Clinical Cancer Research最新文献

{"title":"Chemotherapy Drives Tertiary Lymphoid Structures That Correlate with ICI-Responsive TCF1+CD8+ T Cells in Metastatic Ovarian Cancer.","authors":"Tereza Lanickova, Michal Hensler, Lenka Kasikova, Sarka Vosahlikova, Artemis Angelidou, Josef Pasulka, Hannah Griebler, Jana Drozenova, Katerina Mojzisova, Ann Vankerckhoven, Jan Laco, Ales Ryska, Pavel Dundr, Roman Kocian, David Cibula, Tomas Brtnicky, Petr Skapa, Francis Jacob, Marek Kovar, Ivan Praznovec, Iain A McNeish, Michal J Halaska, Lukas Rob, An Coosemans, Sandra Orsulic, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova","doi":"10.1158/1078-0432.CCR-24-1594","DOIUrl":"10.1158/1078-0432.CCR-24-1594","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication.</p><p><strong>Experimental design: </strong>We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts.</p><p><strong>Results: </strong>We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden.</p><p><strong>Conclusions: </strong>Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"164-180"},"PeriodicalIF":10.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11701433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003744","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":"Genomic and Epigenomic Analysis of Plasma Cell-Free DNA Identifies Stemness Features Associated with Worse Survival in Lethal Prostate Cancer.","authors":"Pradeep S Chauhan, Irfan Alahi, Savar Sinha, Elisa M Ledet, Ryan Mueller, Jessica Linford, Alexander L Shiang, Jace Webster, Lilli Greiner, Breanna Yang, Gabris Ni, Ha X Dang, Debanjan Saha, Ramandeep K Babbra, Wenjia Feng, Peter K Harris, Faridi Qaium, Dzifa Y Duose, Sanchez E Alexander, Alexander D Sherry, Ellen B Jaeger, Patrick J Miller, Sydney A Caputo, Jacob J Orme, Fabrice Lucien, Sean S Park, Chad Tang, Russell K Pachynski, Oliver Sartor, Christopher A Maher, Aadel A Chaudhuri","doi":"10.1158/1078-0432.CCR-24-1658","DOIUrl":"10.1158/1078-0432.CCR-24-1658","url":null,"abstract":"<p><strong>Purpose: </strong>Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood.</p><p><strong>Experimental design: </strong>We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA.</p><p><strong>Results: </strong>Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P < 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing.</p><p><strong>Conclusions: </strong>We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness. See related commentary by Nawfal et al., p. 7.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"151-163"},"PeriodicalIF":10.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035361","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":"FDA Approval Summary: Olutasidenib for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase 1 Mutation.","authors":"Ashley C Woods, Kelly J Norsworthy, Moran Choe, Brenda J Gehrke, Haiyan Chen, Jonathon Vallejo, Lili Pan, Xiling Jiang, Hongshan Li, Jeffrey Kraft, Jiang Liu, Rosane Charlab, Olanrewaju O Okusanya, Brian Booth, Richard Pazdur, Marc R Theoret, R Angelo de Claro","doi":"10.1158/1078-0432.CCR-24-2196","DOIUrl":"10.1158/1078-0432.CCR-24-2196","url":null,"abstract":"<p><p>On December 1, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia, Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase 1, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase 1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence to transfusion independence in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150 mg twice daily of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% confidence interval, 27%-43%), with a median duration of response of 25.9 months [95% confidence interval, 13.5-not reached]. Of the 86 patients who were transfusion dependent at baseline, 29 became transfusion independent (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"12-17"},"PeriodicalIF":10.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544089","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":"Unearthing a Prostate Cancer cfDNA Signature that \"Stems\" from AR Alterations.","authors":"Rashad Nawfal, Razane El Hajj Chehade, Jacob E Berchuck","doi":"10.1158/1078-0432.CCR-24-2849","DOIUrl":"10.1158/1078-0432.CCR-24-2849","url":null,"abstract":"<p><p>Androgen receptor alterations portend a poor prognosis in patients with advanced prostate cancer. A recent study identified a stemness signature enriched in cell-free DNA from androgen receptor-altered patients, associated with worse outcomes. These findings highlight the potential of epigenomic liquid biopsy tools to discover novel clinically relevant tumor molecular subtypes. See related article by Chauhan et al., p. 151.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"7-9"},"PeriodicalIF":10.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567613","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":"Integrating Molecular Imaging and Transcriptomic Profiling in Advanced HER2-Positive Breast Cancer Receiving Trastuzumab Emtansine: An Analysis of the ZEPHIR Clinical Trial.","authors":"Mattia Rediti, Danai Fimereli, Magdalena Mileva, Zéna Wimana, David Venet, Patrick Flamen, Thomas Guiot, Elisabeth G E de Vries, Carolien P Schröder, Catharina Willemien Menke-van der Houven van Oordt, Marion Maetens, Samira Majjaj, Denis Larsimont, Françoise Rothé, Christos Sotiriou, Géraldine Gebhart","doi":"10.1158/1078-0432.CCR-24-1007","DOIUrl":"10.1158/1078-0432.CCR-24-1007","url":null,"abstract":"<p><strong>Purpose: </strong>The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). In this study, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake and to dissect the mechanisms involved in T-DM1 resistance.