Clinical Cancer Research最新文献

{"title":"Phase 1 trial of selinexor in pediatric recurrent/refractory solid and CNS tumors (ADVL1414): A Children's Oncology Group Phase 1 Consortium Trial.","authors":"Adam L Green, Charles G Minard, Xiaowei Liu, Stephanie L Safgren, Kerice Pinkney, Lauren Harris, Gabrielle Link, John DeSisto, Stephan Voss, Marvin D Nelson, Joel M Reid, Elizabeth Fox, Brenda J Weigel, Julia Glade Bender","doi":"10.1158/1078-0432.CCR-24-2754","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2754","url":null,"abstract":"<p><strong>Background: </strong>Selinexor is a first-in-class, central nervous system (CNS)-penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880).</p><p><strong>Methods: </strong>A rolling-six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics (PK) of selinexor administered once (QW, 35-45 mg/m2) or twice (BIW, 20-35 mg/m2) weekly during a 28-day cycle (Part A). Ten additional patients with high-grade glioma (HGG) were treated at the QW MTD (Part B).</p><p><strong>Results: </strong>In Part A, 49 patients were enrolled. Continuous BIW dosing was limited by extended hematologic toxicity. The MTD on a BIW schedule for three weeks on/one-week off (BIW 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and AST/ALT increase. On a continuous QW schedule, the MTD was 35 mg/m2/dose, DLTs included seizure and thrombocytopenia. In Part B (HGG expansion), there were no additional DLTs observed. Non-dose-limiting toxicity included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range 1-9); Eight of 59 patients (13.5%) received 5-9 cycles, five of whom had HGG.</p><p><strong>Conclusions: </strong>Selinexor-related toxicities were primarily hematologic and neurologic requiring dose or dose-frequency reduction. The MTD and recommended initial phase 2 dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose QW.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491006","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":"ESR1 Y537S and D538G mutations drive resistance to CDK4/6 inhibitors in estrogen receptor-positive breast cancer.","authors":"Chang-Ching A Lin, María Rosario Chica-Parrado, Nisha Unni, Ellen Jaeger, Yisheng V Fang, Lei Guo, Fabiana Napolitano, Pamela Luna, Michelle Harris, Calvin Chao, Lin Xu, Carlos L Arteaga, Ariella B Hanker","doi":"10.1158/1078-0432.CCR-24-2307","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2307","url":null,"abstract":"<p><strong>Purpose: </strong>Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. In this study, we aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation.</p><p><strong>Patients and methods: </strong>A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (tumor tissue: 1,070; ctDNA: 1,885) or CDK4/6i naïve (tumor tissue: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i palbociclib in vitro and in vivo.</p><p><strong>Results: </strong>In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in patients who received CDK4/6i compared to those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib.</p><p><strong>Conclusions: </strong>We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482126","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":"Update on Retinoblastoma Predisposition and Surveillance Recommendations for Children.","authors":"Junne Kamihara, Jaclyn Schienda, Rose B McGee, Danielle Novetsky Friedman, Surya P Rednam, Jack J Brzezinski, Sun Young Kim, Kerri D Becktell, Philip J Lupo, Brenda L Gallie, Mary-Louise C Greer, Jordan R Hansford, Garrett M Brodeur","doi":"10.1158/1078-0432.CCR-24-3271","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3271","url":null,"abstract":"<p><p>Hereditary retinoblastoma is a classic cancer predisposition syndrome with risks beginning in early infancy. About 45% of children with retinoblastoma (RB) have hereditary disease. These children are at risk for both intraocular disease as well as additional neoplasms throughout their lifetime. Germline pathogenic variants (GPVs) in RB1 typically lead to bilateral intraocular disease, elevated risks of trilateral RB, and risks of subsequent malignant neoplasms (non-ocular tumors), especially sarcomas and melanomas. There is further increased risk of subsequent malignant neoplasms if radiation treatment is used. Herein, with a reconvening of the AACR Childhood Cancer Predisposition Workshop, we expand on strategies for identifying individuals with hereditary RB, with a focus on testing strategies for children with RB. We also provide updates from previous recommendations. Given the high penetrance of retinal tumors, we review the importance of close intraocular surveillance and consider recent data regarding surveillance for subsequent malignant neoplasms. Finally, we discuss the importance of counseling for survivors of intraocular disease to address risks of adult-onset tumors as well as to consider reproductive risks.