Clinical Cancer Research最新文献

{"title":"First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer","authors":"Timothy A. Yap, Jonathan W. Goldman, Shaveta Vinayak, Antoaneta Tomova, Erika Hamilton, Yoichi Naito, Antonio Giordano, Igor Bondarenko, Toshinari Yamashita, Li Zhou, Allison Moreau, Heather Neumann, Jessica Tougias, Feng Liu, Jennifer Park, Maria Delioukina, Komal Jhaveri","doi":"10.1158/1078-0432.ccr-24-2740","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2740","url":null,"abstract":"Purpose: The discovery that cyclin E overexpression is a key CDK4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2, and simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6. Patients and Methods: Dose escalation included 78 patients with advanced breast cancer, triple negative breast cancer, or ovarian cancer who received oral PF-06873600 1–50 mg twice daily (BID) (Part 1A, n=51), or PF-06873600 with endocrine therapy (Part 1B, n=16; Part 1C n=11) to determine the recommended dose for expansion (RDE). Dose expansion (Part 2A, n=45; Part 2C, n=28) assessed preliminary antitumor activity, safety and tolerability at the RDE in combination with fulvestrant in patients with HR+/HER2– mBC. Pharmacodynamics and translational readouts were assessed by phosphorylated Rb and Ki67 in tumor biopsies and circulating tumor DNA (ctDNA). Results: The RDE of PF-06873600 was 25mg BID. During dose escalation, six of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. Most common all-causality adverse events (N=151) were nausea (62.9%), anemia (44.4%) and fatigue (43.7%). Reductions in Ki67-positive cells, pRb H-score, and ctDNA levels were observed. Three RECIST partial responses (PRs) were observed in Part 1. In Part 2A there were three PRs (objective response rate [ORR] 6.7%, 95% CI: 1.4–18.3%) and, in Part 2C, five PRs (ORR 22.7%, 95% CI: 7.8–45.4%). Conclusions: PF-06873600 demonstrated a benefit–risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in HR+/HER2– mBC. ClinicalTrials.gov identifier: NCT03519178","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"74 1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841243","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":"Facts and hopes in radioimmunotherapy of oligometastatic disease.","authors":"Daniel Huang,Connor Lynch,Sean P Pitroda,Ralph R Weichselbaum","doi":"10.1158/1078-0432.ccr-24-2522","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2522","url":null,"abstract":"The oligometastatic state, characterized by limited metastatic dissemination, challenges the view that metastatic cancer is widespread and incurable. Evidence suggests that select patients with restricted metastases may achieve long-term disease control or even cure with local therapies, such as surgery or stereotactic body radiation therapy (SBRT). Radiotherapy induces complex, dose-dependent effects on the tumor microenvironment, including the release of immunogenic cytokines and damage-associated molecular patterns (DAMPs), enhanced antigen presentation on cancer cells, and infiltration of effector T cells, natural killer (NK) cells, and macrophages. These immunomodulatory effects provide a compelling basis for combining SBRT with immune checkpoint inhibitors (ICIs) to enhance local and systemic anti-tumor immunity. Several prospective phase I-II trials have investigated various combinations of radiotherapy and immunotherapy in the oligometastatic setting, demonstrating acceptable safety profiles and promising efficacy signals. However, clinical outcomes reported with combined radioimmunotherapy have largely been mixed, which likely reflects variability in SBRT dosing, sequencing of therapy, type of immunotherapy, patient selection, and tumor characteristics. Notably, studies employing comprehensive ablative SBRT to all metastatic sites appear to more consistently demonstrate superior outcomes over standard-of-care systemic therapy, as opposed to sub-ablative or single-lesion irradiation. Advancing the therapeutic paradigm of radioimmunotherapy combinations for oligometastatic disease requires improved patient selection based on clinical, molecular, or radiographic features; rigorous optimization of radiotherapy dose-fractionation to maximize immune priming while minimizing toxicities; and rational integration with novel immunotherapeutic agents that target complementary immune pathways.