</p><p><strong>Experimental design: </strong>RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.</p><p><strong>Results: </strong>We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, whereas immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.</p><p><strong>Conclusions: </strong>To the best of our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role for ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"110-121"},"PeriodicalIF":10.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521166","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":"Long-term effect and safety of mesenchymal stromal cell therapy for radiation-induced hyposalivation in head and neck cancer survivors: A randomised, phase-2, trial.","authors":"Amanda-Louise Fenger Carlander, Kathrine Kronberg Jakobsen, Tobias Todsen, Natasja Paaske, Anne Kathrine Østergaard Madsen, Simone Kloch Bendtsen, Jens Kastrup, Jeppe Friborg, Charlotte Duch Lynggaard, Anne Werner Hauge, Robin Christensen, Christian Grønhøj, Christian von Buchwald","doi":"10.1158/1078-0432.CCR-24-2663","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2663","url":null,"abstract":"<p><strong>Background: </strong>The long-term effect of adipose-derived mesenchymal stromal cells (ASCs) to restore radiation-induced salivary gland hypofunction in previous head and neck cancer patients have not been validated in larger settings.</p><p><strong>Methods: </strong>The study was the 12-months follow-up of a randomised trial, including patients with hyposalivation. Patients were randomised to receive allogeneic ASCs or placebo in the submandibular glands. Primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module and the Xerostomia Questionnaire) and safety.</p><p><strong>Results: </strong>Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASCs did not increase UWS compared to placebo: increase in UWS was 0.02 mL/min (95% CI 0.01 to 0.04) in the ASC group and 0.02 mL/min (95% CI 0 to 0.03) in the placebo group, p=0.56. ASCs reduced the symptom burden for dry mouth with -10.07 units (95% CI -13.39 to -6.75) compared to -4.15 units (95% CI -7.46 to -0.84) in the placebo group, p=0.01. Compared to placebo, ASCs did not improve sticky saliva (-9.27 vs. -4.55 units, p=0.13), swallowing (-4.50 vs. 3.49 units, p=0.5) or xerostomia -3.12 vs. -2.74 units, p=0.82). Treatment was safe and associated with a transient immune response.</p><p><strong>Conclusion: </strong>Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASCs and placebo increased UWS, but ASCs did not prove superior to placebo in restoring salivary gland function, based on salivary flow rate.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920887","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 I clinical trial adding OX40 agonism to in situ therapeutic cancer vaccination in patients with low-grade B cell lymphoma highlights challenges in translation from mouse to human studies.","authors":"Tanaya Shree, Debra Czerwinski, Sarah Haebe, Anuja Sathe, Sue Grimes, Brock Martin, Michael Ozawa, Richard Hoppe, Hanlee Ji, Ronald Levy","doi":"10.1158/1078-0432.CCR-24-2770","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2770","url":null,"abstract":"<p><strong>Purpose: </strong>Activating T cell costimulatory receptors is a promising approach for cancer immunotherapy. In preclinical work, adding an OX40 agonist to in situ vaccination (ISV) with SD101, a TLR9 agonist, was curative in a mouse model of lymphoma. We sought to test this combination in a Phase I clinical trial for patients with low-grade B cell lymphoma.</p><p><strong>Patients and methods: </strong>We treated 14 patients with low-dose radiation, intratumoral SD101, and intratumoral and intravenous BMS986178, an agonistic anti-OX40 antibody. The primary outcome was safety. Secondary outcomes included overall response rate and progression-free survival.</p><p><strong>Results: </strong>Adverse events were consistent with prior experience with low-dose radiation and SD101. No synergistic or dose-limiting toxicities were observed. One patient had a partial response, and 9 patients had stable disease, a result inferior to our experience with TLR9 agonism and low-dose radiation alone. Flow cytometry and single cell RNA sequencing of serial tumor biopsies revealed that T and NK cells were activated after treatment. However, high baseline OX40 expression on T follicular helper and T regulatory type 1 cells, as well as high post-treatment soluble OX40, shed from these T cells upon activation, associated with progression-free survival of less than 6 months.</p><p><strong>Conclusions: </strong>Clinical results of T cell costimulatory receptor agonism have now repeatedly been inferior to the motivating preclinical results. Our study highlights potential barriers to clinical translation, particularly differences in preclinical and clinical reagents and the complex biology of these coreceptors in heterogenous T cell subpopulations, some of which may antagonize immunotherapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913791","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":"TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer.","authors":"Rachel O Abelman, Bogang Wu, Haley Barnes, Arielle Medford, Bryanna Norden, Annika Putur, Elena Bitman, Win Thant, Ting Liu, Caroline Weipert, Geoffrey Fell, Laura M Spring, Seth Wander, Beverly Moy, Neelima Vidula, Steven J Isakoff, Andreas Varkaris, Dejan Juric, Ryan Corcoran, Leif W Ellisen, Aditya Bardia","doi":"10.1158/1078-0432.CCR-24-2771","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2771","url":null,"abstract":"<p><strong>Purpose: </strong>Antibody-drug conjugates (ADCs) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer (MBC). However, knowledge of ADC resistance mechanisms and potential impact on sequential use of ADCs is limited. Here, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in MBC.