Clinical Cancer Research最新文献

{"title":"Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality.","authors":"Ali T Arafa, Siddhartha Yadav, Catherine H Marshall, Elizabeth Mauer, Minxuan Huang, Binyam Yilma, Ymke van der Pol, Stamatina Fragkogianni, Emily A Teslow, Samuel Kellen, Ella Boytim, Christine Luo, Megan Ludwig, Weijie Zhang, Arockia Jayaraj, Deborah K Armstrong, William B Isaacs, Justin M Drake, Hai Dang Nguyen, R Stephanie Huang, Calvin Y Chao, Emil Lou, Scott M Dehm, Fergus J Couch, Justin H Hwang, Emmanuel S Antonarakis","doi":"10.1158/1078-0432.CCR-24-2058","DOIUrl":"10.1158/1078-0432.CCR-24-2058","url":null,"abstract":"<p><strong>Purpose: </strong>Germline alterations in homologous recombination repair (gHRR) genes affect the pathogenesis, treatment options, and survival of patients with cancer. However, distinct gHRR gene alterations may differentially affect treatment response and oncogenic signaling. In this study, we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities.</p><p><strong>Experimental design: </strong>We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants [germline BRCA1, germline BRCA2, germline PALB2, germline ATM (gATM), and germline CHEK2] were analyzed. HRs were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis were used to compare transcriptomic profiles.</p><p><strong>Results: </strong>Somatic TP53 mutations were depleted in gATM carriers (P < 0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with germline BRCA1/2 mutations were associated with improved survival in patients with ovarian cancer and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (P < 0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (P < 0.001). Finally, using gene dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function.</p><p><strong>Conclusions: </strong>gATM-associated cancers seem to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1730-1745"},"PeriodicalIF":10.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12045718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522734","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":"Spatially Resolved, Multiregion Proteomics for Prediction of Immunotherapy Outcome in Deficient Mismatch Repair Metastatic Colorectal Cancer.","authors":"Bahar Saberzadeh-Ardestani, Zhenglong Liu, Mariam I Stein, Will A Sherman, Christy E Trussoni, Charles W Abbott, Dongyao Yan, Skyler Smith, Kandavel Shanmugam, Rondell P Graham, Alos Diallo, Joshua J Levy, Tamas Ordog, Frank A Sinicrope","doi":"10.1158/1078-0432.CCR-24-0853","DOIUrl":"10.1158/1078-0432.CCR-24-0853","url":null,"abstract":"<p><strong>Purpose: </strong>Digital proteomic profiling was performed to identify spatial context in relationship to patient response and survival after anti-PD-1 therapy in metastatic colorectal cancer.</p><p><strong>Experimental design: </strong>Primary colorectal cancers with deficient mismatch repair from patients treated with anti-PD-1 antibodies were analyzed (N = 30) using digital spatial profiling (GeoMx nCounter). At the invasive margin, 71 proteins were profiled in 10 regions of interest/slide that were segmented into 3 compartments labeled with pan-cytokeratin (epithelia), CD45 (stromal cells), and SYTO13 (nuclei). In an independent cohort (n = 13), digital spatial profiling data and single-cell transcriptomic data were analyzed. Differential protein abundance, after Benjamini-Hochberg correction, was examined by clinical response and progression-free survival (PFS) using multivariable Cox regression.</p><p><strong>Results: </strong>Protein abundance varied significantly between epithelial and stromal compartments. Nonresponders to anti-PD-1 showed higher fibronectin and smooth muscle actin abundance in the epithelial compartment that was associated with significantly shorter PFS (adjusted HR: 6.49 and 4.52, respectively; P < 0.05). In CD45+ stroma, increased expression of proteins related to T cells (CD3 and CD4), NK cells (CD56), antigen presentation (CD40), immune activation (CD27, ICOS), and apoptosis (GZMA) were found in responders (vs nonresponders) to anti-PD-1; each marker was significantly associated with longer patient PFS (0.02 < adjusted HR < 0.17; P < 0.05). In a separate cohort, consistent results by compartment were found for fibronectin and CD56. Gene expression data revealed that fibronectin and smooth muscle actin were primarily derived from cancer-associated fibroblasts.</p><p><strong>Conclusions: </strong>Spatially resolved protein profiles within microenvironments of deficient mismatch repair colorectal cancers can influence patient response and survival after anti-PD-1, highlighting their potential clinical significance.