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"49 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846340","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":"Anti-tumor immunity mediated by engineered allogeneic stem cells exploiting TRAIL-induced cell death and FLT3L immunomodulation","authors":"Thijs A. van Schaik, Kok-Siong Chen, Nobuhiko Kanaya, Lucia Moreno-Lama, Nicolas W. Freeman, Mian Wang, Wanlu Li, Yu Shrike. Zhang, Vladimir Vrbanac, Raymond Huang, Hiroaki Wakimoto, David Reardon, Khalid Shah","doi":"10.1158/1078-0432.ccr-24-3835","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3835","url":null,"abstract":"Purpose: Death receptor (DR)-targeted therapies offer a promising tumor cell-specific therapeutic strategy for highly malignant brain tumors, such as glioblastoma (GBM). However, whether DR-mediated cell death leads to activation of the adaptive immune system and impacts the tumor immune microenvironment (TIME) remains unknown. In this study we explored the 1) immunomodulatory role of secretable human DR4/5 ligand, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (S-TRAIL); and 2) the therapeutic potential of allogeneic stem cells (SCs) delivered S-TRAIL and myeloid progenitor cell activating cytokine, FMS-like tyrosine kinase 3 ligand (FLT3L). Experimental Design: We created syngeneic murine immune -active and -suppressive mouse GBM tumor models expressing a human-murine chimeric DR5. Next, we created therapeutic SCs that release FLT3L and S-TRAIL and assessed their efficacy in GBM tumor models. To facilitate clinical translation, we tested the mechanism-based efficacy of encapsulated SC-TRAIL/FLT3L in both syngeneic and humanized mouse tumor-models of GBM-resection. Results: We show that S-TRAIL induced apoptosis in GBM cells provokes infiltration and maturation of dendritic cells (DC) within the TIME in vivo. Next, we show that local transplantation of encapsulated bimodal SCs post-surgical GBM-resection improves the survival probability and induces upregulation of conventional DC type 1 (cDC1) and CD8+ T cells. Furthermore, treatment with encapsulated off-the-shelf clinical-grade bimodal human SCs in GBM-bearing humanized mice results in a significant decrease in tumor-volumes. Conclusions: This study uncovers the immunological role of TRAIL-mediated cell death in the TIME and provides evidence for the encapsulated cell-based therapy to kill residual tumor-cells and induce long-term immunity.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"17 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841244","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":"Sarcopenia and Skeletal Muscle Loss after CAR T-cell Therapy in Diffuse Large B cell Lymphoma","authors":"Khushali Jhaveri, Ram Thapa, Dalia Ercan, Aditi Saha, Jerald Noble, Pranit Singh, Johannes Fahrmann, Neeraj Saini, Ranran Wu, Jennifer B. Dennison, Sam Hanash, Robert R. Jenq, Karnav Modi, Nicholas Figura, Julio Chavez, Bijal Shah, Taiga Nishihori, Aleksandr Lazaryan, Farhad Khimani, Christina Bachmeier, Kenneth Gage, Asmita Mishra, Fabiana Perna, Marco L. Davila, Jay Spiegel, Kai Rejeski, Marion Subklewe, Frederick L. Locke, Ciara Freeman, Nathan Parker, Michael D. Jain","doi":"10.1158/1078-0432.ccr-24-3782","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3782","url":null,"abstract":"Purpose: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy is associated with an inflammatory state that may exacerbate sarcopenia. The relationship between CAR T-cell therapy, sarcopenia, and metabolism is poorly understood. Experimental Design: In 83 large B-cell lymphoma patients, the skeletal muscle index (SMI) was measured from clinical images obtained at baseline and days 30 and 90 post-therapy. Serum metabolomics (n=57 patients) was performed in the first 4 weeks. Results: Baseline sarcopenia was present in over half of patients and associated with shorter median overall survival (OS) than for non-sarcopenic patients (10.5 versus 34.3 months; P=0.006). This reduction was due to increased non-relapse mortality (NRM) with all six NRM events occurring in patients with baseline sarcopenia. In the first 30 days after CAR T-cell therapy, 1/3 of patients experienced skeletal muscle loss greater than 10%. Muscle loss was associated with higher tumor burden and neurotoxicity but was not significantly associated with long term survival. Serum metabolomics revealed an early (weeks 1-2) increase in purine metabolites, followed by a later (weeks 3-4) increase in triglyceride levels. The serum metabolite with the highest fold-increase from baseline was adipic acid, attributed to the inpatient hospital menu of Jello and other tart beverages. Conclusions: Skeletal muscle loss after CAR T-cell therapy is common and is associated with fatty acid catabolism. Patients with baseline sarcopenia have poor tolerance and reduced survival. Future studies of dietary and exercise interventions may improve CAR T-cell therapy outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841284","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 1 Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients With Advanced Myeloid Malignancies","authors":"Courtney D. DiNardo, Amir T. Fathi, Ashwin Kishtagari, Kapil N. Bhalla, Alfonso Quintás-Cardama, Sarah A. Reilly, Caroline Almon, Caitlin Patriquin, Salah Nabhan, Kathleen Healy, Denice Hickman, Michael P. Collins, Alexis Khalil, Dillon Corrigan, Tina Zhao, Jessica Piel, Kelly Lyons, Kim Horrigan, Virna Schuck, Paul Martin, GiNell Elliott, David L. Lahr, Mia Bosinger, Katie D'Aco, Gromoslaw Aleksander. Smolen, Murphy Hentemann, Sanam Loghavi, Samuel Agresta, Michael R. Savona, Eytan M. Stein","doi":"10.1158/1078-0432.ccr-24-3790","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3790","url":null,"abstract":"Purpose: Safety and preliminary clinical activity of