Clinical Cancer Research最新文献

{"title":"First-in-Human Phase I Study of a CD16A Bispecific Innate Cell Engager, AFM24, Targeting EGFR-Expressing Solid Tumors.","authors":"Anthony El-Khoueiry, Omar Saavedra, Jacob Thomas, Claire Livings, Elena Garralda, Gabriele Hintzen, Laura Kohlhas, Dessislava Vanosmael, Joachim Koch, Erich Rajkovic, Paulien Ravenstijn, Paolo Nuciforo, Todd A Fehniger, Mark Foster, Melissa M Berrien-Elliott, Susanne Wingert, Sina Stäble, Daniela Morales-Espinosa, Delcia Rivas, Michael Emig, Juanita Lopez","doi":"10.1158/1078-0432.CCR-24-1991","DOIUrl":"10.1158/1078-0432.CCR-24-1991","url":null,"abstract":"<p><strong>Purpose: </strong>Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on NK cells/macrophages and EGFR on tumor cells, redirecting antitumor activity toward tumors. The safety and tolerability of AFM24 were evaluated in this phase I/IIa dose-escalation/dose-expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR.</p><p><strong>Patients and methods: </strong>The main objective in phase I was to determine the MTD and/or recommended phase II dose. The primary endpoint was the incidence of dose-limiting toxicities during the observation period. Secondary endpoints included the incidence of treatment-emergent adverse events and pharmacokinetics.</p><p><strong>Results: </strong>In the dose-escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14-720 mg). One patient experienced a dose-limiting toxicity of grade 3 infusion-related reaction. Infusion-related reactions were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics was dose-proportional, and CD16A receptor occupancy on NK cells approached saturation between 320 and 480 mg. Paired tumor biopsies demonstrated the activation of innate and adaptive immune responses within the tumor. The best objective response was stable disease in 10/35 patients; four patients had stable disease for 4.3 to 7.1 months.</p><p><strong>Conclusions: </strong>AFM24 was well tolerated, with 480 mg established as the recommended phase II dose. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors, with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1257-1267"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022357","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}

{"title":"Mitochondria Targeting of Oxidative Phosphorylation Inhibitors to Alleviate Hypoxia and Enhance Anticancer Treatment Efficacy.","authors":"Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink","doi":"10.1158/1078-0432.CCR-24-3296","DOIUrl":"10.1158/1078-0432.CCR-24-3296","url":null,"abstract":"<p><p>Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity have hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared with healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243, and IACS-010759 and the potential of mitochondria-targeted OXPHOSi and their influence on reactive oxygen species production. Furthermore, the effect of the mitochondria-targeting moiety triphenylphosphonium on mitochondria is discussed as it affects mitochondrial bioenergetics.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1186-1193"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078587","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":"Impact of Race/Ethnicity on Clinical and Genomic Characteristics, Trial Participation, and Genotype-Matched Therapy among Patients with Metastatic Breast Cancer.","authors":"Rupali Sood, Andrzej Niemierko, Lianne Ryan, Laura Spring, Beverly Moy, Aditya Bardia, Neelima Vidula","doi":"10.1158/1078-0432.CCR-24-2825","DOIUrl":"10.1158/1078-0432.CCR-24-2825","url":null,"abstract":"<p><strong>Purpose: </strong>Race/ethnicity may affect outcomes in metastatic breast cancer (MBC) due to biological and social determinants. We evaluated the impact of race/ethnicity on clinical, socioeconomic, and genomic characteristics, clinical trial participation, and receipt of genotype-matched therapy among patients with MBC.</p><p><strong>Experimental design: </strong>A retrospective study of patients with MBC who underwent cell-free DNA testing (cfDNA, Guardant360, 74 gene panel) between 11/2016 and 11/2020 was conducted. Receipt of genotype-matched therapy targeted at a cfDNA actionable mutation was determined. Pearson χ2 and Wilcoxon rank-sum tests were used to compare categorical and continuous variables between groups. Multivariable logistic regression was used to assess the association of race and receiving matched therapy.</p><p><strong>Results: </strong>A total of 425 patients with MBC and cfDNA results were identified (White: 369, Black: 27, Hispanic: 15, and Asian: 14). White patients traveled further for cancer care than other groups (P < 0.001). White patients had the highest rates of commercial insurance, Black patients had the highest rates of state-supported insurance, and Asian patients had the highest uninsured rates (P < 0.001). Clinical trial enrollment did not differ by race/ethnicity (P = 0.34). The proportion of patients with ≥1 actionable mutation in cfDNA did not vary by race/ethnicity (P = 0.18). The highest rates of matched therapy were observed in White patients (P < 0.001). After multivariable logistic regression adjusting for subtype, commercial versus other insurance, Charlson Comorbidity Index, and distance to center, White patients remained more likely to receive matched therapy (P = 0.024).