{"title":"Dissecting Out a Rare Mutation, STAT: Features of STAT3-Mutant Myeloid Neoplasms.","authors":"Michael J Hochman, David A Frank","doi":"10.1158/1078-0432.CCR-24-1692","DOIUrl":"10.1158/1078-0432.CCR-24-1692","url":null,"abstract":"<p><p>The transcription factor STAT3 drives the expression of genes promoting cellular proliferation, survival, and pluripotency. The description of STAT3 mutations and their clinical correlates in myeloid neoplasms, such as acute myeloid leukemia and myelodysplastic syndromes, raises new insights into both the pathogenesis and the targeted therapy of these diseases. See related article by Ye et al., p. 4681.</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":"141896871","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}
Crescenzo Massaro, Hilal N Sensoy, Manon Mulders, Celine De Schrijver, Cristina Gómez-Martín, Juan Simon Nieto, Tonny Lagerweij, Alisha Atmopawiro, Jennifer Pérez-Boza, Maarten Bebelman, Leontien Bosch, Simone Foderaro, Mafalda Neves Ferreira, Monique A J van Eijndhoven, Jan R T van Weering, Carmela Dell'Aversana, Lucia Altucci, Cemile Dilara Savci-Heijink, Niels W C J van de Donk, Cristina Giorgio, Laura Brandolini, Marcello Allegretti, Dirk Michiel Pegtel, Serena Rubina Baglio
{"title":"Tumor-Secreted Extracellular Vesicles Counteract Therapy Response by Triggering Inflammatory Mesenchymal Stem Cell Development.","authors":"Crescenzo Massaro, Hilal N Sensoy, Manon Mulders, Celine De Schrijver, Cristina Gómez-Martín, Juan Simon Nieto, Tonny Lagerweij, Alisha Atmopawiro, Jennifer Pérez-Boza, Maarten Bebelman, Leontien Bosch, Simone Foderaro, Mafalda Neves Ferreira, Monique A J van Eijndhoven, Jan R T van Weering, Carmela Dell'Aversana, Lucia Altucci, Cemile Dilara Savci-Heijink, Niels W C J van de Donk, Cristina Giorgio, Laura Brandolini, Marcello Allegretti, Dirk Michiel Pegtel, Serena Rubina Baglio","doi":"10.1158/1078-0432.CCR-23-4097","DOIUrl":"10.1158/1078-0432.CCR-23-4097","url":null,"abstract":"<p><strong>Purpose: </strong>Therapy resistance is a major clinical hurdle in bone cancer treatment and seems to be largely driven by poorly understood microenvironmental factors. Recent evidence suggests a critical role for a unique subpopulation of mesenchymal stem cells with inflammatory features (iMSC), though their origin and function remained unexplored. We demonstrate that cancer-secreted extracellular vesicles (EV) trigger the development of iMSCs, which hinder therapy response in vivo, and set out to identify strategies to counteract their function.</p><p><strong>Experimental design: </strong>The role of iMSCs in therapy resistance was evaluated in an orthotopic xenograft mouse model of osteosarcoma. EV-induced alterations of the MSC transcriptome were analyzed and compared with single-cell RNA sequencing data of biopsies from patients with osteosarcoma and multiple myeloma. Functional assays identified EV components driving iMSC development. We assessed the efficacy of clinical drugs in blocking iMSC-induced resistance in vivo.</p><p><strong>Results: </strong>We found that iMSCs are induced by interaction with cancer EVs and completely abrogate the antimetastatic effect of TGFβ signaling inhibition. Importantly, EV-induced iMSCs faithfully recapitulate the inflammatory single-cell RNA signature of stromal cells enriched in biopsies from patients with multiple myeloma and osteosarcoma. Mechanistically, cancer EVs act through two distinct mechanisms. EV-associated TGFβ induces IL6 production, whereas the EV-RNA cargo enhances TLR3-mediated chemokine production. We reveal that simultaneous blockade of downstream EV-activated pathways with ladarixin and tocilizumab disrupts metastasis formation and overcomes iMSC-induced resistance.</p><p><strong>Conclusions: </strong>Our observations establish iMSCs as major contributors to drug resistance, reveal EVs as triggers of iMSC development, and highlight a promising combination strategy to improve therapy response in patients with bone cancer.</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":"141901067","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}
C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay