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491008","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":"Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatin in patients with HER2-negative BC and HRD -long-term survival of the GeparOLA study.","authors":"Peter A Fasching, Sabine Schmatloch, Jan Hauke, Julia Rey, Christian Jackisch, Peter Klare, Theresa Link, Claus Hanusch, Jens Huober, Andrea Stefek, Johannes Holtschmidt, Andreas Schneeweiss, Christoph Uleer, Wolfgang D Schmitt, Gabriele Doering, Kerstin Rhiem, Carsten Denkert, Rita K Schmutzler, Christine Solbach, Eric Hahnen, Andreas Hartkopf, Michael Untch, Vesna Bjelic-Radisic, Valentina Nekljudova, Jens-Uwe Blohmer, Sibylle Loibl","doi":"10.1158/1078-0432.CCR-24-2806","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2806","url":null,"abstract":"<p><strong>Backgound: </strong>The GeparOLA study evaluated paclitaxel(P) plus olaparib(O) in neoadjuvant chemotherapy (NACT) for patients with HER2-negative early breast cancer (eBC) with homologous recombination deficiency (HRD). HRD was defined by high HRD-score or germline(g)/tumor(t) BRCA1/2 mutations (g/tBRCA1/2mut). Here, we report long-term outcome data.</p><p><strong>Patients and methods: </strong>GeparOLA (NCT02789332) was a randomized, multicenter, prospective, open-label, phase II trial. Patients with HER2-negative eBC, HRD, indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and triple-negative[TN]BC or cT1c and Ki-67>20%), were randomly assigned to P+O or P+carboplatin(Cb), both followed by epirubicin+cyclophosphamide(EC). Long-term efficacy endpoints were secondary endpoints and included invasive disease-free survival(iDFS), distant disease-free survival(DDFS) and overall survival(OS).</p><p><strong>Results: </strong>Between 09/2016 and 07/2018, 107 patients were randomized and 106 (PO N=69;PCb N=37) started treatment. The median age was 47.0 years; 35.8% had cT1 tumors; 31.4% were cN+; 86.8% had G3 tumors; 89.6% had Ki-67>20% and 72.6% were TN. After median follow-up of 49.8 months, 18(15 PO; 3 PCb) iDFS events and 7(6 PO; 1 PCb) deaths were reported. The 4-year iDFS (76.0%PO vs 88.5%PCb, HR=2.86 [95%CI 0.83-9.90],log-rank p=0.081), DDFS (81.2%PO vs 93.4%PCb, HR=3.03 [95%CI 0.67-13.67],log-rank p=0.129) and OS (89.2%PO vs 96.9%PCb, HR=3.27 [95%CI 0.39-27.20],log-rank p=0.244) tended to be inferior with O. Patients without g/tBRCA1/2mut benefited from Cb [7/30 patients had iDFS/DDFS events in PO vs 0/16 in PCb].</p><p><strong>Conclusion: </strong>For HER2-negative eBC with HRD, olaparib showed a tendency for inferior outcomes compared to carboplatin, particularly in patients without g/tBRCA1/2mut. In patients with g/tBRCA1/2mut olaparib may replace carboplatin.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491003","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":"Germline pathogenic DROSHA variants are linked to pineoblastoma and Wilms tumor predisposition","authors":"Peter N. Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y. Lin, Angshumoy Roy, Allison Pribnow, Melissa R. Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A. Jackson, Mark M. Sasaki, Trent Fowler, Anita Ng, Ryan J. Corbett, Rebecca S. Kaufman, Jeremy S. Haley, David J. Carey, Kuan-lin Huang, Sharon J. Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B. McGee, Joshua D. Schiffman, Kenneth S. Chen, Douglas R. Stewart, D. Williams Parsons, Sharon E. Plon, Kris Ann P. Schultz, Kenan Onel","doi":"10.1158/1078-0432.ccr-24-2785","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2785","url":null,"abstract":"Purpose: DROSHA, DGCR8, and DICER1 regulate microRNA biogenesis and are commonly mutated in cancer. Whereas DGCR8 and DICER1 germline pathogenic variants (GPVs) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n=8) or Wilms tumor (WT, n=1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing altered-1 (PB-miRNA1) subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875-1:4,843, but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and WT are also associated with DICER1 GPVs, our results suggest the tissues-of-origin for these tumors are uniquely tolerant of general microRNA loss. The PB-miRNA1 pineoblastoma subtype is associated with older age of diagnosis and better outcome than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, WT, or other DICER1/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477777","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":"Pembrolizumab with chemotherapy for patients with recurrent or metastatic nasal cavity and paranasal sinus squamous cell carcinoma: A prospective phase ll study.","authors":"Yuquan Qian, Le Tang, Jiarui Yao, Yiming Zhu, Ye Zhang, Haizhen Lu, Weihua Li, Changming An, Lin Gui","doi":"10.1158/1078-0432.CCR-24-4148","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4148","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with recurrent or metastatic sinonasal squamous cell carcinoma (R/M SNSCC) lack standardized systemic treatment and prospective studies. We evaluated the anti-tumor response and safety of pembrolizumab with nab-paclitaxel and platinum in R/M SNSCC.