Clinical Cancer Research最新文献

{"title":"Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies.","authors":"Bojana Jovanović, Sarah E Church, Kara M Gorman, Khrystyna North, Edward T Richardson, Molly DiLullo, Victoria Attaya, Julie Kasparian, Ayesha Mohammed-Abreu, Gregory Kirkner, Melissa E Hughes, Nancy U Lin, Elizabeth A Mittendorf, Stuart J Schnitt, Sara M Tolaney, Shom Goel","doi":"10.1158/1078-0432.CCR-23-1242","DOIUrl":"10.1158/1078-0432.CCR-23-1242","url":null,"abstract":"<p><strong>Purpose: </strong>Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated.</p><p><strong>Experimental design: </strong>To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, and carrying out transcriptomic profiling using the NanoString BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival.</p><p><strong>Results: </strong>Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival.</p><p><strong>Conclusions: </strong>Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11474168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970767","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":"HER2 Antibody-Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor.","authors":"Tom Zhang, Christopher A Febres-Aldana, Zebing Liu, Jenna-Marie Dix, Ryan Cheng, Raymond G Dematteo, Allan J W Lui, Inna Khodos, Leo Gili, Marissa S Mattar, Jeanine Lisanti, Charlene Kwong, Irina Linkov, Murray J Tipping, Elisa de Stanchina, Igor Odintsov, Marc Ladanyi, Romel Somwar","doi":"10.1158/1078-0432.CCR-24-1835","DOIUrl":"10.1158/1078-0432.CCR-24-1835","url":null,"abstract":"<p><strong>Purpose: </strong>Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.</p><p><strong>Experimental design: </strong>ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody-drug conjugates (ADC)-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine-were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays.</p><p><strong>Results: </strong>ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd-treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status.</p><p><strong>Conclusions: </strong>ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906033","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":"Trastuzumab Deruxtecan With Nivolumab in HER2-Expressing Metastatic Breast or Urothelial Cancer: Analysis of the Phase Ib DS8201-A-U105 Study","authors":"Erika Hamilton, Matthew D. Galsky, Sebastian Ochsenreither, Gianluca Del Conte, Miguel Martín, Maria José. de Miguel, Evan Y. Yu, Anja Williams, Maria Gion, Antoinette R. Tan, Laila Agrawal, Annemie Rutten, Jean-Pascal Machiels, Sara Cresta, Philip R. Debruyne, Audrey Hennequin, Victor Moreno, Anna Minchom, Frances Valdes-Albini, Daniel Petrylak, Li Li, Zenta Tsuchihashi, Fumitaka Suto, Fu-Chih Cheng, Maha Kandil, Daniel Barrios, Sara Hurvitz","doi":"10.1158/1078-0432.ccr-24-1513","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1513","url":null,"abstract":"Purpose: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC). Patients and Methods: Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review. Results: Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3). Conclusion: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T‑DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440198","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":"Pediatric Cancer Screening in Hereditary Gastrointestinal Cancer Risk Syndromes: An Update from the AACR Childhood Cancer Predisposition Working Group.","authors":"Suzanne P MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P Kuiper, Harry Lesmana, Julia Meade, Kim E Nichols, Christopher C Porter, Sharon A Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, Sharon E Plon","doi":"10.1158/1078-0432.CCR-24-0953","DOIUrl":"10.1158/1078-0432.CCR-24-0953","url":null,"abstract":"<p><p>Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072182","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":"DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies.","authors":"Kris Ann P Schultz,Alexander T Nelson,Paige H R Mallinger,Anne K Harris,Junne Kamihara,Shari Baldinger,Kenneth S Chen,Dinel Pond,Jessica N Hatton,Anna Dybvik,Sarah G Mitchell,Melissa R Perrino,Tal Ben-Ami,Denis Kachanov,Yan Su,Chao Duan,Damon R Olson,Dave Watson,Amanda L Field,Laura A Harney,Ann Garrity Carr,A Lindsay Frazier,Dominik T Schneider,David B Wilson,Suzanne P MacFarland,Peter J Schoettler,Andrew J Bauer,Louis P Dehner,D Ashley Hill,Douglas R Stewart,Yoav H Messinger","doi":"10.1158/1078-0432.ccr-24-1532","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1532","url":null,"abstract":"BACKGROUNDDICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available.EXPERIMENTAL DESIGNIndividuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study.RESULTSReview of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years.CONCLUSIONOngoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436015","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":"Efficacy and safety of the anti-IL1RAP antibody nadunolimab (CAN04) in combination with gemcitabine and nab-paclitaxel in patients with advanced/metastatic pancreatic cancer.","authors":"Eric Van Cutsem, Joelle Collignon, Rikke L Eefsen, Sebastian Ochsenreither, Zanete Zvirbule, Audrius Ivanauskas, Dirk Arnold, Edita Baltruskeviciene, Per Pfeiffer, Jeffrey Yachnin, Susanne Magnusson, Camilla Rydberg Millrud, Annika Sanfridson, Nedjad Losic, Ignacio Garcia-Ribas, Dominique Tersago, Ahmad Awada","doi":"10.1158/1078-0432.CCR-24-0645","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-0645","url":null,"abstract":"<p><strong>Purpose: </strong>Interleukin (IL)-1 pathway upregulation is implicated in pancreatic ductal adenocarcinoma (PDAC) progression, therapy resistance, and survival. Nadunolimab is an IL-1 receptor accessory protein (IL1RAP)-targeting antibody with enhanced antibody-dependent cellular cytotoxicity that blocks IL-1α/IL-1β signaling. We investigated efficacy and safety of nadunolimab in PDAC, in combination with gemcitabine/nab-paclitaxel (GN).</p><p><strong>Patients and methods: </strong>Patients with previously untreated locally advanced/metastatic PDAC received nadunolimab (1.0-7.5 mg/kg) every two weeks with standard GN. The primary objective was safety; secondary objectives were anti-tumor response, progression-free survival (PFS) and overall survival (OS). Correlations between serum and tumor biomarkers and clinical response were explored.</p><p><strong>Results: </strong>76 patients were enrolled, median age 63 years (range 43-89), 42% female, 97% with metastatic disease, 9% having received adjuvant chemotherapy. The most frequent Grade ≥3 adverse event was neutropenia (66%), typically during Cycle 1. Infusion-related reactions occurred in 29% (Grade 3, 3%). Only 1 of 76 patients had grade 3 or above peripheral neuropathy. No marked dose-dependent differences in safety or efficacy were observed between the four dose groups. Median OS overall was 13.2 months (95%CI 10.6-15.5) and 1-year survival was 58%. Median iPFS (iRECIST) was 7.2 months (95%CI 5.2-8.5). Treatment efficacy was higher in patients with high versus low tumor baseline IL1RAP expression (OS 14.2 vs 10.6 months, p=0.026). A reduction in serum IL-8 on treatment correlated with prolonged OS.</p><p><strong>Conclusions: </strong>Nadunolimab combined with GN shows promising efficacy and manageable safety in locally advanced/metastatic PDAC. Higher tumor baseline IL1RAP expression correlated with better outcome.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388484","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 Approval Summary: Capecitabine Labeling Update under Project Renewal","authors":"Sundeep Agrawal, Clara Lee, William F. Pierce, Elizabeth Everhart, Adriene King-Ducre, Melanie Royce, Christy L. Osgood, Laleh Amiri-Kordestani, Haw-Jyh Chiu, Tiffany K. Ricks, Lili Pan, Jeanne Fourie Zirkelbach, Rosane Charlab, Michael Pacanowski, Tamy Kim, Richard Pazdur, Paul G. Kluetz, Jennifer J. Gao","doi":"10.1158/1078-0432.ccr-24-1708","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1708","url":null,"abstract":"On December 14, 2022, the U.S. Food and Drug Administration (FDA) approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase (DPD) deficiency, and edited other sections of the USPI to conform with FDA’s current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA’s Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385204","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 preoperative window-of-opportunity study of oral SERD, imlunestrant, in newly diagnosed ER-positive, HER2-negative early breast cancer: Results from EMBER-2 Study.","authors":"Patrick Neven, Nicole Stahl, Maria Vidal, Miguel Martín, Peter A. Kaufman, Nadia Harbeck, Kelly K. Hunt, Stacey Carter, Francois-Clement Bidard, Peter A. Fasching, Philippe Aftimos, Duncan Wheatley, Erika Hamilton, Rebecca Aft, Swati Kulkarni, Peter Schmid, Manali Bhave, Roohi Ismail-Khan, Claudia Karacsonyi, Shawn T. Estrem, Bastien Nguyen, Umut Ozbek, Eunice Yuen, Vanessa Rodrik-Outmezguine, Eva Ciruelos","doi":"10.1158/1078-0432.ccr-24-2113","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2113","url":null,"abstract":"Purpose: Imlunestrant is an oral SERD with favorable safety and preliminary efficacy in patients with ABC. PD biomarker data can optimize drug dosing; herein is the PD data from the EMBER-2 study. Methods: Postmenopausal women with untreated, operable ER-positive, HER2-negative EBC were randomized to 400mg vs 800mg of imlunestrant daily for ~2 weeks before surgery. A single arm testing 200mg daily was later accrued. PD biomarker changes (ER, PR, Ki-67 by IHC, and mRNA expression of ER-related genes) were evaluated in paired tumor samples (pre-/ post-treatment). Safety and PK were also assessed. Results: Among evaluable paired samples (n=75), PD profiles demonstrated consistent ER targeting between 400 and 800mg doses with less toxicity at the 400mg dose. Although inducing the lowest rate of CCCA, PD and PK results were similar for the 200mg dose. Conclusion: EMBER-2 combined with existing phase 1 data has identified 400mg as the optimal imlunestrant dose.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385278","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":"Tissue-based Profiling Techniques to Achieve Precision Medicine in Cancer: Opportunities and Challenges in Melanoma.","authors":"Tuba N Gide, Yizhe Mao, Richard A Scolyer, Georgina V Long, James S Wilmott","doi":"10.1158/1078-0432.CCR-24-1109","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1109","url":null,"abstract":"<p><p>Immunotherapies targeting the programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) checkpoint receptors have revolutionised the treatment of metastatic melanoma. However, half of treated patients do not respond to or eventually progress on standard therapies and many experience adverse events as a result of drug toxicity. The identification of accurate biomarkers of clinical outcomes are required in order to move away from the one-size-fits-all treatment approach of standard clinical practice, and towards a more personalised approach to enable the administration of the optimal therapy for any given patient and further improve patient outcomes. Recent clinical trials have proven the potential of multi-omics analyses, including genomic, gene expression, and tumour immune profiling, of patients' tumour biopsies, to predict a patient's response to subsequently administered immunotherapies. However, reproducibility of such multi-omics analyses, tissue requirements, and clinical validation have limited the practical application of these approaches in routine clinical workflows. In this review, we discuss several pivotal tissue-based profiling techniques that can be utilised to identify potential genomic, transcriptomic and immune biomarkers predictive of clinical outcomes following treatment with immune checkpoint inhibitors in melanoma. Furthermore, we highlight the key opportunities and challenges associated with the use of each of these techniques. The development and implementation of multimodal predictive models which combine data derived from these various methods is the future for achieving precision medicine for patients with melanoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380140","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":"Determination of MYD88 and CXCR4 mutation for clinical detection and their significance in Waldenström macroglobulinemia.","authors":"Yuting Yan, Ying Yu, Wenjie Xiong, Jun Wang, Yao Yao, Yujiao Jia, Yanshan Huang, Yuxi Li, Tingyu Wang, Rui Lv, Hao Sun, Haoxu Wang, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Zhen Yu, Dehui Zou, Mu Hao, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Shuhua Yi","doi":"10.1158/1078-0432.CCR-23-3939","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-23-3939","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [cytotoxic group, the Rituximab/Bortezomib-based group, and the Bruton's tyrosine kinase inhibitor (BTKi) group].</p><p><strong>Experimental design: </strong>385 symptomatic WM patients were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and/or droplet digital PCR (ddPCR).</p><p><strong>Results: </strong>The overall MYD88 mutation rate was 87.8%, relatively lower than that in Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with NGS exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering IPSSWM clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of IPSSWM classification (MYD88: HR=0.229, P=0.030; CXCR4: HR=3.349, P=0.012).</p><p><strong>Conclusions: </strong>Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380139","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}