</p><p><strong>Conclusions: </strong>Racial/ethnic minority patients were less likely to receive matched therapy. Further research is needed to identify barriers to precision medicine.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1315-1322"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045551","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":"Corticosteroid-Dependent Association between Prognostic Peripheral Blood Cell-Free DNA Levels and Neutrophil-Mediated NETosis in Patients with Glioblastoma.","authors":"Jacob E Till, Nicholas J Seewald, Zachariya Yazdani, Zhuoyang Wang, Dominique Ballinger, Heather Samberg, Siri Dandu, Camilla Macia, Melinda Yin, Aseel Abdalla, Timothy Prior, Shivani S Shah, Thara Patel, Emily McCoy, Maikel Mansour, Carson A Wills, Veronica Bochenek, Jonathan Serrano, Matija Snuderl, Richard E Phillips, Donald M O'Rourke, Nduka M Amankulor, Ali Nabavizadeh, Arati S Desai, Kandace Gollomp, Zev A Binder, Wanding Zhou, Stephen J Bagley, Erica L Carpenter","doi":"10.1158/1078-0432.CCR-24-3169","DOIUrl":"10.1158/1078-0432.CCR-24-3169","url":null,"abstract":"<p><strong>Purpose: </strong>Noninvasive prognostic biomarkers to inform clinical decision-making are an urgent unmet need for the management of patients with glioblastoma (GBM). We previously showed that higher circulating cell-free DNA (ccfDNA) concentration is associated with worse survival in GBM. However, the biology underlying this is unknown.</p><p><strong>Experimental design: </strong>We prospectively enrolled 129 patients with treatment-naïve GBM with blood drawn prior to initial resection (baseline) and at the time of the first postradiotherapy MRI. We performed ccfDNA methylation deconvolution to determine cellular sources of ccfDNA. ELISA was performed to detect citrullinated histone 3 (citH3), a marker of neutrophil extracellular traps (NET). Multiplex proteomic analysis was used to measure soluble inflammatory proteins.</p><p><strong>Results: </strong>We found that neutrophils contributed the highest proportion of prognostic ccfDNA. The percentage of ccfDNA derived from neutrophils was correlated with total [ccfDNA] but only in patients receiving preoperative corticosteroids. At baseline and on therapy, [citH3] was significantly higher in the plasma of patients with GBM receiving corticosteroids compared with corticosteroid-naïve GBM or no-cancer controls. Unsupervised hierarchical clustering of ccfDNA methylation patterns yielded two clusters, with one enriched for patients with the NETosis phenotype and who received corticosteroids. Unsupervised clustering of circulating inflammatory proteins yielded similar results.</p><p><strong>Conclusions: </strong>These data suggest neutrophil-mediated NETosis is the dominant source of prognostic ccfDNA in patients with GBM and may be associated with glucocorticoid exposure. If further studies show that pharmacological inhibition of NETosis can mitigate the deleterious effects of corticosteroids, these plasma markers will have important clinical utility as noninvasive correlative biomarkers.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1292-1304"},"PeriodicalIF":10.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064148","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}

{"title":"Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-doublet Chemotherapy for Non-small Cell Lung Cancer Harboring EGFR Mutation","authors":"Shintaro Kanda, Seiji Niho, Takayasu Kurata, Shogo Nomura, Yosuke Kawashima, Eiji Iwama, Toshihide Yokoyama, Yasutaka Watanabe, Hiroshi Tanaka, Yutaka Fujiwara, Yoshitaka Zenke, Koichi Azuma, Hirokazu Taniguchi, Ryo Toyozawa, Yukio Hosomi, Haruyasu Murakami, Satoshi Hara, Akihiro Bessho, Nobuyuki Yamamoto, Yuichiro Ohe","doi":"10.1158/1078-0432.ccr-24-3532","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3532","url":null,"abstract":"Purpose: This study was performed to confirm the superiority in overall survival (OS) of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) (gefitinib or osimertinib) monotherapy versus EGFR-TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSqNSCLC) harboring EGFR mutation. Patients and Methods: This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or EGFR-TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS). Results: From December 2015 to October 2020, 501 patients were randomized. The EGFR-TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n=308, osimertinib cohort: n=193). There was no survival advantage in the EGFR-TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (hazard ratio, 0.985; 91.4% confidence interval, 0.796–1.219; one-sided P=0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR-TKI plus intercalated chemotherapy group (hazard ratio, 0.762; 95% confidence interval, 0.628–0.925; one-sided P=0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population. Conclusions: The intercalation of cisplatin plus pemetrexed after the response to EGFR-TKI improved PFS but not OS compared with EGFR-TKI monotherapy as the first-line treatment for advanced NSqNSCLC harboring EGFR mutation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736627","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":"Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders.","authors":"David