;A. Diaz-Lopez ,&nbsp;J. Sanchez-Pina ,&nbsp;J.A. Garcia-Vela ,&nbsp;A. Salar ,&nbsp;R. Cordoba ,&nbsp;S. Novelli ,&nbsp;M.J. Rodriguez-Salazar ,&nbsp;S. Gonzalez De Villambrosia ,&nbsp;R. Del Campo ,&nbsp;H.D. Luzardo ,&nbsp;D. Garcia ,&nbsp;J.A. Garcia-Marco ,&nbsp;J.M. Sancho ,&nbsp;P. Abrisqueta ,&nbsp;A. Martin ,&nbsp;M. Bastos-Oreiro","doi":"10.1016/j.esmoop.2025.105873","DOIUrl":"10.1016/j.esmoop.2025.105873","url":null,"abstract":"<div><h3>Background</h3><div>Many prognostic variables have been described in diffuse large B-cell lymphoma (DLBCL) and combined in prognostic scores, which are not usually fully objective and may be complex to apply. With the aim of designing and validating a simple, inexpensive, objective, and reproducible prognostic tool in DLBCL, the Laboratory Prognostic Index (LAB-PI) was developed.</div></div><div><h3>Patients and methods</h3><div>Laboratory parameters routinely evaluated at DLBCL diagnosis were analysed before treatment initiation in a DLBCL cohort (<em>n</em> = 221). The variables associated with event-free survival (EFS) were combined into the new score and graded according to their prognostic impact in multivariate analysis. Patients were clustered according to their risk. The LAB-PI was validated in an independent cohort (<em>n</em> = 885) and compared with other DLBCL scores.</div></div><div><h3>Results</h3><div>The LAB-PI included three laboratory variables routinely assessed at DLBCL diagnosis: elevated lactate dehydrogenase (LDH) (1 point), anaemia (1 point), and high β2-microglobulin (B2M) up to two times the upper limit of normal (ULN) (1 point) or greater than two times the ULN (2 points). Cases were clustered into four groups according to their prognosis in the validation cohort: low risk (0 points, 5-year EFS 87%), low-intermediate risk (1-2 points, 5-year EFS 69%), high-intermediate risk (3 points, 5-year EFS 55%), and high risk (4 points, 5-year EFS 37%). The LAB-PI was comparable with the International Prognostic Index (IPI), National Cancer Comprehensive Network (NCCN)-IPI, and Grupo Español de Linfomas/Trasplante de Médula ósea (GELTAMO)-IPI in predicting prognosis and remained useful in subanalysis according to age and stage.</div></div><div><h3>Conclusion</h3><div>The LAB-PI predicts outcome in newly diagnosed DLBCL patients by a single blood assessment including LDH, haemoglobin, and B2M.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105873"},"PeriodicalIF":8.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term outcome data for patients with hormone receptor-positive early breast cancer participating in the WSG PlanB trial after preselection by gene expression analysis: 10-year survival results from the WSG PlanB registry","authors":"U. Nitz ,&nbsp;M. Graeser ,&nbsp;O. Gluz ,&nbsp;S. Kümmel ,&nbsp;M. Just ,&nbsp;C. Jackisch ,&nbsp;C. zu Eulenburg ,&nbsp;M. Christgen ,&nbsp;N. Harbeck ,&nbsp;West German Study Group","doi":"10.1016/j.esmoop.2025.105891","DOIUrl":"10.1016/j.esmoop.2025.105891","url":null,"abstract":"<div><h3>Background</h3><div>The PlanB registry evaluated long-term follow-up data for clinical candidates for chemotherapy enrolled in the PlanB trial in hormone receptor (HR)-positive early breast cancer (eBC) patients preselected using the 21-gene expression assay.</div></div><div><h3>Patients and methods</h3><div>PlanB randomly assigned pT1-4c, pN+, pN0/high-risk human epidermal growth factor receptor 2 (HER2)-negative eBC patients to four cycles of epirubicin + cyclophoshamide followed by four cycles of docetaxel (EC-T arm) or to six cycles of docetaxel + cyclophosphamide (TC); patients with locally HR-positive tumors and recurrence score (RS) &lt;12 received endocrine therapy (ET) only. Following the end of PlanB, patients with HR-positive tumors were included in a prospective, noninterventional PlanB registry. The primary objective was to compare invasive disease-free survival (iDFS); the secondary objectives were the comparisons of overall survival (OS), and distant disease-free survival (dDFS).