Clinical Cancer Research最新文献

{"title":"YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers.","authors":"Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Hayato Kawachi, Masaki Ishida, Yohei Matsui, Soichi Hirai, Ryota Nakamura, Kenji Morimoto, Naoki Furuya, Sachiko Arai, Yasuhiro Goto, Yoshihiko Sakata, Kazumi Nishino, Michiko Tsuchiya, Akihiro Tamiya, Go Saito, Satoshi Muto, Takayuki Takeda, Koji Date, Yasuhito Fujisaka, Satoshi Watanabe, Daichi Fujimoto, Hisanori Uehara, Mano Horinaka, Toshiyuki Sakai, Seiji Yano, Shinsaku Tokuda, Koichi Takayama","doi":"10.1158/1078-0432.CCR-24-1762","DOIUrl":"10.1158/1078-0432.CCR-24-1762","url":null,"abstract":"<p><strong>Purpose: </strong>Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.</p><p><strong>Experimental design: </strong>Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion-positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes.</p><p><strong>Results: </strong>In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.</p><p><strong>Conclusions: </strong>The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment. See related commentary by Ortiz-Cuaran and Leonce, p. 958.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1127-1141"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567627","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":"Visualization of P2X7 Receptors in Living Human Gliomas: an 18F-GSK1482160 PET Imaging and Neuropatholopy Study","authors":"Weiyan Zhou, Qi Yue, Yifan Yuan, Qi Huang, Kun He, Tao Hua, Junbin Han, Yingfang He, Yihui Guan, Liang Chen, Fang Xie, Ying Mao","doi":"10.1158/1078-0432.ccr-24-2830","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2830","url":null,"abstract":"Purpose: PET imaging targeting the purinergic receptor subtype 7 (P2X7R) is of high interest for assessing glioma microenvironment. No reports were published regarding the P2X7R imaging in gliomas. Therefore, we compared the uptake characteristics of 18F-GSK1482160, a novel P2X7R ligand, to conventional 11C-MET PET and contrast-enhanced MRI in patients with gliomas. Experimental Design: Thirteen glioma patients (8 grade II, 5 grade III/IV) at initial diagnosis were consecutively included and underwent 18F-GSK1482160 PET, 11C-MET PET and MRI. The semi-quantitative analyses were performed in both 18F-GSK1482160 and 11C-MET PET images. Dynamic 18F-GSK1482160 PET analysis (n=8) generated parametric maps of binding potential (BPND) for the lesions. The tumor tissue was quantitatively assessed for P2X7R expression and infiltration of glioma associated microglia/macrophages (GAMs). Results: The multilinear reference tissue model (MRTM) was sufficient for quantifying 18F-GSK1482160. The SUVRmean for duration of 50-70min correlated best to mean BPND in the dynamic scan analysis. A strong linear relationship between the uptakes of 18F-GSK1482160 and 11C-MET was observed. The two tracers showed distinct spatial distribution by metabolic volume comparison, but were both associated with tumor grade and lesion contrast-enhancement status. IDH-wildtype gilomas tended to have higher tracer uptake for both tracers without reaching the level of significance. P2X7R in gliomas was expressed predominately by GAMs, and its expression exhibited positive correlation with uptake of 18F-GSK1482160 (r=0.7783, p=0.0029) in the tumors. Conclusions: The first-in-man study of P2X7R-PET demonstrated PET with 18F-GSK1482160 and 11C-MET provides complementary information characterizing tumor heterogeneity and the cellular composition of the microenvironment in untreated gliomas.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"90 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635147","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":"Enhancement of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma.","authors":"Yago Nieto, Jeremy Ramdial, Benigno Valdez, Peter F Thall, Roland Bassett, Melissa Barnett, Samer Srour, Chitra Hosing, Amin Alousi, Muzaffar Qazilbash, Uday Popat, Alison Gulbis, Terri Lynn Shigle, Sairah Ahmed, Maria Guillermo Pacheco, Richard Champlin, Elizabeth J Shpall, Borje S Andersson","doi":"10.1158/1078-0432.CCR-24-3544","DOIUrl":"10.1158/1078-0432.CCR-24-3544","url":null,"abstract":"<p><strong>Purpose: </strong>More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.</p><p><strong>Patients and methods: </strong>Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days -11 to -3, plus vorinostat (1,000 mg orally/day, days -10 to -3), gemcitabine (2,475 mg/m2/day i.v., days -8 and -3), busulfan (target AUC 4,000 µmol/L.minute-1/day i.v., days -8 to -5), melphalan (60 mg/m2/day i.v., days -3 and -2), and rituximab (CD20+ tumors; 375 mg/m2, day -10), with ASCT.