</p><p><strong>Methods: </strong>Patients with MBC treated with ADCs with available post-treatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency (MAF) and functional characterization were assessed, and incidence was compared to that in MBC patients not receiving ADC treatment and in The Cancer Genome Atlas (TCGA).</p><p><strong>Results: </strong>Plasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, G359E) in 12.9% of patients (4/31) at time of disease progression on ADC, compared to 0.7% (3/420) in non-ADC treated MBC patients and 0.5% reported in TCGA. Appearance of mutations was associated with clinical cross-resistance, as median duration on first ADC was 455 days versus 52 days for second ADC. Functional characterization of three novel TOP1 mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and Deruxtecan.</p><p><strong>Conclusions: </strong>We describe the recurrent emergence of functionally altered, resistance-associated TOP1 mutations in vivo under selective pressure from ADCs, and the potential impact on mediating cross-resistance to sequential ADCs. TOP1 mutation may represent a biomarker of resistance in this setting, and additional work is needed to optimize biomarkers and ADC payload design to improve outcomes for sequential use of ADCs.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913864","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 neoadjuvant immunotherapy combinations in resectable non-small-cell lung cancer.","authors":"Martin Schuler","doi":"10.1158/1078-0432.CCR-24-1441","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1441","url":null,"abstract":"<p><p>Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small-cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window: Several signal-finding studies explored a limited number of cycles prior to surgery, and reproducibly reported complete or major histopathological responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathological responses experienced particularly favorable long-term outcomes. It is yet unclear, whether there is true synergism between immunotherapy and chemotherapy, and whether outcomes are further improved by adding postoperative checkpoint inhibition. While these pivotal trials qualify neoadjuvant chemo-immunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. Here, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small-cell lung cancer are reviewed.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913862","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":"Structurally-oriented classification of FOXA1 alterations identifies prostate cancers with opposing clinical outcomes and distinct molecular and immunologic subtypes.","authors":"Justin Hwang, Pornlada Likasitwatanakul, Sachin Kumar Deshmukh, Sharon Wu, Jason J Kwon, Eamon Toye, David Moline, Mark G Evans, Andrew Elliott, Rachel Passow, Christine Luo, Emily John, Nishant Gandhi, Rana R McKay, Elisabeth I Heath, Chadi Nabhan, Natalie Reizine, Jacob J Orme, Josep M Domingo Domenech, Oliver Sartor, Sylvan C Baca, Scott M Dehm, Emmanuel S Antonarakis","doi":"10.1158/1078-0432.CCR-24-3471","DOIUrl":"10.1158/1078-0432.CCR-24-3471","url":null,"abstract":"<p><strong>Purpose: </strong>10-15% of prostate cancers (PCa) harbor recurrent FOXA1 aberrations whereby the alteration type and the effect on the forkhead( FKH) domain impacts protein-function. We developed a FOXA1 classification system to inform clinical management.</p><p><strong>Experimental design: </strong>5,014 PCa were examined using whole exome and transcriptome sequencing from the Caris database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain: these were in the first part of the FKH domain (class 1A: amino acids [AA] 168-246), within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted-truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269, class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.</p><p><strong>Results: </strong>FOXA1 alterations did not influence survival when considered in aggregate, but had distinct prognostic effects when stratified by class. Class 1A alterations were associated with overall improved survival (HR=0.57, p=0.03); a similar trend was seen with Class 1B (HR=0.88, p=0.07). Conversely, class 1C exhibited worse survival upon 2nd-generation androgen receptor signaling inhibitor (ARSI) treatment (HR=1.93, p<0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR=2.05, p<0.001) and worse outcomes to first-line androgen-deprivation therapies (HR=2.5, p<0.001). Class 3A alterations indicated improved survival (HR=0.70; p=0.01) whereas class 3B alterations portended poor outcomes (HR=1.50; p<0.001). Amplifications (class 4) indicated poor outcomes (HR=1.48; p=0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European-Americans, African-Americans had increased class 1C alterations whereas Asian-Pacific patients had increased class 1B alterations.</p><p><strong>Conclusions: </strong>FOXA1alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision making for PCa patients and uncovers important racial differences.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913863","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}