</div></div><div><h3>Results</h3><div>The registry included 699 patients (ET only: <em>n</em> = 119, TC: <em>n</em> = 298, EC-T: <em>n</em> = 289). In the TC and EC-T groups, respectively, 41% and 41% were postmenopausal; 63% and 55% were pN0; and 23% and 24% had RS &gt;25. Ten-year survival rates (10.3 years median follow-up) in the TC and EC-T arms were, respectively, 90.8% [95% confidence interval (CI) 86.6% to 93.7%] and 92.1% (95% CI 88.2% to 94.7%, <em>P</em> = 0.546) for iDFS; 94.4% (95% CI 90.9% to 96.5%) and 93.2% (95% CI 89.5% to 95.6%, <em>P</em> = 0.789) for dDFS, and 96.8% (95% CI 94.0% to 98.3%) and 96.3% (95% CI 93.3% to 98.0%, <em>P</em> = 0.974) for OS. Overall, 10-year OS was 94.2% (95% CI 88.9% to 97.1%) in RS &lt;12 (77.9% received ET-only), 96.8% (95% CI 94.4% to 98.2%) in RS 12-25, and 96.1% (95% CI 90.9% to 98.4%) in RS &gt;25 group. RS was not predictive of the efficacy of EC-T versus TC.</div></div><div><h3>Conclusions</h3><div>Ten-year outcomes for TC and EC-T were similar and excellent; six cycles of TC is an effective option in HER2-negative eBC with pN0 or pN1 and intermediate-to-high-risk disease, according to gene expression analysis.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105891"},"PeriodicalIF":8.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical benefit of additional whole-exome sequencing over panel sequencing in an all-comer real-world molecular tumor board","authors":"E. Krieghoff-Henning ,&nbsp;T. Michaeli ,&nbsp;T. Boch ,&nbsp;J. Kirchhof ,&nbsp;V. Haselmann ,&nbsp;M. Neumaier ,&nbsp;W.-K. Hofmann ,&nbsp;J. Betge ,&nbsp;M. Ebert ,&nbsp;A. Teufel ,&nbsp;V. Ast ,&nbsp;C. Sauer ,&nbsp;C. Cotarelo ,&nbsp;R. Lozynskyy ,&nbsp;M. Janning ,&nbsp;F. Marmé ,&nbsp;M. Sütterlin ,&nbsp;A. Streuer ,&nbsp;F. Siegel ,&nbsp;C. Brochhausen ,&nbsp;S. Loges","doi":"10.1016/j.esmoop.2025.105894","DOIUrl":"10.1016/j.esmoop.2025.105894","url":null,"abstract":"<div><h3>Background</h3><div>Panel sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS) often uncover therapeutic targets for cancer patients. However, it is still largely unclear to what extent patients directly benefit from broader analyses over panel sequencing alone.</div></div><div><h3>Materials and methods</h3><div>We analyzed the molecular findings and recommendations issued by our molecular tumor board (MTB) in a cohort of patients who had received both a well-established diagnostic panel of medium size (up to 203 genes) and in-house WES, focusing on the number of recommendations that were issued on the basis of WES results only.</div></div><div><h3>Results</h3><div>Our cohort consisted of 38 patients with advanced cancers, of whom about two-thirds had common and one-third had rare cancers. They received a total of 45 (range 0-4) treatment recommendations overall, of which 29 had a clinical level of evidence (LoE) and/or entailed a feasible study enrollment and were thus considered highly actionable. Sixteen recommendations, of which seven were highly actionable, were issued only on the basis of WES results (five own, two previous WES). Three out of those seven recommendations and one additional recommendation based on a previous large panel were related to complex molecular biomarkers such as homologous recombination deficiency or high tumor mutational burden, with poly (ADP-ribose) polymerase inhibitors or checkpoint inhibitors as recommended treatment. As expected, a higher proportion of the WES-only recommendations (63% versus 42% of recommendations overall) were based on non-clinical LoEs. One of eight recommendations implemented so far was based on biomarkers derived by WES only.</div></div><div><h3>Conclusions</h3><div>In our MTB, WES enabled some additional clinically highly actionable recommendations for selected patients, suggesting that some patients do benefit from additional WES. These recommendations were often related to complex biomarkers, which may in principle also be derived from larger panels. These findings should be re-investigated prospectively in larger cohorts.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105894"},"PeriodicalIF":8.