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1783-1795"},"PeriodicalIF":10.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448136","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":"Targeting the MAP kinase pathway in colorectal cancer: A journey in personalized medicine.","authors":"Jordan W Appleyard,Christopher J M Williams,Paolo Manca,Filippo Pietrantonio,Jenny F Seligmann","doi":"10.1158/1078-0432.ccr-25-0107","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0107","url":null,"abstract":"The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients with RAS and BRAF wild-type disease. Guidelines further recommend treatment limitation to those with left-primary tumor location (PTL). Despite such progress, anti-EGFR response remains variable within the biomarker-selected population, indicating the presence of additional mechanisms of resistance and underscoring the need for novel positive predictive biomarkers, and novel targeted agents. This review explores established and emerging predictive biomarkers of anti-EGFR efficacy, including tumor genetic alterations beyond RAS and BRAF, as well as the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG). To date, biomarker discovery and validation have largely been performed within post hoc analyses of existing clinical trial datasets. We highlight ongoing prospective clinical trials aiming to validate earlier findings and describe how novel biomarkers are being used to re-evaluate anti-EGFR agents in treatment settings where earlier trials, among non-biomarker selected populations, yielded negative results - including right-PTL, locally advanced disease, and anti-EGFR rechallenge strategies. Additionally, we discuss how our improved understanding of the molecular mechanisms underpinning anti-EGFR response and resistance is being leveraged to develop novel targeted agents.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"36 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897437","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 Breast Cancer 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":"10.1158/1078-0432.CCR-24-2806","url":null,"abstract":"<p><strong>Purpose: </strong>The GeparOLA study evaluated paclitaxel plus olaparib (PO) in neoadjuvant chemotherapy for patients with HER2-negative early breast cancer with homologous recombination deficiency (HRD). HRD was defined by high HRD score or germline (g)/tumor (t) BRCA1/2 mutations (g/tBRCA1/2mut). In this study, 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 early breast cancer with HRD with an indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and triple-negative breast cancer, or cT1c and Ki-67 >20%) were randomly assigned to PO or paclitaxel + carboplatin (PCb), both followed by epirubicin + cyclophosphamide. Long-term efficacy endpoints were secondary endpoints and included invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival, with a planned median follow-up of >4 years.</p><p><strong>Results: </strong>Between September 2016 and July 2018, 107 patients were randomized and 106 (PO N = 69 and PCb N = 37) started treatment. The median age was 47.0 years; of all patients, 35.8% had cT1 tumors, 31.4% were cN+, 86.8% had G3 tumors, 89.6% had Ki-67 >20%, and 72.6% were triple negative. After a median follow-up of 49.8 months, 18 (15 in PO and three in PCb) iDFS events and seven (six in PO and one in PCb) deaths were reported. The 4-year iDFS (76.0% PO vs. 88.5% PCb, hazard ratio = 2.86; 95% CI, 0.83-9.90; log-rank P = 0.081), DDFS (81.2% PO vs. 93.4% PCb, hazard ratio = 3.03; 95% CI, 0.67-13.67; log-rank P = 0.129), and overall survival (89.2% PO vs. 96.9% PCb, hazard ratio = 3.27; 95% CI, 0.39-27.20; log-rank P = 0.244) tended to be inferior with olaparib. Patients without g/tBRCA1/2mut benefited from Cb (seven of 30 patients had iDFS/DDFS events in PO vs. 0/16 in PCb; log-rank P = 0.037), whereas no difference for patients with g/tBRCA1/2mut was observed (hazard ratio = 1.16, log-rank P = 0.83).</p><p><strong>Conclusions: </strong>For HER2-negative early breast cancer with HRD, olaparib showed a tendency for inferior outcomes compared with Cb, particularly in patients without g/tBRCA1/2mut. In patients with g/tBRCA1/2mut, olaparib may replace Cb.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1596-1604"},"PeriodicalIF":10.0,"publicationDate":"2025-05-01","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":"Timing of ctDNA 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":"10.1158/1078-0432.CCR-24-3200","url":null,"abstract":"<p><strong>Purpose: </strong>Multiple clinical trials are investigating 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 day 14 versus day 30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation.</p><p><strong>Experimental design: </strong>From 2019 to 2023, 611 patients with stage I to III colorectal cancer were enrolled. Blood was collected preoperatively and postoperatively on ∼day 14 and ∼day 30. The cfDNA levels were assessed using digital PCR, and ctDNA was assessed using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8 mL of plasma.</p><p><strong>Results: </strong>Despite elevated cfDNA in 85% of day 14 samples, performance was comparable between the two timepoints (sensitivity, 31% vs. 32% and specificity, both 98%). A 50-ng cfDNA input cap reduced ctDNA detection probability, affecting 78% of day 14 samples and 65% of day 30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day 14; HR, 9.0, 95% confidence interval, 5.5-14.8 and day 30: HR, 12.5, 95% confidence interval, 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in the ctDNA level from day 14 to day 30 was associated with a 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>Conclusions: </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":"1676-1685"},"PeriodicalIF":10.0,"publicationDate":"2025-05-01","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}

{"title":"Health-Related Quality of Life in Patients with HR+/HER2- Early Breast Cancer Treated with Ribociclib Plus a Nonsteroidal Aromatase Inhibitor: Results from the NATALEE Trial.","authors":"Peter A Fasching, Dennis Slamon, Zbigniew Nowecki, Bozena Kukielka-Budny, Daniil Stroyakovskiy, Denise A Yardley, Chiun-Sheng Huang, Arlene Chan, Stephen Chia, Miguel Martín, Hope S Rugo, Sherene Loi, Sara Hurvitz, Michael Untch, Karen Afenjar, Rodrigo Fresco, Andriy Danyliv, Ilia Ferrusi, Zheng Li, Gabriel Hortobagyi","doi":"10.1158/1078-0432.CCR-24-1724","DOIUrl":"10.1158/1078-0432.CCR-24-1724","url":null,"abstract":"<p><strong>Purpose: </strong>The phase III NATALEE trial reported a statistically significant invasive disease-free survival benefit with ribociclib plus nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone in stage II/III hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer. In this study, we report health-related quality of life (HRQOL) data from NATALEE.</p><p><strong>Patients and methods: </strong>Patients were randomized to receive ribociclib plus NSAI or NSAI alone. Patient-reported outcome scores [European Organisation for Research and Treatment of Cancer core quality of life questionnaire global health status and physical, social, and emotional functioning domains; the supplementary European Organisation for Research and Treatment of Cancer breast cancer-specific QOL questionnaire breast symptoms scale; health on a visual analog scale of the generic EuroQOL 5-level instrument; and the Hospital Anxiety and Depression Scale] were assessed. The prespecified primary HRQOL endpoint was physical functioning. Mean scores and time-categorical and prespecified linear-time repeated-measure models were used to evaluate HRQOL changes during treatment.</p><p><strong>Results: </strong>HRQOL was evaluated in all patients in the ribociclib plus NSAI (n = 2,549) and NSAI alone (n = 2,552) arms. Compliance was high in both arms (≈93%-97%). Mean scores did not differ meaningfully from baseline for any analyzed domain. Likewise, neither a meaningful change from baseline (in either treatment arm) nor a difference between arms was observed during treatment in the time-categorical, model-adjusted mean scores for any HRQOL domains-using published thresholds for interpreting longitudinal and between-group differences, with all values being within 0.5 SD of their baseline values. Linear-time regression analysis confirmed these findings.</p><p><strong>Conclusions: </strong>These analyses of NATALEE show that adding adjuvant ribociclib to an NSAI does not negatively affect HRQOL in patients with HR+/HER2- early breast cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1625-1635"},"PeriodicalIF":10.