FHD-286, a dual BRG1/BRM inhibitor, were evaluated in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Patients and methods: In this multicenter, open-label, phase 1, dose escalation study (NCT04891757), patients received FHD-286 orally once daily (QD) at 2.5, 5, 7.5, and 10 mg. Results: Forty patients (median age 65.5 years; 85% with adverse genetic status; 65% with ≥3 prior therapy lines) received FHD-286 for 28 days (median). FHD-286 was not tolerated at 10 mg QD. Across all doses, treatment-related adverse events (TRAEs) were predominantly Grade 1-2, most commonly dry mouth (27.5%) and increased alanine aminotransferase (20%). Dose-limiting Grade 3 hyperbilirubinemia and Grade 3 muscular weakness occurred at 5 and 10 mg QD, respectively. The most common serious TRAE was differentiation syndrome (DS) (10%). An independent committee retrospectively adjudicated DS in 15% of patients (five Grade 3, one Grade 4). FHD-286 plasma exposure increased with dose and accumulated with continuous dosing. Exposures were typically higher with concomitant CYP3A4 inhibitors. Myeloid differentiation and leukemic burden reduction were observed across cytogenetic and mutational backgrounds, notably in patients with enhancer-driven genotypes. There were no objective responses. Conclusions: DS was the most frequent serious TRAE. While antileukemic activity was observed, no objective responses were achieved and disease progression frequently occurred within 1-2 treatment cycles. Blast reductions were reported across cytogenetic and mutational profiles, coupled with myeloid differentiation via BRG1/BRM inhibition. This novel mechanism warrants further investigation of FHD-286 in combination with other agents in myeloid malignancies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"60 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841283","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":"Finding Rearrangements in the Cell-Free DNA Haystack","authors":"Kurtis D. Davies","doi":"10.1158/1078-0432.ccr-25-0432","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0432","url":null,"abstract":"Circulating tumor DNA (ctDNA) analysis is now a widely used diagnostic approach in the management of patients with solid tumors, including gene fusion-driven lung cancer. However, the accurate detection of genetic rearrangements in ctDNA presents considerable technical challenges. Consequently, studies that assess and compare methodologies for detection are vital.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841285","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":"Clocking Recurrence: Circulating Tumor HPV DNA Kinetics in Anal Cancer.","authors":"Aron Bercz,Daniel L Faden,J Joshua Smith,Paul B Romesser","doi":"10.1158/1078-0432.ccr-25-0421","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0421","url":null,"abstract":"Detection of circulating tumor human papillomavirus DNA (ctHPVDNA) three months after completing definitive chemoradiation for localized anal squamous cell carcinoma associates with disease recurrence and inferior recurrence-free survival. These findings provide valuable insights into the temporal significance of ctHPVDNA detection in anal cancer and its potential implications for early intervention.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"116 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Update on Surveillance in Von Hippel-Lindau Disease.","authors":"Surya P Rednam,Kerri D Becktell,Anita Villani,Garrett M Brodeur,Lisa J States,Andrea S Doria,Junne Kamihara,Kami Wolfe Schneider,Stephan D Voss,Elysa Widjaja,Kristin Zelley,Yoshiko Nakano,Kristian W Pajtler,Maria Isabel Achatz,David Malkin,Lisa R Diller,Bailey Gallinger,Chieko Tamura,Jonathan D Wasserman","doi":"10.1158/1078-0432.ccr-24-3525","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3525","url":null,"abstract":"Von Hippel-Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body including the central nervous system, visual-auditory systems, and intra-abdominal organs. This neoplasia leads to significant morbidity and potential mortality in affected individuals. Tumor surveillance enables early intervention and leads to improved clinical outcomes. Since the 2017 publication of VHL tumor surveillance recommendations from the inaugural AACR Childhood Cancer Predisposition Workshop, several other groups have proposed alternative consensus surveillance recommendations. Although these screening paradigms share some common elements, they also deviate from each other in some substantial ways. Clinical data continues to accrue in VHL, allowing the condition to be better characterized. Furthermore, surgical techniques have improved over time, and the option of targeted medical therapy has emerged for individuals with VHL. It is critical that surveillance strategies continue to be refined. In this perspective, we provide an up-to-date clinical overview of VHL, describe recently proposed tumor screening regimens, and finally present our updated consensus tumor surveillance recommendations during childhood and adolescence from the 2023 AACR Childhood Cancer Predisposition Workshop.