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological complete response and survival after neoadjuvant chemotherapy in patients with stage I TNBC: a registry-based study","authors":"M. de Graaf ,&nbsp;R.C.A.M. Gielen ,&nbsp;S. Balduzzi ,&nbsp;S. Siesling ,&nbsp;S.C. Linn ,&nbsp;M. Kok","doi":"10.1016/j.esmoop.2025.105923","DOIUrl":"10.1016/j.esmoop.2025.105923","url":null,"abstract":"<div><h3>Background</h3><div>Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is a strong prognostic factor in patients with early-stage triple-negative breast cancer (TNBC). One-third of all patients with early-stage TNBC have stage I disease. Chemotherapy is recommended for most patients with stage I TNBC with an increasing use in the neoadjuvant setting supported by recent guidelines. However, little is known on the chemotherapy benefit for stage I TNBC, in particular the likelihood of a pCR and the prognostic value of pCR in this setting.</div></div><div><h3>Patients and methods</h3><div>Patients with cT1N0M0 TNBC who received standard of care NACT followed by surgery between 2012 and 2022 were identified from the Netherlands Cancer Registry. Baseline factors associated with pCR (ypT0/is, ypN0) and the impact of pCR on overall survival (OS) were evaluated.</div></div><div><h3>Results</h3><div>A total of 1144 patients treated with anthracycline-taxane-based NACT were identified. Most patients had cT1N0 disease [<em>n</em> = 1077 (94%)] of no special subtype [<em>n</em> = 1034 (90%)]. In total, 656 patients (57.3%) had a pCR. Younger age [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.38-2.30], higher tumor grade [OR 2.11, 95% CI 1.58-2.81] and smaller tumors [OR 2.03, 95% CI 1.15-3.69] were significantly associated with a higher likelihood of pCR, while patients with a lobular carcinoma were less likely to have a pCR (OR 0.17, 95% CI 0.03-0.67). Platinum-based treatment did not significantly improve the pCR rate (<em>P</em> = 0.9). pCR was associated with a better OS [adjusted hazard ratio (aHR) 0.23, 95% CI 0.11-0.45], with a 5-year OS of 97% versus 90% for patients with and without a pCR, respectively. Of 488 patients with residual disease, 280 (57.4%) received adjuvant capecitabine, which was not significantly associated with improved OS [aHR 0.65, 95% CI 0.30-1.44].</div></div><div><h3>Conclusions</h3><div>Data from this real-world nationwide Dutch registry on neoadjuvant chemotherapy for stage I TNBC, with the majority of patients having cT1cN0 disease of no special subtype, suggests pCR to be associated with a favorable long-term outcome.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105923"},"PeriodicalIF":8.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative analysis of RNA expression signatures and recurrent genomic alterations before treatment: link to menopausal status, short-term endocrine therapy response and disease-free survival in luminal breast cancer","authors":"G. Zhang ,&nbsp;H. Ni ,&nbsp;L. Mishieva ,&nbsp;S. Bartels ,&nbsp;M. Christgen ,&nbsp;H. Christgen ,&nbsp;L.D. Kandt ,&nbsp;M. Raap ,&nbsp;R.E. Kates ,&nbsp;O. Gluz ,&nbsp;M. Graeser ,&nbsp;S. Kümmel ,&nbsp;U. Nitz ,&nbsp;C. Plass ,&nbsp;U. Mansmann ,&nbsp;C. zu Eulenburg ,&nbsp;C. Gerhäuser ,&nbsp;H.H. Kreipe ,&nbsp;N. Harbeck","doi":"10.1016/j.esmoop.2025.105913","DOIUrl":"10.1016/j.esmoop.2025.105913","url":null,"abstract":"<div><h3>Background</h3><div>Endocrine therapy with tamoxifen (TAM) or aromatase inhibitors (AI) is an effective treatment of patients with estrogen receptor-positive, HER2-negative luminal breast cancer. However, many patients do not respond to this therapy, leading to disease recurrence. This study aimed to identify baseline clinical, molecular, and genetic features associated with menopause status, primary endocrine therapy resistance and long-term outcomes in luminal breast cancer.