Clinical Cancer Research最新文献

{"title":"LRP1B loss predicts sensitivity to immunotherapy in patients with NSCLC: an analysis of the phase 3 Checkmate 026 randomized trial.","authors":"Andrew J Armstrong,Hilary Dietz,David Balli,William J Geese,Chunzhe Duan,Yu-Han Hung,Virginia Ip,Gerald Li,Ryon P Graf,Neal Ready","doi":"10.1158/1078-0432.ccr-25-0952","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0952","url":null,"abstract":"PURPOSELow-density lipoprotein receptor-related protein 1b (LRP1b) is a cell surface receptor, commonly altered in many cancers and associated with improved responses, progression free survival (PFS) and overall survival (OS) with immune checkpoint inhibition (ICI).EXPERIMENTAL DESIGNLRP1b alterations were determined by whole exome sequencing (WES) and associated with PFS and objective response rates (ORR) in patients with non-small cell lung cancer (NSCLC) in post-hoc analysis of the randomized controlled phase 3 Checkmate-026 trial (CM026, NCT02041533) examining chemotherapy vs nivolumab, adjusting for tumor mutational burden (TMB) and clinical features. We separately evaluated a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) for associations of LRP1b alterations and progression-free survival with anti-PD-1 immunotherapy.RESULTSIn the CGDB cohort of patients with NSCLC (N=18,369), LRP1b mutations were positively associated with TP53/KRAS alterations and inversely with EGFR/RET/MET/ERBB2 alterations and significantly improved PFS with PD-1 inhibition (n=1569, adjusted HR 0.86 p=0.014). In CM026, patients with LRP1b alterations had a statistically significant improvement in ORR to nivolumab vs. LRP1b wild-type (wt) patients (odds ratio 3.5; 95% CI 1.71-7.13; p=0.0006) but not with chemotherapy (odds ratio 0.63; 95% CI 0.32-1.26; p=0.19), adjusting for TMB, age, gender, histology, smoking and performance status. LRP1b mutations were associated with improved PFS with nivolumab (HR 0.66, p=0.04) but not chemotherapy (HR 1.26, p=0.25), also maintained in multivariate and TMB adjusted analysis.CONCLUSIONSLRP1b mutations are a candidate predictive biomarker for ICI vs. chemotherapy in NSCLC. Further mechanistic characterization of LRP1b and prospective validation are warranted, and might enable future clinical use.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246874","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":"Elraglusib, a glycogen synthase kinase-3β (GSK-3β) inhibitor, plus chemotherapy with or without immunotherapy in patients with recurrent, metastatic salivary gland carcinoma.","authors":"Glenn J Hanna,Nicole Scarfo,Kee-Young Shin,Anne O'Neill,Veronica Bedard,Michael J Dennis,Kartik Sehgal,Vickie Y Jo,Kristine Wong,Andrey Ugolkov,Andrew Mazar,Robert I Haddad","doi":"10.1158/1078-0432.ccr-25-2731","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2731","url":null,"abstract":"BACKGROUNDGSK-3b is a known therapeutic target in cancer. Aberrant nuclear GSK-3β (nGSK-3β) expression has been shown in some salivary gland cancers (SGC). Elraglusib is a small molecule GSK-3β inhibitor with immunomodulatory potential. We hypothesized that elraglusib plus platinum-based chemotherapy and immunotherapy priming would be a novel treatment approach for SGC.DESIGNThis phase 2, open-label trial enrolled patients with recurrent or metastatic SGC (adenoid cystic carcinoma [ACC] vs. other subtypes) with disease progression in the preceding year. Cohort 1 received elraglusib (15 mg/kg IV on days 1, 4) plus carboplatin (AUC 5) or cisplatin (75 mg/m2) every 21-days. Cohort 2 received 2-cycles of pembrolizumab (200 mg IV) every 21-days prior to the same regimen.PRIMARY ENDPOINTbest overall response rate (ORR) by RECIST 1.1 (>5/32 in response to detect 25% ORR).RESULTSThirty-two patients enrolled, 15 (47%) with ACC and 17 (53%) with non-ACC. Best ORR was 9.4% (3/32; 95%CI, 2-25) (3 partial responses, all non-ACC). Nineteen (59%) patients achieved stable disease. Median duration of response: 6.9 months. Common treatment-related adverse events: anemia (22, 69%), nausea (16, 50%), and neutropenia (14, 44%). At median follow-up of 18.3 months, median PFS: 6.4 months (95%CI, 2.3-8.8) and median OS: 18.6 months (95%CI, 9.7-29.4) overall. Median nGSK-3β expression was 50% vs. 2% for responders vs. non-responders.CONCLUSION(S)The trial did not meet its primary endpoint, though 18% of non-ACC patients treated with immune priming followed by cisplatin plus elraglusib achieved response. Higher nGSK-3β expression was observed in tumor samples from responders.