{"title":"YAP1 Status Defines Two Intrinsic Subtypes of LCNEC with Distinct Molecular Features and Therapeutic Vulnerabilities.","authors":"C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay","doi":"10.1158/1078-0432.CCR-24-0361","DOIUrl":"10.1158/1078-0432.CCR-24-0361","url":null,"abstract":"<p><strong>Purpose: </strong>Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.</p><p><strong>Experimental design: </strong>To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.</p><p><strong>Results: </strong>In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK- and AXL-targeting strategies, including a novel preclinical AXL chimeric antigen receptor-expressing T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by the expression of SCLC subtype-defining transcription factors, especially ASCL1 and NEUROD1, and as expected, given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including delta-like ligand 3 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor-expressing T cells, and DNA damage repair inhibition.</p><p><strong>Conclusions: </strong>YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC.</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/PMC11479841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987564","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":"Tissue-resident T cells in Clinical Response and Immune-related Adverse Events of Immune Checkpoint Blockade.","authors":"Ye Zhao,Kai W Wucherpfennig","doi":"10.1158/1078-0432.ccr-23-3296","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-23-3296","url":null,"abstract":"T cell surveillance of tissues is spatially organized: circulating memory T cells perform surveillance of secondary lymphoid organs while tissue-resident memory T cells act as sentinels in barrier tissues. In the context of infection, tissue-resident memory T cells survive long term in barrier tissues and are poised to respond to re-encounter of infectious agents. The activity of such tissue-resident T cells is regulated by the PD-1 and CTLA-4 inhibitory receptors targeted by cancer immunotherapies. This review investigates the hypothesis that T cells with a tissue residency program play an important role in both protective anti-tumor immunity and immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). A series of translational studies have demonstrated that a higher density of tissue-resident T cells within tumors is associated with favorable survival outcomes in a diverse range of cancer types. Tissue-resident T cells have also been implicated in clinical response to immune checkpoint blockade, and dynamic tracking of T cell populations in pre- and on-treatment tumor samples demonstrated that T cells with a tissue residency program responded early to ICB. Investigation of colitis and dermatitis as examples of irAEs demonstrated that tissue-resident memory T cells were reactivated at these epithelial sites, resulting in a highly cytotoxic state and secretion of inflammatory cytokines IFNγ and TNFα. It will therefore be important to consider how a tissue residency program can be enhanced to promote T cell-mediated tumor immunity while preventing the development of irAEs.","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":"142439564","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}
Changhwan Yoon, Do Joong Park, Benjamin Schmidt, Nicholas J Thomas, Hae-June Lee, Teresa S Kim, Yelena Y Janjigian, Deirdre J Cohen, Sam S Yoon
{"title":"Retraction: CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance.","authors":"Changhwan Yoon, Do Joong Park, Benjamin Schmidt, Nicholas J Thomas, Hae-June Lee, Teresa S Kim, Yelena Y Janjigian, Deirdre J Cohen, Sam S Yoon","doi":"10.1158/1078-0432.CCR-24-2134","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2134","url":null,"abstract":"","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":"142459444","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}
Yeong Hak Bang, Choong-Kun Lee, Kyunghye Bang, Hyung-Don Kim, Kyu-Pyo Kim, Jae Ho Jeong, Inkeun Park, Baek-Yeol Ryoo, Dong Ki Lee, Hye Jin Choi, Taek Chung, Seung Hyuck Jeon, Eui-Cheol Shin, Chiyoon Oum, Seulki Kim, Yoojoo Lim, Gahee Park, Chang Ho Ahn, Taebum Lee, Richard S Finn, Chan-Young Ock, Jinho Shin, Changhoon Yoo