</p><p><strong>Patients and methods: </strong>R/M SNSCC patients received pembrolizumab 200mg, nab-paclitaxel 260mg/m2 plus cisplatin 75 mg/m2 or carboplatin at an area under the curve 5 on day 1 every 21 days for up to six cycles, followed by pembrolizumab maintenance until progression or unacceptable toxicity or 35 cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Immunohistochemistry and high-resolution sequencing of the tumor samples were performed.</p><p><strong>Results: </strong>The ORR in 20 patients was 60.0% (95% CI: 36.1%-80.9%) and two patients (2/20, 10%) achieved CR. The DCR was 100%. Median follow-up was 18.1 months (range:5.2-31.7), the median PFS was 12.2 months (95% CI: 9.0 months-not estimated) and the median OS was not reached. Patients with PD-L1 CPS ≥20 exhibited better ORR (80.0% vs 28.6%, p=0.144), median PFS (not reached vs 7.0 months, p=0.0137), and median OS (not reached vs 17.8 months, p=0.0401) compared to those with PD-L1 CPS < 20. Grade 3/4 treatment-related adverse events (AE) accounted for 30.0% (6/20), and all come from hematologic toxicity. Hypothyroidism was the most common immune-related AE (12/20, 60.0%).</p><p><strong>Conclusions: </strong>Pembrolizumab plus nab-paclitaxel and platinum shows promising antitumor activity and manageable safety in first-line R/M SNSCC patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482243","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 Systematic Review with a Demonstrative Case of KIT and DOG-1 Expressing Gastrointestinal Stromal Tumors Harboring ETV6-NTRK3 Fusions.","authors":"Tannaz Ranjbarian, Mark Antkowiak, Robert J Mallory, Terence M Doherty, Mojgan Hosseini, Jill P Mesirov, Paul T Fanta, Jason K Sicklick","doi":"10.1158/1078-0432.CCR-24-3203","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3203","url":null,"abstract":"<p><strong>Introduction: </strong>Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GISTs) in cases lacking KIT, PDGFRA, RAS-pathway, or SDHx alterations. However, some investigators have questioned the rigor of these reports and the true existence of NTRK rearrangements in GIST. This study aims to: 1) resolve whether NTRK gene rearrangements exist in GIST; 2) review the relevant literature; and 3) demonstrate a case of NTRK fusion GIST.</p><p><strong>Methods: </strong>A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an IRB-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic CLIA-certified testing, precision-matched therapy, surgical resection, and pathological analysis.</p><p><strong>Results: </strong>We identified 17 reported cases of GIST with NTRK fusions. Five studies reported GIST with KIT/DOG-1 expression by IHC, wild-type KIT/PDGFRA, and an ETV6-NTRK3 fusion, consistent with GIST. We demonstrate a case of a 72-year-old female status post resection of a high-risk gastric GIST followed by 45 months of adjuvant imatinib. She developed recurrent disease and biopsy revealed mixed epithelioid and spindleoid GIST with IHC expression of KIT (CD117) and DOG-1. Imatinib was re-initiated, but her disease progressed, prompting molecular testing for the first time. RNA sequencing identified an in-frame fusion of ETV6 with NTRK3. Larotrectinib, a pan-NTRK inhibitor, was initiated for 7 months, resulting in shrinkage in five tumors (range: 4.2-77%). Surgical cytoreduction demonstrated a pathological near complete response (1% viable tumor cells).</p><p><strong>Conclusion: </strong>Our findings confirm the existence of ETV6-NTRK3 fusion GIST and demonstrate that these imatinib-resistant GISTs may be exquisitely sensitive to TRK.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481840","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":"Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma.","authors":"Sung Won Chung, Jin Sun Kim, Won-Mook Choi, Jonggi Choi, Danbi Lee, Ju Hyun Shim, Young-Suk Lim, Han Chu Lee, Kang Mo Kim","doi":"10.1158/1078-0432.CCR-24-1228","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1228","url":null,"abstract":"<p><strong>Purpose: </strong>A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved.</p><p><strong>Experimental design: </strong>This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n=62, combination group) and those who received lenvatinib monotherapy (n=137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic condition.</p><p><strong>Results: </strong>Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.24-0.59; P<0.001) and progression-free survival (aHR, 0.41; 95% CI, 0.26-0.64; P<0.001) in the combination group compared to the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the MDM2-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.