</p><p><strong>Results: </strong>Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non-Hodgkin lymphoma); the median age was 35 years (range, 20-61); patients received a median of three prior lines of therapy (range, 2-7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12-56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively.</p><p><strong>Conclusions: </strong>In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"975-982"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969824","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 Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial.","authors":"Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach","doi":"10.1158/1078-0432.CCR-24-2310","DOIUrl":"10.1158/1078-0432.CCR-24-2310","url":null,"abstract":"<p><strong>Purpose: </strong>KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.</p><p><strong>Experimental design: </strong>Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.</p><p><strong>Results: </strong>KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: PFS 4.1 vs. 9.9 months, HR 2.7, P < 0.01; OS 5.4 vs. 19.0 months, HR 3.6, P < 0.01; STK11: PFS 4.2 vs. 11.0 months, HR 2.2, P < 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, P < 0.01]. KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between KEAP1 loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, P = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, P < 0.01) even in patients with KEAP1WT NSCLC. KEAP1WT/STK11WT/NRF2LOW status identified patients-32%-with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, P < 0.01; OS NR vs. 8.0 months, HR 0.1, P < 0.01).</p><p><strong>Conclusions: </strong>KEAP1, STK11, and NRF2 status define patients with KRASG12C-mutant NSCLC with markedly distinct outcomes to adagrasib. These results further support the use of genomic features-mutational and nonmutational-for the treatment selection of patients with KRASG12C-mutant NSCLC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1069-1081"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969827","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":"The dynamically evolving cell states and ecosystem from benign nevi to melanoma","authors":"Xin Li, Xiyuan Zhang, Shuang Zhao, Shiyao Pei, Jie Sun, Liang Dong, Xu Pan, Wenhua Wang, Hao Liu, Yaoxuan Huang, Teng Liu, Jinhai Deng, Chunlan Hu, Chao Lv, Juan Su, Mingzhu Yin, Xiang Chen","doi":"10.1158/1078-0432.ccr-24-2971","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2971","url":null,"abstract":"Purpose: Approximately 30% of non-chronically sun-damaged melanomas originate from nevi, yet the dynamic changes and crucial mechanisms driving the transition from benign nevi to melanoma remain elusive. Experimental Design: Here, we performed single-cell transcriptome sequencing on multiple paired tissue sites from 5 patients diagnosed with melanoma arising in congenital melanocytic nevi (CMN), identifying four distinct states of melanocyte subpopulations during the progression from nevi to melanoma, characterized by dynamic changes in their functions and regulatory pathways. Results: In the nevi state, interferon regulatory factor 1 (IRF1) was specifically upregulated in melanocytes, fibroblasts, and endothelial cells (ECs), potentially activating immune surveillance in the microenvironment. Conversely, the critical inhibitory checkpoint HLA-E for NK cells exhibited high expression in a cluster of malignant melanocytes and fibroblasts enriched in melanoma. This interaction with ligands expressed in NK cells could potentially serve as a key factor leading to immune evasion. In malignant melanoma samples, we detected high expression of Midkine (MDK) in melanocytes. It is a pivotal factor that facilitates melanoma invasion and malignant transformation, potentially through interaction with ECs to stimulate angiogenesis. The targets identified in our study are crucial factors in detecting the malignant transformation of nevi. Ultimately, we developed a malignant progression model capable of predicting patient prognosis and malignant progression status using bulk RNA sequencing (RNA-seq) data. Conclusions: Our study provides a high-resolution atlas of the malignant transformation of melanoma from nevi and highlights potential targets for further investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635280","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":"TOP-1 Priority: Advancing Biomarker-Driven Patient Selection for the use of ADCs","authors":"William R. Gwin, Sara A. Hurvitz","doi":"10.1158/1078-0432.ccr-25-0166","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0166","url":null,"abstract":"A recent study reports the emergence of TOP1 mutations as a potential mechanism of resistance to topoisomerase inhibitor-ADCs in advanced breast cancer. This is a crucial first step in identifying biomarkers to guide ADC therapy selection and underscores the need for caution when sequencing ADCs with similar payloads.