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"60 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246872","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":"The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial.","authors":"Alison M Schram,Abdul Rafeh Naqash,Eric B Haura,Jonathan W Riess,Susanna V Ulahannan,Sai-Hong I Ou,Pamela N Munster,Michael L Cheng,W Clay Gustafson,Bojena Bitman,Robert Friedman,Ruth Penn,Sumit Kar,Vidya Seshadri,Zhican Wang,Lin Tao,Yu Chi Yang,Mallika Singh,Howard A Burris,Justin G Meyerowitz","doi":"10.1158/1078-0432.ccr-25-2112","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2112","url":null,"abstract":"PURPOSEPI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTORC1-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates 4EBP1 and S6K, and exhibits selectivity for mTORC1 over mTORC2. Here, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952).PATIENTS AND METHODSThe safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg IV infusion weekly) were evaluated in 57 patients.RESULTSThe most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Consistent with mTORC1 selectivity, treatment-related hyperglycemia incidence was generally low (4%) and not dose limiting. Additionally, we tested potential prophylaxis with tacrolimus mouthwash (TM), which was predicted to block the mechanism of action of RMC-5552 locally and alleviate treatment-related oral mucositis. Between 8- to 12-mg dosing, mucositis was 65% without TM versus 31% with TM. In this study, the disease-control rate was 64%, and one patient with PTEN and PIK3CA-altered endometrial cancer had a complete response and treatment ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among circulating tumor DNA was observed.CONCLUSIONSThe success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses, and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240903","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":"BET bromodomain inhibition reverses CDK4/6 inhibitor resistance in estrogen receptor-positive breast cancer via induction of miR-34a-5p.","authors":"Renyan Liu,Xin Wang,Timothy B Branigan,Daryl Griffin,Caoibhne McSweeney,Jie Hao,Constantia Pantelidou,Zachary T Herbert,Heta Jadhav,Geoffrey I Shapiro","doi":"10.1158/1078-0432.ccr-25-1406","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1406","url":null,"abstract":"PURPOSECDK6 overexpression is one critical determinant of acquired CDK4/6 inhibitor resistance. Because BRD4 is recruited to the CDK6 promoter, we investigated the potential of bromodomain and extra-terminal domain (BET) inhibition to reverse CDK4/6 inhibitor resistance.EXPERIMENTAL DESIGNCell viability and survival assays and cell line xenografts were utilized to evaluate BET inhibition in palbociclib-resistant breast cancer cells. Vehicle- and BET inhibitor-treated cells were subjected to RNA sequencing. CDK6 promoter activity was assessed with luciferase assays, and the miRPathDB V2.0 database was used to identify potential miRNAs mediating the effects of BET inhibition. Experiments were conducted to determine whether continued palbociclib treatment is essential for BET inhibitor efficacy and to explore associated mechanisms.RESULTSIn CDK4/6 inhibitor-resistant models overexpressing CDK6, a cell cycle gene signature was differentially downregulated following BET inhibition. The BET inhibitors JQ1 and ZEN-3694 reduced the expression of CDK6 and cyclin D1, reinstated CDK4/6 inhibitor-induced cell cycle arrest, and triggered apoptosis in vitro, as well as tumor regression in vivo. Mechanistically, BET inhibition downregulated CDK6 expression through the induction of miR-34a-5p, rather than by directly repressing the CDK6 promoter. Introduction of a miR-34a-5p inhibitor abrogated BET inhibitor-mediated molecular changes, whereas a miR-34a-5p mimic replicated the effects of BET inhibition. Lastly, resistant cells exhibited downregulation of BCL-2 in the presence of continued palbociclib, associated with reduced ER⍺ expression, facilitating sensitivity to BET inhibition.CONCLUSIONSOur findings highlight BET inhibition or application of miR-34a-5p mimics as promising strategies to reverse CDK4/6 inhibitor resistance in a subset of ER+ breast cancers.