{"title":"Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as a Potential Biomarker for Immune Checkpoint Inhibitors in Patients with Biliary Tract Cancer.","authors":"Yeong Hak Bang, Choong-Kun Lee, Kyunghye Bang, Hyung-Don Kim, Kyu-Pyo Kim, Jae Ho Jeong, Inkeun Park, Baek-Yeol Ryoo, Dong Ki Lee, Hye Jin Choi, Taek Chung, Seung Hyuck Jeon, Eui-Cheol Shin, Chiyoon Oum, Seulki Kim, Yoojoo Lim, Gahee Park, Chang Ho Ahn, Taebum Lee, Richard S Finn, Chan-Young Ock, Jinho Shin, Changhoon Yoo","doi":"10.1158/1078-0432.CCR-24-1265","DOIUrl":"10.1158/1078-0432.CCR-24-1265","url":null,"abstract":"<p><strong>Purpose: </strong>Recently, anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD1/L1) immunotherapy has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TIL) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD1.</p><p><strong>Experimental design: </strong>Pretreatment hematoxylin and eosin (H&E)-stained whole-slide images from 339 patients with advanced BTC who received anti-PD1 as second-line treatment or beyond, were employed for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD1. Next, data and images of the BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IP in BTC.</p><p><strong>Results: </strong>Overall, AI-IP were classified as inflamed [high intratumoral TIL (iTIL)] in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 patients (49.3%), and immune-desert (low TIL overall) in 132 patients (38.9%). The inflamed IP group showed a substantially higher overall response rate compared with the noninflamed IP groups (27.5% vs. 7.7%, P < 0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the noninflamed IP group (OS, 12.6 vs. 5.1 months; P = 0.002; PFS, 4.5 vs. 1.9 months; P < 0.001). In the TCGA cohort analysis, the inflamed IP showed increased cytolytic activity scores and IFNγ signature compared with the noninflamed IP.</p><p><strong>Conclusions: </strong>AI-IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD1 therapy. Further validation is necessary in the context of anti-PD1/L1 plus gemcitabine-cisplatin.</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":"141987539","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}
Nabil F Saba, Ritu Chaudhary, Kedar Kirtane, Angelo Marra, Asari Ekpenyong, Ashley McCook-Veal, Nicole C Schmitt, Jennifer H Gross, Mihir R Patel, Jill Remick, James E Bates, Mark W McDonald, Soumon F Rudra, William A Stokes, Maria Biernacki, Xiaofei Song, Robbert J C Slebos, Yuan Liu, Conor E Steuer, Dong M Shin, Yong Teng, Christine H Chung
{"title":"Pembrolizumab and Cabozantinib in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Long-term Survival Update with a Biomarker Analysis.","authors":"Nabil F Saba, Ritu Chaudhary, Kedar Kirtane, Angelo Marra, Asari Ekpenyong, Ashley McCook-Veal, Nicole C Schmitt, Jennifer H Gross, Mihir R Patel, Jill Remick, James E Bates, Mark W McDonald, Soumon F Rudra, William A Stokes, Maria Biernacki, Xiaofei Song, Robbert J C Slebos, Yuan Liu, Conor E Steuer, Dong M Shin, Yong Teng, Christine H Chung","doi":"10.1158/1078-0432.CCR-24-1202","DOIUrl":"10.1158/1078-0432.CCR-24-1202","url":null,"abstract":"<p><strong>Purpose: </strong>Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy in different malignancies. We report the long-term efficacy and safety of pembrolizumab and cabozantinib in patients with RMHNSCC and include a correlative biomarker analysis.</p><p><strong>Patients and methods: </strong>This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. The primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, and safety of treated patients and describe correlative biomarkers evaluating p-MET expression and tumor immune microenvironment (TIME) using multiplex immunohistochemistry.</p><p><strong>Results: </strong>With median follow-up of 22.4 months, the median PFS was 12.8 months with a 2-year PFS of 32.6% (95% CI, 18.8%-56.3%) and the median OS was 27.7 months with a 2-year OS of 54.7% [95% confidence interval (CI), 38.9%-76.8%]. The median duration of response was 12.6 months with a 2-year rate of 38.5% (95% CI, 30.8%-81.8%). Long-term treatment-related adverse events included manageable hypothyroidism (5.5%) and grade 1 elevated aspartate aminotransferase and alanine aminotransferase (2.8%). Baseline tumor p-MET expression correlated with ORR (P = 0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS [hazard ratio (HR) = 5.27, P = 0.030; HR = 8.79, P = 0.017; HR = 6.87, P = 0.040, respectively].</p><p><strong>Conclusions: </strong>Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of higher density of CD8+, CD103+, and CSF1-R+ cells in TIME deserve further evaluation in similar clinical settings.</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/PMC11479816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016553","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}