</div></div><div><h3>Patients and methods</h3><div>We analyzed 220 patients from the WSG-ADAPT trial with early-stage, estrogen receptor-positive, HER2-negative breast cancer, who received 3 weeks of preoperative endocrine therapy with TAM or AI. Tumor samples obtained before treatment were profiled using the NanoString BC360 panel, and samples obtained after treatment were analyzed for recurrent genomic alterations by next-generation panel sequencing. A subset of the TCGA-BRCA cohort was used for external validation. Univariate Cox regression analyses were used for prognosis analysis.</div></div><div><h3>Results</h3><div>The NanoString signatures were clustered into three stable blocks: A (reactive microenvironment and stemness), B (immune) and C (proliferation and genomic risk). Non-responders more frequently harbored <em>TP53</em> mutations<em>,</em> which were linked to significantly elevated protumorigenic immune- (interferon-γ, inflammatory chemokines, macrophages and regulatory T cells) and proliferation-related [breast cancer proliferation, genomic risk, and homologous recombination deficiency (HRD)] signature scores. In the AI group, signatures associated with reduced disease-free survival included breast cancer p53 [hazard ratio (HR) 2.74, 95% confidence interval (CI) 1.08-6.94]; genomic risk (HR 2.5, 95% CI 1.07-5.83); HRD (HR 2.44, 95% CI 1.12-5.29) and hypoxia (HR 2.12, 95% CI 1.17-3.87). High expression of programmed cell death protein 1 (HR 0.44, 95% CI 0.21-0.94) and progesterone receptor (HR 0.24, 95% CI 0.07-0.81) indicated better outcomes, respectively. These associations were validated using external data.</div></div><div><h3>Conclusions</h3><div>Endocrine resistance in luminal breast cancer is characterized by elevated immune signatures, increased proliferation, and specific genomic alterations. The integration of clinical information, gene expression patterns, and genetic data enhances patient stratification and potentially informs treatment decisions. These findings support the use of integrative analyses to guide personalized endocrine therapy and improve outcomes.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105913"},"PeriodicalIF":8.3,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the Lung Immune Prognostic Index in non-small-cell lung cancer patients with PD-L1-low/negative tumors receiving chemoimmunotherapy: a real-world multicenter retrospective study","authors":"A. Yoshimura ,&nbsp;T. Takeda ,&nbsp;K. Tanimura ,&nbsp;Y. Chihara ,&nbsp;H. Kawachi ,&nbsp;Y. Yamanaka ,&nbsp;N. Tamiya ,&nbsp;R. Honda ,&nbsp;T. Yamada ,&nbsp;K. Uryu ,&nbsp;S. Shiotsu ,&nbsp;H. Yoshioka ,&nbsp;T. Yamada ,&nbsp;T. Kurata ,&nbsp;K. Takayama","doi":"10.1016/j.esmoop.2025.105906","DOIUrl":"10.1016/j.esmoop.2025.105906","url":null,"abstract":"<div><h3>Background</h3><div>Chemoimmunotherapy has become one of the standard first-line treatment options for advanced non-small-cell lung cancer (NSCLC) across programmed death-ligand 1 (PD-L1) strata, yet outcomes in PD-L1-low/negative disease remain suboptimal. We evaluated whether the Lung Immune Prognostic Index (LIPI) at treatment initiation has prognostic value in this subgroup.</div></div><div><h3>Patients and methods</h3><div>We conducted a multicenter retrospective cohort study across nine Japanese hospitals (January 2016-September 2021). Clinical data, including results of pretreatment blood tests at first-line treatment initiation, were collected and used to categorize LIPI (good, intermediate, or poor). Endpoints were progression-free survival (PFS) and overall survival (OS). Kaplan–Meier and log-rank tests were used; prespecified multivariable Cox models were adjusted for LIPI (poor versus good/intermediate), PD-L1 tumor proportion score, Eastern Cooperative Oncology Group performance status, liver/brain metastases, treatment regimen, and age.</div></div><div><h3>Results</h3><div>We analyzed 176 patients (median age 71 years: PD-L1-low, 60.8%; PD-L1-negative, 39.2%). Median PFS and OS were 7.3 months [95% confidence interval (CI) 6.4-9.0 months] and 21.5 months (95% CI 15.4-24.6 months), respectively. Poor LIPI was associated with worse outcomes than good/intermediate LIPI (PFS: 3.6 versus 9.0 months, OS: 7.8 versus 23.9 months, both <em>P</em> &lt; 0.001). In multivariable models, poor LIPI remained independently prognostic [PFS: adjusted hazard ratio (HR) 2.64, 95% CI 1.66-4.21; OS: adjusted HR 2.82, 95% CI 1.73-4.61].