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241052","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":"Amphiregulin as a Mediator of Radiation-Induced Systemic Effects in Metastatic Cancer: Balancing Local Control with Distant Progression.","authors":"András Piffkó,Sean P Pitroda,Hua Laura Liang,Ralph R Weichselbaum","doi":"10.1158/1078-0432.ccr-25-2598","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2598","url":null,"abstract":"Metastasis-directed therapies such as stereotactic body radiotherapy (SBRT) are increasingly employed in metastatic cancer patients with limited disease burden. While effective for local control, emerging evidence suggests SBRT may have unintended systemic effects that reshape the tumor-immune landscape. A recent study identifies amphiregulin (AREG), an EGFR ligand, as a key mediator of radiation-induced changes in metastatic behavior. In clinical cohorts and murine models, SBRT led to marked AREG upregulation. Rather than promoting tumor cell proliferation directly, AREG acted through the myeloid compartment, inducing monocyte differentiation into immunosuppressive macrophages and enabling immune escape. Elevated AREG-either at baseline or following SBRT-was associated with increased metastatic progression and inferior survival. Mechanistically, AREG signaling induced CD47 expression on tumor cells, further impairing macrophage-mediated clearance. Therapeutically, AREG blockade, especially combined with anti-CD47 antibodies, synergized with radiotherapy to suppress both local and distant disease in preclinical models. These findings reveal both challenges and opportunities: while radiation effectively suppresses new metastatic seeding, it may reorganize the biological ecosystem in ways that unmask dormant disease. Understanding these dual effects offers therapeutic opportunities through combination approaches targeting radiation-induced pathways. AREG emerges as both a biomarker and therapeutic target. Integrating biomarker-informed strategies with metastasis-directed therapies may be essential for achieving durable disease control and optimizing outcomes in metastatic cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"104 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229001","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":"Pilot Study of Daily Exemestane in Women with Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer","authors":"Britt K. Erickson, Howard Bailey, Rebecca C. Arend, Dina El-Rayes, Mahmoud A. Khalifa, Amy Skubitz, Kristin Boylan, Andrew C. Nelson, Anna Burton, Bharat Thyagarajan, Thomas Havighurst, KyungMann Kim, Eileen Dimond, Katina DeShong, Brandy Heckman-Stoddard, Goli Samimi, Eva Szabo, Lisa Barroilhet","doi":"10.1158/1078-0432.ccr-25-1878","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1878","url":null,"abstract":"Objective: To evaluate exemestane, an aromatase inhibitor, as a preventive intervention for endometrial cancer. Methods: This is a multi-center, single-arm, ‘window of opportunity’ pilot study of exemestane (25 mg daily for 21-42 days) in postmenopausal individuals undergoing hysterectomy for endometrial intraepithelial neoplasia (EIN) or low-grade endometrial cancer (EC). The primary objective is to determine change in proliferation, measured by Ki-67 expression, in pre- and post-treatment endometrial tissues specimens. Secondary outcomes include measurement of circulating serum estradiol and progesterone levels, pathologic response, tissue biomarkers, safety, and adverse effects. Results: Forty participants were accrued to the study. Preoperative diagnoses included EIN (n=11, 27.5%), grade 1 EC (n=26, 65%), and grade 2 EC (n=3, 7.5%). Median Ki-67 score decreased from 40.7% [IQR (33.9, 50.3)] at baseline to 18.1% [IQR (8.8, 31.8)] at surgery, representing a median absolute change of 20.4% [IQR (-29.9, -6.7), p<0.001]. In a matched historical control cohort, participants also had a decrease in Ki-67 score with a median absolute change from baseline of -6.7% [IQR (-12.7, -1.3), p 0.001]. However, the decrease in Ki-67 was greater in the study participants than the historic controls, with a median difference between the groups of -13.4% [IQR (-23.3, 6.9), p ]. Both tissue ER and PR expression declined significantly with exemestane treatment (p<0.001). However, serum estradiol levels did not change between baseline and post-treatment (p=0.16). Conclusion: In this pilot study, exemestane demonstrated anti-proliferative effects in endometrial intraepithelial neoplasia and