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522739","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":"Amplification of extrachromosomal MYC paralogs shapes immunosuppressive tumor microenvironment in small cell lung cancer","authors":"Jingwei Zhang, Yueqi Jin, Haodong Lin, Jiaming Deng, Yan Ju, Xueyan Hu, Jianqi She, Zhijian Liang, Kongxu Dai, Mantang Qiu, Kunkun Sun, Jun Wang, Fan Yang, Jian Chen, Ence Yang, Xiao Li","doi":"10.1158/1078-0432.ccr-24-3399","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3399","url":null,"abstract":"Purpose: Immunotherapy has demonstrated promise in small cell lung cancer (SCLC), but certain patients encounter limited benefits, highlighting the need for immunosuppressive biomarkers. Extrachromosomal circular DNA (ecDNA) promotes amplification of MYC-paralogs (MYC, MYCN and MYCL), driving cross-resistance in SCLC. Here, we aim to investigate whether ecDNA-mediated MYC-paralogs amplification (ecMYC+) represents immunosuppressive features in SCLC. Experimental Design: Bulk RNA sequencing data were retrieved from public database and paraffin-embedded samples. The overexpression and amplification of MYC-paralogs were identified using immunohistochemistry and fluorescence in situ hybridization. Imaging mass cytometry and multiplex immunohistochemistry were used to characterize spatial distribution of tumor immune microenvironment (TIME). The copy number of MYC-paralogs was investigated using real-time polymerase chain reaction. RNA-sequencing and flow cytometry were performed in SCLC cell lines. Results: The mean copy number of ecDNAs and the frequency of ecMYC+ cell lines were higher in SCLC than that in the other lineages (SCLC 22/47 vs others 15/282). In ecMYC+ SCLC, multiple immune-related pathways were downregulated while nucleotide metabolism processes were upregulated. Inhibition of nucleotide metabolism induced ecDNA elimination, along with activated antigen presenting pathways. Highly dispersed MYC-paralogs amplifications were detected in resected treatment-naïve SCLC samples. Through the resolution of 103,341 cells from 24 pathological regions, we observed higher expression of MKI67, VEGFA, FAP and FOXP3 and reduced T cell infiltration in ecMYC+ samples. Moreover, ecMYC+ samples exhibited elevated cellular neighborhoods dominated by Ki67+ tumors, with reduced spatial interaction with immune cells. Conclusions: Extrachromosomal amplification of MYC-paralogs shapes suppressive TIME, identifying potential subgroup of immunotherapy resistant patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"61 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889620","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 Phase II Randomized Study of Paclitaxel alone or combined with Pelareorep with or without Avelumab in Metastatic Hormone Receptor Positive Breast Cancer: the BRACELET-01/PrE0113 study","authors":"Amy S. Clark, Fengmin Zhao, Paula Klein, Alberto J. Montero, Carla Falkson, Elisa Krill-Jackson, Kendrith Rowland, Sagar Sardesai, Jason Incorvati, Patrick Dillon, Antonio C. Wolff, Richard Trauger, Thomas C. Heineman, Matthew C. Coffey, Kathy D. Miller","doi":"10.1158/1078-0432.ccr-24-2701","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2701","url":null,"abstract":"Purpose: Pelareorep (Pel) is a type 3 oncolytic reovirus that upregulates PD-L1 expression. We determined the objective response rate (ORR) with paclitaxel (Pac), Pac + Pel, or Pac + Pel + avelumab (Ave). Patients and Methods: Patients with hormone receptor positive (HR+) HER2 negative metastatic breast cancer (MBC) who had progressed on at least one line of endocrine therapy with a CDK 4/6 inhibitor and had not received chemotherapy for MBC were eligible. Patients were randomized 1:1:1 to Pac, Pac/Pel or Pac/Pel/Ave after a three-patient run-in confirmed safety of the triplet. Response was assessed every 8 weeks until week 16 and then every 12 weeks using RECIST v1.1. The primary endpoint was 16-week ORR. Statistical comparison across arms was not planned. Results: 48 patients enrolled with 45 randomized, 16-week ORR was 20%, 31% and 14% in the Pac, Pac/Pel and Pac/Pel/Ave arms, respectively. Median progression-free survival (PFS) was 6.4 months (m), 12.1m and 5.8m in the Pac, Pac/Pel and Pac/Pel/Ave arms respectively. There were more adverse events, particularly infusion reactions, in the combination arms than the Pac arm. Expansion of peripheral T cell clones were observed by cycle (C)4 in Pac/Pel but not the Pac or Pac/Pel/Ave arms. Conclusions: The addition of Pel to Pac was associated with increased toxicity, expanded peripheral T-cell clones, and numerically increased ORR and PFS compared to Pac; Pac/Pel/Ave further increased toxicity and blunted T cell responses without obvious increase in efficacy. Investigation of the Pac/Pel combination warrants consideration with careful attention to acute toxicity.