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"55 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143640638","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":"Protein profiles predict treatment responses to the PI3K inhibitor umbralisib in patients with chronic lymphocytic leukemia.","authors":"Yanping Yin, Haifeng Xu, Liye He, Jennifer R Brown, Anthony R Mato, Tero Aittokallio, Sigrid S Skånland","doi":"10.1158/1078-0432.CCR-24-2911","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2911","url":null,"abstract":"<p><strong>Purpose: </strong>The management of chronic lymphocytic leukemia (CLL) has significantly improved with targeted therapies. However, many patients experience a suboptimal response. To optimally select the best therapy, predictive biomarkers are necessary. Here, we used the PI3K inhibitor umbralisib as a model to (i) understand how targeted treatment affects cell signaling and immunophenotypes in responders and non-responders; (ii) identify molecular features that predict individual treatment responses; and (iii) suggest alternative treatment options for the non-responders.</p><p><strong>Experimental design: </strong>We performed functional phenotyping of CLL cells from patients enrolled in two clinical trials with umbralisib, administered either as a monotherapy (NCT02742090, n=55) or in combination with the BTK inhibitor acalabrutinib (NCT04624633, n=12).</p><p><strong>Results: </strong>We found that umbralisib monotherapy led to significant changes in (phospho)protein levels, including AKT (pS473), in responders but not in non-responders. Furthermore, the proportion of cytotoxic natural killer cells increased at the end of study, but only in responders, suggesting a role in the anti-tumor response. To identify molecular predictors of response, we used the baseline levels of 30 (phospho)proteins in the monotherapy cohort as input features for a machine learning model, which achieved a significant prediction accuracy in cross-validation and maintained its predictive power in the combination cohort. Drug sensitivity profiling of the CLL cells at baseline suggested that PI3K + Bcl-2 inhibitors are effective in umbralisib non-responders.</p><p><strong>Conclusions: </strong>Functional phenotyping reveals differential cellular responses to umbralisib treatment in responders and non-responders; predicts treatment response of individual CLL patients; and suggests alternative treatment options for the non-responders.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623693","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":"Mutational Landscape of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Association with Immune Checkpoint Inhibitor Outcome","authors":"Patricia McCoon, Ying Wang, Zhongwu Lai, Qu Zhang, Weimin Li, Sophie Wildsmith, Nassim Morsli, Rajiv Raja, Nicholas Holoweckyj, Jill Walker, Melissa de los Reyes, Ricard Mesía, Lisa Licitra, Robert L. Ferris, Jérôme Fayette, Dan P. Zandberg, Lillian L. Siu, Robert Haddad","doi":"10.1158/1078-0432.ccr-24-2198","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2198","url":null,"abstract":"Purpose: Understanding the mutational landscape of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is important in identifying biomarkers to determine which patients may benefit from immune checkpoint inhibitors (ICIs). Patients and Methods: The HAWK (NCT02207530), CONDOR (NCT02319044), and EAGLE (NCT02369874) studies evaluated R/M HNSCC treatment with durvalumab or durvalumab-tremelimumab. Tumor tissue samples pooled from HAWK/CONDOR (n=153) and plasma cell-free DNA samples from EAGLE (n=285) were analyzed to identify somatic alterations and association with survival. Results: The mutational landscape was similar in tissue and plasma. Compared with wild-type, TP53 mutations were associated with significantly shorter OS (HR; 95% CI) with standard of care (SoC; 2.12; 1.20–3.78 EAGLE) and ICIs (1.49; 1.05–2.12; HAWK/CONDOR and 1.44; 0.99–2.10; EAGLE). In EAGLE, patients with TP53 mutations had significantly longer OS with