</div></div><div><h3>Conclusions</h3><div>In first-line chemoimmunotherapy-treated PD-L1-low/negative NSCLC, baseline LIPI can be used to independently stratify PFS and OS and identify a subgroup with poor prognosis. LIPI may support risk stratification at first-line treatment initiation. Prospective studies are warranted to validate these findings and optimize personalized treatment approaches.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105906"},"PeriodicalIF":8.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision medicine strategy in pancreatic ductal adenocarcinoma","authors":"A. Tarabay ,&nbsp;L. Swales ,&nbsp;C. Smolenschi ,&nbsp;E. Akoury ,&nbsp;M. Valéry ,&nbsp;A. Fuerea ,&nbsp;T. Pudlarz ,&nbsp;V. Boige ,&nbsp;E. Rouleau ,&nbsp;M. Gelli ,&nbsp;M.A. Bani ,&nbsp;R. Barbe ,&nbsp;A. Hollebecque ,&nbsp;M. Ducreux ,&nbsp;A. Boilève","doi":"10.1016/j.esmoop.2025.105899","DOIUrl":"10.1016/j.esmoop.2025.105899","url":null,"abstract":"<div><h3>Background</h3><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options. Integration of molecular profiling may enable personalized treatment approaches. We evaluated the clinical utility of molecularly matched treatment (MMT) in a real-life cohort of PDAC patients.</div></div><div><h3>Patients and methods</h3><div>A retrospective chart review of clinical/molecular data was carried out, including all PDAC patients with a contributive molecular profile. Survival outcomes were compared across three groups: patients with actionable molecular alterations (MAs) who received MMT (MA/MMT), patients with actionable alterations without MMT (MA/No MMT), and patients without actionable alterations (No MA/No MMT).</div></div><div><h3>Results</h3><div>Among 342 patients (median age 61 years; 48% female; 95% Eastern Cooperative Oncology Group 0-1), molecular profiling was carried out using tissue (50%), liquid biopsy (45%), or both (5%). The most common gene alterations were <em>KRAS</em> (84%), <em>TP53</em> (72%), and <em>CDKN2A</em> (26%). Actionable alterations were found in 69 patients (20%), with 31 (45%) receiving MMT. Targeted therapies included notably olaparib (BRCA2), trastuzumab (HER2), and KRAS G12C inhibitors. Median overall survival (OS) from metastatic diagnosis was significantly longer in the MA/MMT group (32.9 months) compared with MA/No MMT (12.9 months) and No MA/No MMT groups (17.6 months) (<em>P</em> = 0.0008). From initial diagnosis, OS was 34.9, 27.1, and 21.5 months, respectively (<em>P</em> = 0.005). Median progression-free survival from MMT initiation was 5.5 months. The mean growth modulation index was 1.7 in the MA/MMT group versus 0.8 in the MA/No MMT group (<em>P</em> &lt; 0.05). In variate analysis, MMT was correlated with improved OS [hazard ratio (HR) 0.51, <em>P</em> &lt; 0.001 from metastasis; HR 0.59, <em>P</em> &lt; 0.01 from diagnosis].</div></div><div><h3>Conclusion</h3><div>To conclude, molecular profiling identified actionable alterations in 20% of PDAC patients. MMT was associated with a significant survival benefit, supporting molecular profiling into routine management, especially with the perspective of KRAS inhibitors.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105899"},"PeriodicalIF":8.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human study of a thorium-227-labeled mesothelin-targeting antibody-chelator conjugate (MSLN-TTC), in patients with malignant mesothelioma and other solid tumors","authors":"A. Minchom ,&nbsp;O. Lindén ,&nbsp;D.G. Knapen ,&nbsp;R. Hassan ,&nbsp;F.I. Lin ,&nbsp;K. Jalkanen ,&nbsp;V. Subbiah ,&nbsp;A. Tafuri ,&nbsp;D. Ferreira ,&nbsp;V. Jardine ,&nbsp;A. Cleton ,&nbsp;J. Pinkert ,&nbsp;F. Bladt ,&nbsp;H. Hennekes ,&nbsp;E.F. Smit","doi":"10.1016/j.esmoop.2025.105905","DOIUrl":"10.1016/j.esmoop.2025.105905","url":null,"abstract":"<div><h3>Introduction</h3><div>BAY 2287411 [²²⁷Th-anetumab corixetan; mesothelin-targeting antibody-chelator conjugate (MSLN-TTC)] is a targeted alpha therapy consisting of a fully human mesothelin-targeting monoclonal antibody conjugated with a 3,2-hydroxypyridinone (3,2-HOPO) chelator radiolabeled with the alpha particle-emitting radionuclide thorium-227. This phase I study determined the safety, pharmacokinetics, and antitumor activity of MSLN-TTC in mesothelin-expressing mesothelioma and serous ovarian cancer.