Clinical Cancer Research最新文献

{"title":"Global Transcriptional Complexity of Estrogen Receptor Low Positive Breast Cancers in a Prospective Swedish Population-based SCAN-B Cohort.","authors":"Siker Kimbung,Srinivas Veerla,Kadum Muhammad,Anna Ehinger,Johan Vallon-Christersson,Martin Malmberg,Niklas Loman","doi":"10.1158/1078-0432.ccr-24-3435","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3435","url":null,"abstract":"PURPOSEThere is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology.EXPERIMENTAL DESIGNWe analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; >10%) tumors.RESULTSThe transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly non-luminal PAM50 subtypes and down-regulated ER signaling. All TNBC molecular subtypes were represented within ER-low/HER2-negative BC. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors and only 2 genes were significantly differentially expressed above 1.5 fold-difference between the groups. However, borderline ER-low tumors (with exactly10% ER) were mostly assigned labels associated with luminal disease biology suggesting possible endocrine responsiveness. Lymphocyte infiltration was comparable between ER-low and ER-neg but was significantly higher relative to ER-pos tumors. Within ER-low/HER2-negative disease, HR-positivity and low/intermediate PAM50 ROR score inferred from RNAseq data and lymphocyte fraction ≥30%, were respectively associated with better prognosis.CONCLUSIONSER-low/HER2-negative is not a distinct BC molecular biological entity but an integral part of TNBC deserving similar treatments. Nonetheless, a few borderline cases with moderately active ER-signaling can potentially respond to ET. HR-related signatures and TILs may stratify ER-low/HER2-negative tumors according to risk for recurrence. The true benefit of ET in ER-low BC requires prospective investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"121 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831681","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 chemotherapy and surgery versus surgery for organ preservation of T3 and T4a nasal and paranasal sinus squamous cell carcinoma (NPNSCC) ECOG-ACRIN EA3163.","authors":"Nabil F Saba,Yael Flamand,Derrick T Lin,Christine H Chung,Mark W McDonald,Styliani Flampouri,Saad A Khan,Carl H Snyderman,Ehab Y Hanna,Ivan H El-Sayed,Clementino A Solares,Christopher H Le,Maged Ghaly,Peter H Hwang,Dong M Shin,Rita S Axelrod,Chukwuemeka V Ikpeazu,Douglas R Adkins,Fenghai Duan,Marc Cohen,Michael A Samuels,Paul L Swiecicki,Rathan M Subramaniam,A Bapsi Chakravarthy,Barbara A Burtness","doi":"10.1158/1078-0432.ccr-24-4085","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4085","url":null,"abstract":"PURPOSENeoadjuvant chemotherapy for structure preservation (SP) in nasal and paranasal sinus squamous cell carcinoma (NPNSCC) has been described in single-institution but not randomized studies. EA3163 was a randomized study investigating whether cytoreductive neoadjuvant chemotherapy would improve SP or overall survival (OS).PATIENTS AND METHODSPatients with T3/T4a and select T4b NPNSCC requiring orbital or base of skull (BOS) resection were randomized to surgery (Arm A), versus surgery preceded by docetaxel/cisplatin x3 cycles (Arm B). Degree of anticipated SP (orbit and BOS) was required preoperatively and post-chemotherapy. SP was noted at surgery. Co-primary objectives were SP rate (orbit/BOS) and OS. 82 patients needed to be accrued for 81% power with 0.1 one-sided alpha using Fisher's exact test for SP rate and 83% with 0.1 one-sided alpha using log-rank test for OS.RESULTSAmong 23 evaluable patients, overall SP rate was 30%: 15% in Arm A (N=2/13, 95%CI: 1.9-45.4%), 50% in Arm B (N=5/10, 95%CI: 18.7-81.3%) (p=0.17). Among 18 patients with pathologic T3/T4a disease, overall SP rate was 39%: 18% in Arm A (N=2/11, 95%CI: 2.3-51.8%), 71% in Arm B (N=5/7, 95%CI: 29.0-96.3%) (p=0.049). Orbit and BOS-specific preservation rates were 38% (95%CI: 8.5-75.5%) vs 83% (95%CI: 35.9-99.6%), and 33% (95%CI: 9.9-65.1%) vs 67% (95%CI: 29.9-92.5%) in Arm A vs B, respectively. The most common grade ≥3 toxicities included mucositis, anemia, nausea and lymphopenia (all >10%). No grade 5 events were reported.CONCLUSIONSThese results support neoadjuvant chemotherapy as an effective intervention for SP in T3/T4a NPNSCC and deserve further evaluation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"26 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831563","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 Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer (\"PREDICT\") - Baseline findings for CA125.","authors":"Rudolf Kaaks,Victoria Cooley,Trasias Mukama,Lauren R Teras,Alpa V Patel,Giovanna Masala,Marta Crous-Bou,Holly R Harris,Hilde Langseth,Heljä-Marja Surcel,Nicolas Wentzensen,Kathryn Terry,Naoko Sasamoto,Shelley Tworoger,Renée Turzanski Fortner","doi":"10.1158/1078-0432.ccr-24-1845","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1845","url":null,"abstract":"PURPOSEEpithelial ovarian cancer (EOC) is a lethal malignancy. CA125, the \"best\" available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by \"omics\" technologies. Discovery studies for EOC biomarkers should be conducted in pre-diagnosis blood samples from prospective cohorts to maximize likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage, while reducing methodologic biases.EXPERIMENTAL DESIGNIndividual cohorts with pre-diagnosis blood samples have insufficient sample size for such studies. thus, we established \"PREDICT\" (\"Prospective Early Detection Consortium for Ovarian Cancer\")-a collaboration of nine prospective studies-to assemble a sufficient number of EOC cases with blood samples collected ≤18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay.RESULTSThe discrimination capacity for single CA125 measurements in samples collected <6 months prior to diagnosis was high (area under the curve (AUC), PREDICT overall=0.92; range across cohorts of non-pregnant individuals=0.89-0.98), and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed.CONCLUSIONSOngoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and microRNAs, using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multi-modal screening, as a complement to CA125 and combined with imaging.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831628","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":"Ad-SGE-DKK3 Gene Therapy Overcomes Resistance to Immune Checkpoint Blockade in Pleural Mesothelioma","authors":"Hee-Jin Jang, Meera Patel, Daniel Y. Wang, Sung Wook Kang, Jong Min Choi, Claire Lee, Monica Vilchis, Ji Seon Shim, Sonali Mitra, Priyanka Ranchod, Allen Kuncheria, William Hudson, Peter Jindra, Veronica Lenge De Rosen, Maheshwari Ramineni, Ernest Ramsay. Camp, Farrah Kheradmand, R. Taylor Ripley, Shawn S. Groth, Hyun-Sung Lee, Bryan M. Burt","doi":"10.1158/1078-0432.ccr-24-4024","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4024","url":null,"abstract":"Purpose: Immune checkpoint inhibitors (ICIs) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3) in overcoming treatment resistance. Experimental Design: We performed preclinical studies to elucidate DKK3’s role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with objective response rate (ORR) as the primary outcome. Results: DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and reduced extracellular vesicle secretion and Colony Stimulating Factor 1 (CSF1). DKK3 sensitized the tumor-immune microenvironment to ICIs and enabled eradication of tumors by PD-1 blockade. In our trial, twelve patients received intratumoral Ad-SGE-DKK3 plus intravenous nivolumab. ORR was 16.6% and 41.7% had stable disease, for a 58.3% rate of durable clinical response (DCB). Median overall survival was 14.5 months, and median progression-free survival was 4.5 months. Grade 3 adverse events occurred in 41.7% of patients. Serial tumor biopsies and serum analyses revealed that DCB patients had increased tumor-infiltrating bulk and effector memory CD8 T cells, reduced circulating memory CD8 T cells, and sustained lower soluble mesothelin and CSF1 levels compared to progressors. Conclusions: Combination Ad-SGE-DKK3 plus nivolumab demonstrated a tolerable safety profile and potential efficacy in patients with chemotherapy-refractory epithelioid pleural mesothelioma. ClinicalTrials.gov identifier: NCT04013334.