durvalumab-tremelimumab versus SoC (P = 0.045). KMT2D mutations were associated with a trend towards longer OS (HR; 95% CI) versus wild-type in HAWK/CONDOR (0.81; 0.56–1.19), and a trend towards longer OS with ICIs versus SoC in EAGLE. For both mutations, an ECOG performance status of 1 was associated with worsened OS, and PD-L1 positivity was associated with improved OS. Conclusions: This is the first large-scale study to show the mutational landscape of R/M HNSCC and its association with clinical outcomes in patients treated with ICIs or SoC. TP53 mutation was a negative prognostic marker, however, treatment with durvalumab-tremelimumab significantly improved survival over SoC. Further investigation of KMT2D as a predictive biomarker for immunotherapy in R/M HNSCC is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618365","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 Diagnostic Utility of Washout CYFRA 21-1 in Lymph Node Metastasis of Thyroid Cancer.","authors":"Jeongmin Lee, Yuri Shin, Jeongun Kwak, Hye Lim Park, Sohee Lee, Mee Kyung Kim, Ja Seong Bae, Chan Kwon Jung, So Lyung Jung, Jung-Min Lee, Sang-Ah Chang, Dong-Jun Lim","doi":"10.1158/1078-0432.CCR-24-3562","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3562","url":null,"abstract":"<p><strong>Purpose: </strong>Traditional methods, fine-needle aspiration cytology (FNAC) and washout thyroglobulin (Tg), do not always provide sufficient accuracy for diagnosing lymph node (LN) metastasis in thyroid cancer. This study aimed to validate the diagnostic performance of washout cytokeratin fragment 21-1 (CYFRA 21-1) as a complementary biomarker for diagnosing metastatic LNs in thyroid cancer and to explore its relationship with molecular analysis and distant metastasis.</p><p><strong>Patients and methods: </strong>In this retrospective cohort study involving 230 LNs in 224 patients with PTC, FNAC, washout Tg, and CYFRA 21-1 levels were measured in suspicious LNs. The final LN outcomes were confirmed by surgical histology.</p><p><strong>Results: </strong>Among the 230 LNs, 145 (63.0%) were benign and 85 (37.0%) were metastatic. The optimal cut-off value for washout CYFRA 21-1 was established at 1.12 ng/mL (Area under curve AUC, 0.959; 95% confidence interval CI, 0.936-0.982) with sensitivity of 93.4% and specificity of 97.8%. The cut-off value for washout Tg was 12.61 ng/mL (AUC 0.832, 95% CI, 0.772-0.892). The diagnostic performance of CYFRA 21-1 remained consistent across the preoperative (1.14 ng/mL) and postoperative assessment (1.10 ng/mL). The combination of FNAC and washout CYFRA 21-1 showed high sensitivity (93.1%), specificity (95.6%), negative predictive value (95.3%), and diagnostic accuracy (94.6%) than FNAC with washout Tg. Washout CYFRA 21-1 level was associated with TERT mutations (odds ratio, OR 3.35, P<0.001), LN metastasis (OR 5.43, P=0.019), and distant metastasis (OR 4.27, P =0.019).</p><p><strong>Conclusions: </strong>Incorporating washout CYFRA 21-1 into the diagnostic process improves the accuracy of metastatic LN detection in thyroid cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604005","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 Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome.","authors":"Maria Isabel Achatz, Anita Villani, Alison A Bertuch, Gaëlle Bougeard, Vivian Y Chang, Andrea S Doria, Bailey Gallinger, Lucy A Godley, Mary-Louise C Greer, Junne Kamihara, Payal P Khincha, Wendy K Kohlmann, Christian P Kratz, Suzanne P MacFarland, Luke D Maese, Kara N Maxwell, Sarah G Mitchell, Yoshiko Nakano, Stefan M Pfister, Jonathan D Wasserman, Emma R Woodward, Judy E Garber, David Malkin","doi":"10.1158/1078-0432.CCR-24-3301","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3301","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic (P/LP) variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural AACR Childhood Cancer Predisposition Workshop, understanding the genotype:phenotype relationships in LFS have evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The \"Toronto Protocol\" remains the current standard for life-long surveillance; however, as outlined in this Perspective, modifications should be considered as to the use of certain modalities to target organs in an age-dependent manner. The Working Group's recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 P/LP variant carrier population based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS, and present our updated consensus tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603928","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}