low-grade endometrial cancer. This agent warrants further evaluation for the prevention of endometrial cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228973","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":"FDA-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Selecting Dosages for First-In-Human Trials","authors":"Hao Zhu, Alex N. Phipps, Ying Yuan, Brad A. Davidson, Stacy S. Shord, Jiang Liu, Patricia M. LoRusso","doi":"10.1158/1078-0432.ccr-25-0095","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0095","url":null,"abstract":"Dosage optimization has become a focus in oncology drug development, as highlighted by recent U.S. Food and Drug Administration initiatives including Project Optimus. Traditionally, most oncology drug development programs identify a maximum tolerated dosage and advance this dose in subsequent clinical trials and premarket applications. This approach has been routinely applied for cytotoxic chemotherapeutics, where higher dosages generally yield more efficacy as well as toxicity. However, it is less suited for the more targeted pharmacology of modern oncology drugs, where excessive escalation may only add additional toxicity. Instead, paradigms that utilize the totality of data accumulated throughout drug development can better determine optimized dosages that minimize the risk of underdosing, leading to exposure to subtherapeutic dosages, and overdosing, leading to unnecessary toxicities. Appropriate selection of dosing in first-in-human (FIH) trials is crucial, as it facilitates the efficient identification of optimized doses for subsequent trials. Nonclinical research and clinical data from previous trials can inform both FIH dosage selection and trial design. When background data is lacking, modeling and simulation techniques have been developed to integrate information to determine rational starting dose. Additionally, innovative model-informed clinical trial designs allow for statistically guided dose escalation and recommendation, and can be updated in real time to maximize potential patient benefit within the FIH trial. Unfortunately, these techniques remain underutilized. Here, in this first paper in a series of three discussing innovative strategies for dosage optimization, we highlight expectations and provide suggestions for the future of dosage selection and optimization in FIH oncology trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202994","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":"FDA-AACR Strategies for Optimizing Dosages for Oncology Drug Products: Early Phase Trials Using Innovative Trial Designs and Biomarkers","authors":"Olanrewaju O. Okusanya, Gabriela I. Patilea-Vrana, Anthony Sireci, Alexia Iasonos, Brad A. Davidson, Jiang Liu, Stacy S. Shord, Patricia M. LoRusso, Timothy A. Yap","doi":"10.1158/1078-0432.ccr-25-1918","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1918","url":null,"abstract":"Dosage selection for oncology drugs has traditionally relied on initial dose-finding trials to determine a maximum tolerated dose (MTD), which is then further evaluated in approval-supporting registrational trials. While this approach may have established optimized dosages for cytotoxic chemotherapeutics, many modern oncology drugs developed through this approach have been poorly optimized, requiring additional dosage optimization efforts in the post-market setting. Recent initiatives of the U.S. Food and Drug Administration outline the unsustainability of this approach, instead recommending the identification of a potentially optimized dosage at earlier stages through direct comparison of multiple dosages before marketing application submission. The selection of dosages for further investigation outside of the MTD requires fit-for-purpose techniques that address the specific promises and concerns of the drug under investigation. Although such strategies have been developed, they are currently rarely applied in favor of the MTD paradigm. Innovative trial elements, including various integral, integrated, and exploratory biomarkers as well as backfill and randomized dose expansion cohorts represent potential avenues to create and leverage additional data, and thereby make more informed dosing decisions. Additionally, modeling approaches such as clinical utility index can integrate these disparate datatypes into a single metric, facilitating more quantitative selection. This article, the second in a series of three articles addressing different stages of dose optimization, outlines best practices and areas for further development regarding innovative techniques for the selection of dosages for further evaluation prior to final dosage selection for registrational trials in oncology.