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836546","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 Context Shapes the Relationship Between Genomic Alterations and Response to AR Inhibitors and Chemotherapy in Metastatic Prostate Cancer.","authors":"Kalpit Shah,Matthew H Secrest,Wei Zhou,Shu Wang,Dan Canter,Yuxiang Zhang,Dexter Jin,Ethan Sokol,Malgorzata Nowicka,Armande Ang Houle,Ciara Metcalfe,Steven Gendreau,Carsten Schröder,Matthew Wongchenko,Gerhardt Attard","doi":"10.1158/1078-0432.ccr-24-1812","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1812","url":null,"abstract":"PURPOSEMany preclinical hypotheses, including reciprocal feedback activation between AR-PI3K pathway in PTEN loss and ASI-induced \"BRCAness\" regardless of BRCA1/2 status, have struggled to translate into clinical benefit for metastatic prostate cancer patients. This gap in translatability, particularly in mCRPC, may stem from a limited understanding of prostate cancer evolution. A key challenge is how early-stage tumor genetics correlate with mCRPC. By examining clinical, genomic, and molecular changes over time, we aim to refine clinical trial design.EXPERIMENTAL DESIGNUsing a comprehensive dataset from electronic health records (EHR) with genomic profiling, we observed a shift in the prognostic value of biomarkers from mHSPC to mCRPC. Additionally, genomic and transcriptomic analyses of primary tumors from the IPATential150 trial and mCRPC samples from the SU2C cohort examined the changing AR-PI3K signaling correlation.RESULTSPI3K-AKT pathway alterations lost their prognostic significance in later stages. While AR and PI3K-AKT signaling were inversely correlated in primary tumors, this relationship was disrupted in mCRPC, independent of PIK3CA/AKT1/PTEN status. We identified broad transcriptional rewiring associated with AR signaling, increasing tumor heterogeneity. Improving understanding of early-stage disease, we identified a high-risk mHSPC subset enriched for AR alterations. Additionally, in a subset of patients, AR ligand-binding domain mutations preceded amplification, potentially leading to preferential amplification of the mutant AR form.CONCLUSIONSOur findings underscore the dynamic nature of prostate tumor biology and emphasize the need for translational research to validate preclinical hypotheses in clinically relevant settings, ultimately improving trial design and therapeutic strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831560","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":"Personalized neoadjuvant chemotherapy for gastrointestinal cancers - shaping imprecision to be precise.","authors":"Dan Høgdall,Jakob V Schou,Julia Johanna Almer Bromann,Jesper B Andersen,Colm J O'Rourke","doi":"10.1158/1078-0432.ccr-24-4309","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4309","url":null,"abstract":"Neoadjuvant chemotherapy can down-size or down-stage tumors, minimize post-surgical recurrence risk, or even replace surgery when deployed appropriately for patients with gastrointestinal cancers. However, accomplishing these goals is rate-limited by all-comer treatment protocols, median arm-based comparisons in clinical trials, and the persisting omission of precision approaches for cytotoxic agents. Despite heterogeneity in benefit from standard-of-care regimens, mounting biological data support the presence of actionable sensitivities or potentially targetable dependencies in most tumors. Conceptually, such tumor vulnerabilities could be a gamechanger. In treatment-resistant malignancies (biliary tract cancer, pancreatic ductal adenocarcinoma), individualized neoadjuvant treatment may increase the curative surgery frequencies that currently only occur in a minority of patients. For more treatment-sensitive gastrointestinal cancers, tailored chemotherapy strategies might reduce the need for high-intensity regimens, minimize post-surgical morbidity and allow dose de-escalation for selected patients without compromising oncological outcomes. Personalizing chemotherapy strategies remains inferential from comparing outcomes of molecularly distinct patients receiving a single treatment, or unselected patients (with comparable baseline characteristics) on different regimens. We discuss the critical importance of harnessing tumor biology to develop and implement predictive signatures for personalized neoadjuvant chemotherapy (alone or in combination with other modalities). This includes exploiting transcriptomics to retrospectively understand the molecular basis of treatment outcomes from patient biopsies, identifying existing agents to replace or supplement current standard-of-care for those unlikely to respond, and matching novel preclinical treatments to potential responder patients. Deploying mechanistically distinct cytotoxic regimens against gastrointestinal tumors with unique predispositions for DNA damage tolerance is a necessity for boosting neoadjuvant outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"119 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831627","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}