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"74 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819271","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":"Emerging strategies of cell and gene therapy targeting tumor immune microenvironment","authors":"Runtian Wang, Xiaorui Duan, Jian Li, Cheng Zhang, Lin Shen","doi":"10.1158/1078-0432.ccr-24-4308","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4308","url":null,"abstract":"Immunotherapy has profoundly transformed the landscape of cancer treatment, and offered therapeutic opportunities to reverse the immunosuppressive microenvironment. However, the intra-tumoral heterogeneity (ITH) and the evolution towards immune evasion present significant challenges that demand innovative solutions beyond immune checkpoint inhibitors (ICIs). In this context, cell and gene therapy (CGT) emerges as a promising frontier in the new-immunotherapy era with their remarkable flexibility, diversity, and compatibility. In this review, we began with a foundational overview of the classification of CGT in treating solid tumors, and explored how it targets the crosstalk between cancer cells and the tumor immune microenvironment (TIME) from cellular and molecular perspectives. CGT not only remodels the local TIME but also has long-term effects on systemic immune response. Furthermore, this review summarized current challenges and strategic approaches, drawing on insights gained from clinical practice. By bridging mechanistic research with clinical insights, this review underscored the positive feedback from research bench to clinical scenarios. More importantly, we propose that the development of CGT marks the evolution of cancer treatment paradigm: from targeting tumor tissues alone to restoring the disrupted cancer-immune balance as a whole.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"34 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819272","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 Society for Immunotherapy of Cancer Perspective on Liquid Biopsy and Radiomics Based Technologies for Immuno-Oncology Biomarker Discovery and Application.","authors":"Anne Monette, Adriana Aguilar-Mahecha, Emre Altinmakas, Mathew G Angelos, Nima Assad, Gerald Batist, Praveen K Bommareddy, Diana L Bonilla, Christoph H Borchers, Sarah E Church, Gennaro Ciliberto, Alexandria P Cogdill, Luigi Fattore, Nir Hacohen, Mohammad Haris, Vincent Lacasse, Wen-Rong Lie, Arnav Mehta, Marco Ruella, Sam Sater, Alan Spatz, Bachir Taouli, Imad Tarhoni, Edgar Gonzalez-Kozlova, Itay Tirosh, Xiaodong Wang, Sacha Gnjatic","doi":"10.1158/1078-0432.CCR-24-3791","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3791","url":null,"abstract":"<p><p>Immuno-oncology is increasingly becoming the standard of care for cancers, with the identification of biomarkers that reliably classify ICI response, resistance, and toxicity becoming the next frontier towards improvements in immunomodulatory treatment regimens. Recent advances in multi-parametric, multi-omics, and computational data platforms generating an unprecedented depth of data may assist in the discovery of increasingly robust biomarkers for enhanced patient selection and more personalized or longitudinal treatment approaches. Which emerging technologies to implement in future research and clinical settings, used alone or in combination, relies on weighing pros and cons that aid in maximizing data outputs whilst minimizing patient sampling, with high reproducibility and representativeness, and minimal turnaround time and data fragmentation towards later private and public dataset harmonization strategies. The Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify important advances in biomarker technologies and to highlight advances in biomarker discovery using liquid biopsy and in vivo imaging technologies. We address advances in liquid biopsy technologies monitoring cells, proteins, nucleic acids, antibodies, and drugs or analytes, and radiomics technologies monitoring at the whole host-level imaging methods including immuno-PET and MRI technologies able to couple biomarker with physical location. We include a summary of key metrics obtained by these technologies, and their ease of interpretation, limitations and dependencies, technical improvements, and outward comparisons. By highlighting some of the most interesting recent examples contributed by these technologies, and providing examples improving outputs, we hope to guide correlative research directions and assist in their becoming clinically useful in immuno-oncology.