Fandrei, Jean Pegliasco, Florence Pasquier, Nathalie Ibrahim, Maria Kfoury, Céline Berthon, Mael Heiblig, Delphine Lebon, Ambroise Marçais, Mathieu Meunier, Ahmad Al Jijakli, Emilie Lemasle, Sylvain Chantepie, Cecile Pautas, Pierre-Yves Dumas, Celia Salanoubat, Diana Carp, Romain Loyaux, Cyril Quivoron, Arnaud Pages, Bastien Job, Remy Jelin, Gerome Jules-Clement, Iléana Antony-Debré, Aline Renneville, Sophie Cotteret, Raphael Itzykson, Herve Dombret, Nicolas Duployez, Nathalie Droin, Alexandra Leary, Christophe Marzac, Elsa Bernard, Jean-Baptiste Micol","doi":"10.1158/1078-0432.CCR-24-3683","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3683","url":null,"abstract":"<p><strong>Purpose: </strong>PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis (CH), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear.</p><p><strong>Experimental design: </strong>We characterized the clinical and genomic profiles of 112 PPM1D-mutated patients across the spectrum of myeloid disorders using a combination of bulk and single-cell analyses on diagnostic and longitudinal samples.</p><p><strong>Results: </strong>Among all patients, 78% had a history of primary cancer, with DNMT3A and TP53 being the most frequent co-mutated genes. In ten patients with high-grade serous ovarian cancer, longitudinal analysis showed variable dynamics of PPM1D-mutant clones, with 81% of clones expanding during exposure to alkylating agents. Clonal hierarchy estimation revealed that 44% of PPM1D-mutated acute myeloid leukemia (AML) patients had a PPM1D mutation in the founder clone, with rare TP53 co-mutations. Both TP53 wildtype and mutated AML patients had poor overall survival. Single cell DNA and surface protein analysis in seven patients confirmed that PPM1D mutations can arise in the founding clone, and were associated with expression of leukemic markers.</p><p><strong>Conclusions: </strong>PPM1D mutated CH clones can spontaneously regress after treatment discontinuation, however they can also be found in the dominant clone in AML/MDS.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751343","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":"A phase 1, first-in-human, dose-escalation, expansion trial of cytokine encoding synthetic mRNA-mixture alone or with cemiplimab in advanced solid tumors.","authors":"Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean-Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica C Hassel, Ana Arance, Miguel F Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Patrick Brueck, Giovanni Abbadessa, Rahul Marpadga, Helen Lee, Yue Yang, Barbara Buday, Gianfranco Di Genova, Hong Wang, Binfeng Xia, Joon Sang Lee, Céleste Lebbe","doi":"10.1158/1078-0432.CCR-24-1983","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1983","url":null,"abstract":"<p><strong>Purpose: </strong>We investigated SAR441000 (mixture of four mRNAs encoding interleukin [IL]-12, single chain interferon [IF]-α-2b, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a pre-defined dose level (DL) with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine maximum tolerated or maximum administered dose (MAD), overall safety, tolerability, and objective response rate of SAR441000.</p><p><strong>Results: </strong>We enrolled 77 patients previously treated with anti-cancer therapies (escalation monotherapy: N=21; escalation combination: N=15; and expansion combination [PD-1 refractory melanoma]: N=41). MAD at DL8 was 4000 µg. The most common Grade ≥3 treatment-related adverse event was fatigue in escalation phase (monotherapy: 28.6%; combination therapy: 66.7%) and injection-site pain (31.7%) in expansion phase. In combination therapy, one patient in escalation and two in expansion phase achieved partial responses. At 4000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-folds) and IL-15 (1.96-folds), respectively. Increased blood IFN-γ and IP-10 levels were observed for most patients.</p><p><strong>Conclusions: </strong>Intratumoral administration of SAR441000 in combination with cemiplimab, was generally well tolerated with anti-tumor activity in loco-regional disease setting. Anecdotal evidence of pharmacodynamic immune-modulatory effect and distant non-injected lesion anti-tumor response was observed, without significant effect in patients with advanced solid tumors previously treated with anti-PD1 therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729013","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":"Identification of Early-Stage Breast Cancer with Minimal Risk of Recurrence by Breast Cancer Index.","authors":"Marie-France Jilderda, Yi Zhang, Valerie Rebattu, Ranelle Salunga, Wilma Mesker, Jenna Wong, Linda de Munck, Tommy Fornander, Bo Nordenskjöld, Olle Stål, Amanda K L Anderson, Esther Bastiaannet, Kai Treuner, Gerrit-Jan Liefers","doi":"10.1158/1078-0432.CCR-24-3836","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3836","url":null,"abstract":"<p><strong>Purpose: </strong>This study assessed the prognostic ability of Breast Cancer Index (BCI) to identify patients at minimal risk (<5%) of 10-year distant recurrence (DR) who are unlikely to benefit from adjuvant endocrine therapy.