</div></div><div><h3>Methods</h3><div>MSLN-TTC was administered i.v. 1.5, 2.5, or 3.5 MBq of thorium-227 and with a total antibody dose of 10, 30, 50, or 150 mg every 6 weeks to 36 patients included in the intention-to-treat population. Adverse events, tumor response according to RECIST 1.1 and mRECIST criteria, and progression-free survival were determined. Tumor mesothelin expression was assessed retrospectively.</div></div><div><h3>Results</h3><div>In dose escalation, 35 patients (30 with malignant pleural mesothelioma) received MSLN-TTC across three thorium-227 dose levels and four total antibody doses. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached due to treatment discontinuations following 45.7% of the patients developing neutralizing antibodies. The most common treatment-emergent adverse events of any grade were fatigue (10/36, 27.8%), decreased lymphocyte count (7/36, 19.4%), nausea (7/36, 19.4%), anemia (6/36, 16.7%), and infusion-related reaction (6/36, 16.7%). The disease control rate was 34.3%, including 12 stable diseases (12/36, 34.3%). No complete or partial responses were observed. The median progression-free survival was 70 days (95% confidence interval 29-161 days).</div></div><div><h3>Conclusions</h3><div>MSLN-TTC showed good tolerability, but the maximum tolerated dose could not be determined due to discontinuations after antidrug antibody formation. Stable disease was observed in 12 out of 36 patients.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105905"},"PeriodicalIF":8.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-exome ctDNA sequencing reveals intratumoral heterogeneity and drivers of relapse in locally advanced head and neck cancer","authors":"G. Bruixola ,&nbsp;J. Martín-Arana ,&nbsp;F. Gimeno-Valiente ,&nbsp;J.A. Carbonell-Asins ,&nbsp;B. García-Micó ,&nbsp;B. Martínez-Castedo ,&nbsp;D. González-Camblor ,&nbsp;N. Grimalt ,&nbsp;M. García-Bartolomé ,&nbsp;C. Alfaro-Cervelló ,&nbsp;V. Escorihuela ,&nbsp;M.E. Iglesias ,&nbsp;M. Maroñas ,&nbsp;D. Dualde ,&nbsp;A. Cervantes ,&nbsp;N. Tarazona","doi":"10.1016/j.esmoop.2025.105904","DOIUrl":"10.1016/j.esmoop.2025.105904","url":null,"abstract":"<div><h3>Background</h3><div>The mechanisms underlying tumor evolution and treatment resistance in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are not fully understood. This study used whole-exome sequencing (WES) of paired tumor tissue and circulating tumor DNA (ctDNA) to analyze intratumoral heterogeneity (ITH) and clonal dynamics at diagnosis and relapse.</div></div><div><h3>Patients and methods</h3><div>Between January 2017 and September 2022, we enrolled 152 patients with LA-HNSCC treated with radical chemoradiotherapy. Tumor tissue and plasma samples were collected at baseline and at relapse. WES was carried out on DNA extracted from tissue, plasma, and germline samples. Oncogenic variants were analyzed to evaluate tumor evolution and ITH. Concordance, pathway alterations, and associations with survival were examined.</div></div><div><h3>Results</h3><div>Out of the 152 patients selected, 81 were excluded based on clinical criteria. Of the 71 remaining patients, 37 had the complete set of samples of adequate quality for analysis. The most frequent mutations involved <em>TP53</em> (48%), <em>KMT2D</em> (34%), and <em>NOTCH1</em> (34%) at diagnosis. Pathogenic germline variants, including actionable mutations in <em>BRCA2, CHK2</em>, and <em>KIT</em>, were identified in 13.5% of cases. Concordance between tissue and plasma was low (median 11.8% at baseline, 12.4% at relapse), with up to 67% of oncogenic variants found only in ctDNA. Longitudinal analysis revealed limited overlap (10.3%) between baseline and relapse ctDNA, with some emerging resistance-associated mutations in PI3K-mTORC2 and ATM-CHK2 pathways. Alterations in IL6-JAK-STAT3 and RHO GTPase pathways were enriched in locoregional relapses (adjusted <em>P</em> &lt; 0.001). Mutations in MMP15 and PTPRE were linked to shorter locoregional progression-free survival, whereas PDE2A mutations were associated with prolonged progression-free survival.