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802742","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":"Navigating Complexity: Perspectives on Risk Assessment in the Era of New Blood-based Tests for Early Cancer Detection.","authors":"Christina A Clarke, Breeana L Mitchell, Emma Alme, Jonathan P Beer, Tomasz M Beer, Michelle A Beidelschies, Jody Hoyos, Eric A Klein, Peter Kuhn, Nancy Krunic, Kathryn Lang, Jerry S H Lee, Dorys Lopez Ramos, David Morgenstern, Girish Putcha, Elissa Quinn, Victoria M Raymond, Wendy S Rubinstein, Stephanie A Sanchez, Ryan W Serra, Mark D Stewart, Lauren C Leiman","doi":"10.1158/1078-0432.CCR-24-4269","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4269","url":null,"abstract":"<p><p>In recent years there has been a surge in the development of new, blood-based, single- and multi-cancer detection tests (SCD and MCD), which can detect cancer signals prior to the onset of symptoms or clinical diagnosis of cancer. Recognizing the need for consensus definitions and standardized evidence development frameworks for these new types of blood test, the Early Detection and Screening (ED&S) Working Group of the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative initiative dedicated to advancing standards and best practices, developed and published a lexicon for liquid-biopsy based SCD and MCD tests. During the preparation of the lexicon, the group recognized challenges regarding the definitions of key terms and concepts describing absolute and relative risk assessment of intended use populations for cancer screening tests. This article captures the working group's discussions on 1) risk assessment including considerations for adapting historical SCD risk terminology like \"average risk\" and \"elevated risk\" to MCD tests; 2) the implications of this terminology for describing intended use populations; 3) and the existing gaps in evidence for determination of absolute risks.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802732","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":"Azacitidine, Venetoclax and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase 1b/2 Study and Correlative Analysis","authors":"Naval Daver, Jayastu Senapati, Hagop M. Kantarjian, Bofei Wang, Patrick K. Reville, Sanam Loghavi, Musa Yilmaz, Courtney D. DiNardo, Tapan M. Kadia, Mhd Yousuf Yassouf, Abhishek Maiti, Sankalp Arora, Guillermo Montalban Bravo, Guilin Tang, Gautam Borthakur, Koji Sasaki, Naveen Pemmaraju, Joie Alvarez, Graciela M. Nogueras Gonzalez, Jing Ning, Ghayas C. Issa, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Guillermo Garcia-Manero, Hussein A. Abbas","doi":"10.1158/1078-0432.ccr-25-0229","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0229","url":null,"abstract":"Purpose: Magrolimab is a monoclonal antibody directed against macrophage checkpoint CD47 on myeloid leukemia cells that was pre-clinically synergistic with azacitidine-venetoclax, warranting further clinical evaluation. Patients and Methods: In this phase 1b/2 study the triplet combination of azacitidine, venetoclax and magrolimab was evaluated in adult patients with frontline (ineligible for intensive chemotherapy) and relapsed/refractory AML. Azacitidine was dosed at 75mg/m2 for 7 days, venetoclax at 400 mg/day for 28 days, and magrolimab (recommended phase 2 dose [RP2D]) as follows: 1 mg/kg dose on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on day 11, 15 and 22 (cycle 1), followed by 30 mg/kg weekly for cycle 2, then 30 mg/kg every 2 weeks cycle 3 and beyond. The primary endpoint was RP2D for phase 1b and rates of composite complete response (CRc) in phase 2. Results: The frontline cohort included 54 patients (median age 70.1 years); 35 (64.8%) were TP53 mutated (TP53mut). CRc was attained in 34 patients (63%); 49% in TP53mut and 90% in the TP53 wild-type patients. At a median follow-up of 27.9 months, the median event free survival (EFS) and overall survival (OS) was 6.6 months and 9.8 months respectively; for TP53mut patients the median EFS and OS was 5.9 and 7.6 months, while for TP53 wild type it was 9.6 months and 13 months respectively. CRc in the relapsed/refractory cohort (n=52) was 29% and median OS was 3.9 months. The regimen was well tolerated; infections were the most common ≥ grade 3 adverse event (75.4%) with no immune toxicities or deaths related to therapy. scRNAseq was performed on 27 longitudinal samples from 11 TP53mut patients (8 responders). Gene set enrichment analysis revealed enrichment of IFNγ and TNFα signaling in non-responders at baseline, while erythroid differentiation was associated with resistance. Patients at relapse also showed up-regulated CD47 expression and elevated leukemia regeneration score. Conclusions: The triplet regimen was safe but did not lead to promising survival outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"108 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805788","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":"Multimarker assessment of B cell and plasma cell subsets and their prognostic role in the colorectal cancer microenvironment","authors":"Onni