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"43 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889617","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":"INTERLINK-1: A Phase III, Randomized, Placebo-Controlled Study of Monalizumab Plus Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma","authors":"Jérôme Fayette, Lisa Licitra, Kevin Harrington, Robert Haddad, Lillian L. Siu, Yi-Chun Liu, Makoto Tahara, Jean-Pascal Machiels, Danny Rischin, Tanguy Y. Seiwert, Robert L. Ferris, Ulrich Keilholz, Amanda Psyrri, Bhumsuk Keam, Paolo Bossi, Robert Metcalf, Ching-Yun Hsieh, Paul M.J. Clement, Pavel Isaev, Ali Mudunov, José Dinis, Ann Hoeben, Stefan Kasper, Konrad Klinghammer, Michael Hwang, Jorge Blando, Olivier Serrano, Dario Ruscica, Roger B. Cohen","doi":"10.1158/1078-0432.ccr-25-0073","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0073","url":null,"abstract":"Purpose: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor (ICI) treatment and platinum-based chemotherapy are limited. Preliminary data suggested monalizumab plus cetuximab had clinical activity in R/M HNSCC. Participants and methods: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received ICI therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, fortnightly) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer (OPC) or human papillomavirus (HPV)-negative OPC (HPV-unrelated analysis set). Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Results: At data cut-off, 216 participants were randomized in the HPV-unrelated analysis set; 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (hazard ratio [HR], 1.00; 95% CI, 0.66–1.54); median PFS was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% CI, 0.79–1.57); and ORR was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed futility criteria were met (predetermined futility HR &amp;gt;0.874). Grade 3–4 treatment-related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. Conclusions: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889622","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":"Clinical Implications of The Cancer Genome Atlas Molecular Classification System in Esophagogastric Cancer","authors":"Henry S. Walch, Raktim Borpatragohain, Justin Jee, Waleed Chatila, Christopher Fong, Steven B. Maron, Geoffrey Y. Ku, David H. Ilson, Yelena Y. Janjigian, Abraham J. Wu, Pari Shah, Daniel G. Coit, Manjit S. Bains, Valerie W. Rusch, Bernard J. Park, Matthew J. Bott, Katherine Gray, David R. Jones, Michael Berger, Nikolaus Schultz, Vivian E. Strong, Daniela Molena, Smita Sihag","doi":"10.1158/1078-0432.ccr-24-3473","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3473","url":null,"abstract":"Purpose: The Cancer Genome Atlas (TCGA) project defined four distinct molecular subtypes of esophagogastric adenocarcinoma: microsatellite instable (MSI), Epstein–Barr virus (EBV)–associated, genomically stable (GS), and chromosomally instable (CIN). However, an association between molecular subtypes and clinical outcomes has not been clearly demonstrated. Given few actionable biomarkers, we investigated the clinical relevance of TCGA classification system. Experimental Design: We identified all patients with esophagogastric adenocarcinoma whose tumors underwent prospective next-generation sequencing using the Memorial Sloan Kettering–IMPACT assay from 2014 to 2023. We classified all tumors in accordance with TCGA methodology and correlated molecular subtypes with high-quality clinicopathologic data. Results: Among 1,438 included patients, 941 had CIN, 344 had GS, 103 had MSI, and 50 had EBV tumors. Accounting for the clinical stage and tumor grade, molecular classification was independently associated with overall cancer-specific survival (P &amp;lt; 0.001) on Cox multivariable analysis. Furthermore, genomic signatures, patient demographics, pathologic responses to neoadjuvant therapy, patterns of recurrence, and metastatic organotropism differed significantly by molecular subtype. Although most distal esophageal and gastroesophageal junction tumors were CIN, up to 25% of these included GS, MSI, or EBV subtypes in contrast to TCGA. Random forest machine learning demonstrated that the molecular subtype is more influential in predicting response to treatment than tumor location. Conclusions: Molecular classification is independently prognostic and may warrant inclusion in future staging and treatment guidelines. Routine molecular profiling is clinically feasible and may play a role in the management of patients to help guide appropriate treatment selection and clinical trial enrollment in the place of tumor location.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"72 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889592","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}