</div></div><div><h3>Conclusions</h3><div>WES of ctDNA uncovers extensive ITH and identifies molecular drivers of resistance not captured by tissue biopsies. These findings support the use of plasma ctDNA analysis to monitor tumor evolution and personalize follow-up in LA-HNSCC, especially given the anatomical complexity that often limits repeated tissue sampling.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105904"},"PeriodicalIF":8.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bevacizumab plus chemotherapy versus chemotherapy in untreated advanced non-squamous non-small-cell lung cancer patients with brain metastases (BAP BRAIN): an open-label, randomized, multicenter, phase III study","authors":"M. Li ,&nbsp;Y. Pan ,&nbsp;G. Jiang ,&nbsp;Q. Wang ,&nbsp;G. Wu ,&nbsp;W. Feng ,&nbsp;C. Zhou ,&nbsp;Q. Bu ,&nbsp;S. Ma ,&nbsp;H. Jiang ,&nbsp;J. Chen ,&nbsp;H. Yu ,&nbsp;M. Yu ,&nbsp;Q. Liu ,&nbsp;X. Hou ,&nbsp;L. Chen","doi":"10.1016/j.esmoop.2025.105908","DOIUrl":"10.1016/j.esmoop.2025.105908","url":null,"abstract":"<div><h3>Background</h3><div>There is a lack of prospective randomized controlled trials of antiangiogenic therapy in patients with brain metastases. We conducted this phase III, randomized, multicenter study (BAP BRAIN) to evaluate the intracranial efficacy and safety of bevacizumab plus chemotherapy in patients with non-squamous non-small-cell lung cancer (NSCLC) and brain metastases, and provide evidence for this previously unexplored subgroup.</div></div><div><h3>Patients and methods</h3><div>Treatment-naïve, non-squamous NSCLC patients with confirmed brain metastases and without sensitizing epidermal growth factor receptor or anaplastic lymphoma kinase mutations were screened from 11 centers in China. The eligible patients were randomly assigned (1 : 1) to receive bevacizumab plus pemetrexed–platinum or pemetrexed–platinum for four to six cycles, followed by bevacizumab plus pemetrexed or pemetrexed maintenance until disease progression, unacceptable toxicity, or death. The primary endpoint was intracranial progression-free survival (iPFS), and secondary endpoints included PFS, overall survival (OS), intracranial objective response rate (iORR), systemic ORR, and safety.</div></div><div><h3>Results</h3><div>A total of 160 patients were eligible and underwent randomization, and 153 patients received at least one dose of drug and were included in the full analysis set. After a median follow-up of 16.8 months, the median iPFS was 11.07 months in the bevacizumab plus pemetrexed–platinum group versus 7.37 months in the pemetrexed–platinum group [hazard ratio (HR) 0.494, <em>P</em> &lt; 0.001]. Similarly, the median systemic PFS was significantly longer with bevacizumab plus pemetrexed–platinum than with pemetrexed–platinum alone (8.77 months versus 5.23 months, HR 0.540, <em>P</em> &lt; 0.001). The bevacizumab plus pemetrexed–platinum group had better iORR (69.6% versus 32.4%) and ORR (58.2% versus 27.0%) and remission rate of cerebral edema (88.9% versus 41.9%) than the pemetrexed–platinum group. At data cut-off, the median OS was 28.07 months in the bevacizumab plus pemetrexed–platinum group versus 18.53 months in the pemetrexed–platinum group (HR 0.752, <em>P</em> = 0.162). There was no grade ≥3 intracranial hemorrhage, and most of the adverse events were manageable.</div></div><div><h3>Conclusions</h3><div>This study demonstrated encouraging intracranial efficacy and acceptable safety of bevacizumab plus chemotherapy in patients with non-squamous NSCLC and brain metastases in the first-line setting.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":"10 12","pages":"Article 105908"},"PeriodicalIF":8.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}