Sirkiä, Henna Karjalainen, Hanna Elomaa, Sara A. Väyrynen, Anne Tuomisto, Päivi Sirniö, Ville K. Äijälä, Vilja V. Tapiainen, Meeri Kastinen, Erkki-Ville Wirta, Olli Helminen, Sanna Meriläinen, Jukka Rintala, Juha Saarnio, Tero Rautio, Toni T. Seppälä, Markus J. Mäkinen, Jukka-Pekka Mecklin, Jan Böhm, Maarit Ahtiainen, Juha P. Väyrynen","doi":"10.1158/1078-0432.ccr-24-4083","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4083","url":null,"abstract":"Purpose: While the association between cytotoxic T lymphocytes and favorable prognosis in colorectal cancer is well established, the prognostic significance of B lymphocytes remain more ambiguous. This study aimed to assess the characteristics and significance of various B cell and plasma cell subsets in colorectal tumors. Experimental Design: We designed a seven-plex immunohistochemistry assay, combined with machine learning-based image analysis, to identify various B cell and plasma cell populations and applied it to study a cohort of 912 colorectal tumors. We assessed the prognostic significance of B cell and plasma cell densities using Kaplan-Meier estimators and Cox regression models. Additionally, we designed a more clinically applicable three-plex assay, which we used to study B cell and plasma cell densities in a separate validation cohort of 737 patients. Results: High plasma cell density in the center of the tumor was associated with longer cancer-specific survival independent of disease stage, mismatch repair status, T cell densities, and other covariates. In the study cohort, multivariable HR for high (vs. low) plasma cell density was 0.48 (95% CI 0.32–0.72, Ptrend = 0.0005), while the corresponding HR in the validation cohort was 0.37 (95% CI 0.21–0.65, Ptrend = 0.0003). Of the specific subsets, IgG1–IgG2– plasma cells showed the strongest association with improved survival. High B cell densities were not independently associated with better prognosis. Conclusions: Plasma cell densities in the center of the tumor represent a relevant tumor immune biomarker in colorectal cancer, complementing the T cell density measurements.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805789","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 and Derivation of MicroRNA-based Germline Signatures Predicting Radiation Toxicity in Prostate Cancer","authors":"Amar U. Kishan, Kristen McGreevy, Luca Valle, Michael Steinberg, Beth Neilsen, Maria Casado, Minsong Cao, Donatello Telesca, Joanne B. Weidhaas","doi":"10.1158/1078-0432.ccr-24-3951","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3951","url":null,"abstract":"Purpose: While radiation therapy (RT) is one of the primary treatment modalities used in the treatment of cancer, patients often experience toxicity during or after treatment. RT-induced genitourinary (GU) toxicity is a significant survivorship challenge for patients with prostate cancer (PCa), but identifying those at risk has been challenging. Herein, we attempt (i) to validate a previously identified biomarker of late RT-induced GU toxicity, PROSTOX, consisting primarily of microRNA-based germline biomarkers (mirSNPs), and (ii) to investigate the possibility of temporally and genetically defining other forms of RT-associated GU toxicity. Experimental Design: We included 148 patients enrolled in MIRAGE (NCT 04384770), a trial comparing MRI versus CT-guided prostate stereotactic body radiotherapy (SBRT). Linear regression was used to evaluate the association between PROSTOX score and late GU grade toxicity. Machine learning approaches were used to develop predictive models for acute and chronic GU toxicity and the accuracy of all models was assessed using area under the curve (AUC) metrics. A comparative gene ontology (GO) analysis was performed. Results: PROSTOX accurately predicts late GU toxicity, achieving an AUC of 0.76, and demonstrates strong correlation with GU toxicity grade (p-1.2E-9). mirSNP-based signatures can distinguish acute and chronic RT toxicity (AUCs of 0.770 and 0.763). Finally, GO analysis identifies unique pathways involved in each form of GU toxicity &amp;#45;&amp;#45; acute, chronic and late. Conclusions: These findings provide strong evidence for the continued application of mirSNPs to predict toxicity to RT, and to act as a path for the continued personalization of RT with improved patient outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"138 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790129","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}