</p><p><strong>Conclusions: </strong>The combination of lenvatinib and TACE significantly improved survival in HCC patients. The mechanistic foundation appears to be the lenvatinib-triggered degradation of HIF-1α via the MDM2-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482244","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":"Validation of a digital pathology-based multimodal artificial intelligence biomarker in a prospective, real-world prostate cancer cohort treated with prostatectomy","authors":"Anders Bjartell, Agnieszka Krzyzanowska, Vinnie Y.T. Liu, Meghan Tierney, Trevor J. Royce, Martin Sjöström, Marisol Macarena Palominos-Rivera, Emmalyn Chen, Alexandra Kraft, Andre Esteva, Felix Y. Feng","doi":"10.1158/1078-0432.ccr-24-3656","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3656","url":null,"abstract":"Purpose: A multimodal artificial intelligence (MMAI) biomarker was developed using clinical trial data from North American men with localized prostate cancer (PCa) treated with definitive radiation, using biopsy digital pathology images and key clinical information (age, PSA, T-stage) to generate prognostic scores. This study externally validates the biomarker in a prospective, real-world dataset of men who underwent radical prostatectomy (RP) for localized PCa at a tertiary referral center in Sweden. Experimental Design: Association between the MMAI scores (continuously and categorically) and endpoints of interest were performed with Fine-Gray and cumulative incidence analyses for biochemical recurrence (BCR) and logistic regression for adverse pathology (AP) at RP. Results: The analysis included 143 patients with evaluable biopsy pathology images and complete clinical data to generate MMAI scores. Median follow-up was 8.8 years. At diagnosis, median PSA was 7.5 ng/mL, median age 64 years, 29% had Gleason grade group ≥3, and 88 men were evaluable for AP at RP. MMAI was significantly associated with BCR (subdistribution HR 2.45 [95% CI 1.77-3.38], p&amp;lt;0.001) and AP at RP (OR 4.85 [95% CI 2.54-10.78], p&amp;lt;0.001). Estimated 5-yr BCR rates for MMAI Intermediate-High vs Low were 25% (95% CI 16%-36%) vs 4% (95% CI 1%-11%), respectively. Conclusions: The MMAI biomarker, previously shown to be prognostic for distant metastasis and prostate cancer-specific mortality in men receiving definitive radiation, was prognostic for post-RP endpoints: BCR and AP. This biomarker validation study further supports the use of MMAI biomarkers in men with PCa outside North America and those treated with RP.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"50 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470665","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":"Timing of circulating tumor DNA analysis aimed at guiding adjuvant treatment in colorectal cancer.","authors":"Tenna V Henriksen, Christina Demuth, Amanda Frydendahl, Jesper Nors, Marijana Nesic, Mads H Rasmussen, Ole H Larsen, Claudia Jaensch, Uffe S Løve, Per V Andersen, Thomas Kolbro, Ole Thorlacius-Ussing, Alessio Monti, Jeppe Kildsig, Peter Bondeven, Nis H Schlesinger, Lene H Iversen, Kåre A Gotschalck, Claus L Andersen","doi":"10.1158/1078-0432.CCR-24-3200","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3200","url":null,"abstract":"<p><strong>Background: </strong>Multiple clinical trials investigate circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy (ACT) in colorectal cancer. Timely ACT initiation necessitates early ctDNA testing, but the impact of postoperative cell-free DNA (cfDNA) and ctDNA dynamics remains unclear, particularly with cost-reducing input caps employed in some assays. This study investigates ctDNA detection at day14 versus day30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation.</p><p><strong>Patients and methods: </strong>In 2019-2023, 611 stage I-III colorectal cancer patients were enrolled. Blood was collected preoperatively, and postoperatively ~day14 and ~day30. The cfDNA levels were assessed using digital PCR, and ctDNA using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8mL of plasma.</p><p><strong>Results: </strong>Despite elevated cfDNA in 85% of day14 samples, performance was comparable between the two timepoints (sensitivity 31% vs 32%; specificity both 98%). A 50ng cfDNA input cap reduced ctDNA detection probability, impacting 78% of day14 samples and 65% of day30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day14: HR=9.0, 95%CI 5.5-14.8; day30: HR=12.5, 95%CI 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in ctDNA level from day14 to day30 was associated with shorter time to recurrence (Pearson R=-0.63, P=0.003). Combining the timepoints would increase sensitivity (36%) and allow earlier ACT start in 80% of patients.</p><p><strong>Conclusion: </strong>Early ctDNA sampling is feasible and highly prognostic. Supplemental later testing may improve sensitivity while allowing early ACT initiation for most ctDNA positive patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457075","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}