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203654","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":"Radiogenomic profiling of prostate tumors prior to external beam radiotherapy converges on a transcriptomic signature of TGF-β activity driving tumor recurrence","authors":"Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L.K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin","doi":"10.1158/1078-0432.ccr-25-2186","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2186","url":null,"abstract":"Purpose: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies. Experimental Design: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n=60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI (mpMRI) at baseline and 6 months post-treatment, with median follow-up of 6 years. Gene expression differences between patients with and without BCR were analyzed using pathway tools and validated in external datasets. A novel TGF-β gene signature was derived and tested across multiple cohorts (median follow-up: 5–11 years). Results: TGF-β activity was significantly associated with BCR in the discovery cohort (P = 0.0081), and correlated with PTEN/TP53 alterations (P = 0.0246) and baseline mpMRI tumor volume (P = 0.026). TGF-β activity also predicted metastasis-free survival (P = 0.037), and in an independent cohort (n=265) was prognostic for BCR-free (P = 0.05), metastasis-free (P < 0.001), and overall survival (P < 0.001). Conclusions: TGF-β activity is a dominant feature of intermediate-to-unfavorable risk prostate tumors prone to biochemical failure after EBRT with ADT and may serve as an independent prognostic biomarker beyond existing clinical criteria.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203137","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":"Supplementation of Tamoxifen with low-dose Endoxifen in breast cancer patients with impaired tamoxifen metabolism (TAMENDOX): a randomized controlled phase 1/2 trial","authors":"Thomas E. Mürdter, Werner Schroth, Matthew P. Goetz, Roman Tremmel, Svitlana Igel, Elke Schaeffeler, Simon Jäger, Sibylle Loibl, Andreas Gerteis, Lena Pfaff, Christina Bechtner, Denise Wrobel, Ilka Bernhöft, Imma Fischer, Christoph Meisner, Michael Block, Hiltrud Brauch, Matthias Schwab","doi":"10.1158/1078-0432.ccr-25-2103","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2103","url":null,"abstract":"Purpose: Tamoxifen undergoes bioactivation to its active metabolite (Z)-endoxifen, which blocks estrogen-dependent breast tumor growth at high potency. We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in breast cancer patients with compromised tamoxifen bioactivation. Patients and Methods: We conducted a prospective, interventional, three group randomized trial including 235 hormone receptor-positive breast cancer patients who received standard tamoxifen therapy (20mg/day). Patients were stratified by CYP2D6 genotype (n=78), defining poor (PM), intermediate (IM) and normal metabolizers (NM), or by baseline (Z)-endoxifen plasma concentration (n=78), defining ≤15 nM, 15-25 nM and ≥25 nM. Co-treatment with (Z)-endoxifen 3, 1.5 mg/day or placebo was performed, respectively. A control group (n=79) received placebo regardless of metabolizer phenotype. The primary endpoint was the number of patients with (Z)-endoxifen levels >32 nM after six weeks treatment. Adverse events were continuously monitored. Results: A higher proportion of patients in both intervention groups achieved target concentrations >32 nM compared to control (P < 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 PM patients and all patients with baseline (Z)-endoxifen ≤15 nM achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 IM patients and 95% of patients with 15-25 nM baseline (Z)-endoxifen levels achieved the target concentration. Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced Grade 3 adverse events. Conclusion: Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized anti-estrogen treatment for patients with low endoxifen plasma levels.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202996","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}