</p><p><strong>Experimental design: </strong>This prospective translational study included postmenopausal patients with early-stage, HR+ N0 breast cancer from the Stockholm (STO-3) trial who underwent surgery alone (\"untreated\") or surgery plus adjuvant tamoxifen (\"treated\") and the Netherlands Cancer Registry (NCR; surgery alone). The primary endpoint was time to DR. An adjusted BCI model with an additional cut-point was developed that stratified patients into 4 prognostic risk groups.</p><p><strong>Results: </strong>Across cohorts, 16%-22% of patients were classified as minimal risk of 10-year DR. In the Stockholm untreated cohort (n = 283), risks in the minimal, low, intermediate, and high risk groups were 2.3%, 15.5% (hazard ratio, 4.71 [95% CI, 1.09-20.29] versus minimal risk), 19.8% (6.97 [1.61-30.18]), and 35.9% (13.21 [3.07-56.76]), respectively (P < .001). In the Stockholm treated cohort (n = 317), risks were 4.3%, 5.0% (1.16 [0.35-3.85]), 11.7% (2.45 [0.74-8.14]), and 21.1% (5.27 [1.72-16.16]; P < .001). In the NCR cohort (n = 1245), risks were 4.5%, 7.5% (sub-distribution hazard ratio, 1.67 [95% CI, 0.81-3.45]), 10.3% (2.40 [1.14-5.03]), and 13.1% (3.13 [1.50-6.55]; P = .005). BCI risk scores provided additional independent information over standard prognostic factors (likelihood ratio, c2 = 7.98; P = .004).</p><p><strong>Conclusions: </strong>The adjusted BCI model identified women with early-stage, HR+ N0 breast cancer at minimal risk of DR who may consider de-escalating adjuvant endocrine therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718019","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":"Modelling MRD changes in myeloma to understand treatment effects, predict outcomes, and investigate curative potential.","authors":"Walter M Gregory, Thomas J Prior, J Blake Bartlett, Pieter Sonneveld, Meletios A Dimopoulos, Philippe Moreau, Saad Usmani, Thierry Facon","doi":"10.1158/1078-0432.CCR-24-3475","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3475","url":null,"abstract":"<p><strong>Purpose: </strong>We designed mathematical models to describe and quantify the mechanisms and dynamics of minimal residual disease (MRD) in order to better understand these MRD dynamics, to inform future treatment design, including when to stop or change treatment, and to extrapolate from current PFS times to predict future PFS curves.</p><p><strong>Experimental design: </strong>To model individual sequential MRD data from phase III clinical trials (MAIA, CASTOR, and POLLUX) using previously developed mathematical models which would be modified as necessary to accurately correspond with the actual MRD data. These models would then be used to extrapolate PFS curves ahead in time.</p><p><strong>Results: </strong>Patients with low MRD values either showed rapid disease regrowth or the MRD values remained low for a prolonged period. Treatment appeared to be most effective in terms of cell-kill within the first 6 to 12 months. Regrowth rates were correlated with estimated initial residual disease, particularly in MRD negative patients. Three-year model extrapolations of PFS were closely comparable to clinical trial data.</p><p><strong>Conclusions: </strong>This model could provide early prediction of PFS outcomes, which otherwise takes lengthy periods of time to observe with clinical trials. Patients showing rapid rebound from low MRD values may benefit from adding another treatment before reaching progressive disease. The MRD analyses and results presented, such as the results about efficacy occurring early in the first 6 to 12 months, may help guide the development and selection of optimal regimens. Longer follow-up periods and application to other trials and datasets are required to substantiate these findings.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718092","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":"A Proteogenomic View of Synchronous Endometrioid Endometrial and Ovarian Cancer.","authors":"Fabian Coscia, Annelaura B Nielsen, Melanie Weigert, Karen Watters, Melissa Javellana, Michael Anglesio, S Diane Yamada, Ricardo R Lastra, Matthias Mann, Ernst Lengyel","doi":"10.1158/1078-0432.CCR-24-1763","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1763","url":null,"abstract":"<p><strong>Purpose: </strong>Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histological markers to distinguish SEOCs from single-site tumors.</p><p><strong>Experimental design: </strong>We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, Tübingen). For direct comparison to single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrial endometrioid cancer. For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry (MS) based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes.</p><p><strong>Results: </strong>DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors.</p><p><strong>Conclusions: </strong>The integrated proteogenomic data show that SEOCs are distinguishable from endometrial endometrioid or endometrioid ovarian cancers. Based on their proteogenomic similarity to endometrial endometrioid cancers, we conclude that most synchronous endometrial and ovarian cancers represent primary endometrial endometrioid cancers that have metastasized to the ovary.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718045","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}