Maryam Sarraf Yazdy,Yvette L Kasamon,Wenjuan Gu,Lisa R Rodriguez,Susan Jin,Vishal Bhatnagar,Nicholas C Richardson,Marc R Theoret,Richard Pazdur,Nicole J Gormley
{"title":"FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.","authors":"Maryam Sarraf Yazdy,Yvette L Kasamon,Wenjuan Gu,Lisa R Rodriguez,Susan Jin,Vishal Bhatnagar,Nicholas C Richardson,Marc R Theoret,Richard Pazdur,Nicole J Gormley","doi":"10.1158/1078-0432.ccr-24-1729","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1729","url":null,"abstract":"In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.","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":"142439648","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}
Max Piffoux, Jérémie Jacquemin, Mélanie Pétéra, Stéphanie Durand, Angélique Abila, Delphine Centeno, Charlotte Joly, Bernard Lyan, Anne-Laure Martin, Sibille Everhard, Sandrine Boyault, Barbara Pistilli, Marion Fournier, Philippe Rouanet, Julie Havas, Baptiste Sauterey, Mario Campone, Carole Tarpin, Marie-Ange Mouret-Reynier, Olivier Rigal, Thierry Petit, Christine Lasset, Aurélie Bertaut, Paul Cottu, Fabrice André, Ines Vaz-Luis, Estelle Pujos-Guillot, Youenn Drouet, Olivier Trédan
{"title":"Metabolomic Prediction of Breast Cancer Treatment-Induced Neurologic and Metabolic Toxicities.","authors":"Max Piffoux, Jérémie Jacquemin, Mélanie Pétéra, Stéphanie Durand, Angélique Abila, Delphine Centeno, Charlotte Joly, Bernard Lyan, Anne-Laure Martin, Sibille Everhard, Sandrine Boyault, Barbara Pistilli, Marion Fournier, Philippe Rouanet, Julie Havas, Baptiste Sauterey, Mario Campone, Carole Tarpin, Marie-Ange Mouret-Reynier, Olivier Rigal, Thierry Petit, Christine Lasset, Aurélie Bertaut, Paul Cottu, Fabrice André, Ines Vaz-Luis, Estelle Pujos-Guillot, Youenn Drouet, Olivier Trédan","doi":"10.1158/1078-0432.CCR-24-0195","DOIUrl":"10.1158/1078-0432.CCR-24-0195","url":null,"abstract":"<p><strong>Purpose: </strong>Long-term treatment-related toxicities, such as neurologic and metabolic toxicities, are major issues in breast cancer. We investigated the interest of metabolomic profiling to predict toxicities.</p><p><strong>Experimental design: </strong>Untargeted high-resolution metabolomic profiles of 992 patients with estrogen receptor (ER)+/HER2- breast cancer from the prospective CANTO cohort were acquired (n = 1935 metabolites). A residual-based modeling strategy with discovery and validation cohorts was used to benchmark machine learning algorithms, taking into account confounding variables.</p><p><strong>Results: </strong>Adaptive Least Absolute Shrinkage and Selection (adaptive LASSO) has a good predictive performance, has limited optimism bias, and allows the selection of metabolites of interest for future translational research. The addition of low-frequency metabolites and nonannotated metabolites increases the predictive power. Metabolomics adds extra performance to clinical variables to predict various neurologic and metabolic toxicity profiles.</p><p><strong>Conclusions: </strong>Untargeted high-resolution metabolomics allows better toxicity prediction by considering environmental exposure, metabolites linked to microbiota, and low-frequency metabolites.</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":"141893003","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":"Targeting the FGFR Pathway in Patients with Advanced Solid Tumors.","authors":"Chadi Hage Chehade, Zeynep Irem Ozay, Neeraj Agarwal","doi":"10.1158/1078-0432.CCR-24-1711","DOIUrl":"10.1158/1078-0432.CCR-24-1711","url":null,"abstract":"<p><p>In the phase II FUZE trial targeting the FGFR pathway, Debio 1347 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Results from transcriptome-based analysis enhanced our understanding of the genomic landscape of FGFR fusion-driven tumors, informing clinical trial design and generating hypotheses for resistance mechanisms. See related article by Grivas et al., p. 4572.</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":"141901066","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}