Cancer Communications最新文献

{"title":"Inhibition of mTOR attenuates the initiation and progression of BRCA1-associated mammary tumors","authors":"Hye Jung Baek, Geun Hee Han, Eun Joo Cho, Jihao Xu, Min Kyung Ki, Eun Jung Park, Tae Hyun Kim, Dong Hoon Shin, Heesun Cheong, Chu-Xia Deng, Sung Chul Lim, Chang-il Hwang, Daehee Hwang, Sang Soo Kim","doi":"10.1002/cac2.12663","DOIUrl":"10.1002/cac2.12663","url":null,"abstract":"<p>Inherited mutation in breast cancer susceptibility gene 1 (<i>BRCA1</i>) is strongly associated with mammary tumors that exhibit triple-negative characteristics, are insensitive to endocrine-targeted therapies, and show basal-like properties, including aggressive phenotypes [<span>1, 2</span>]. It has been reported that the average cumulative risk of breast cancer for <i>BRCA1</i> mutation carriers by age 70 years is 57% (95% confidence interval [CI]: 47%-66%) [<span>3</span>]. Despite the high incidence and aggressive characteristics of <i>BRCA1</i>-associated breast cancer, few substantial improvements in preventing or treating this cancer have been made, largely due to the challenges of clinic-based cohort studies. During malignant transformation, cancer progression is facilitated by metabolic reprogramming–one of the hallmark characteristics of cancer. Previously, we found that inhibition of AKT is a potential strategy for the prevention and therapeutic management of <i>Brca1</i>-mutant mammary tumors. However, pharmacological inhibition proved less effective and less safe compared to genetic perturbation, limiting its potential for clinical application [<span>4</span>]. Meanwhile, mTOR, a key regulator of metabolism and a downstream target of the PI3K/AKT signaling pathway, has emerged as a promising therapeutic target for several diseases, including treatment of cancer [<span>5</span>].</p><p>In addition to identifying the contribution of mTOR signaling to BRCA1-deficient cells (Supplementary Figure S1), we provide genetic and pharmacological evidence using multi-orthogonal preclinical models [<span>6-8</span>] that mTOR is closely involved in the development and growth of <i>Brca1</i>-mutated mammary tumors (Figure 1A). To investigate the role of mTOR in the absence of BRCA1, we assessed the development of mammary glands in post-pubertal <i>Brca1/Mtor</i>-mutant mice by examining ductal and lobular development of the fourth mammary gland. Measurements of mammary gland density using the Branch software (ver. 1.1 [<span>9</span>]) showed that ductal length and branching were significantly diminished in the mammary glands of <i>Brca1<sup>co/co</sup>Mtor<sup>co/co</sup>MMTV-Cre</i> mice (Figure 1B,C, Supplementary Figure S2). To determine whether mTOR contributes to BRCA1-deficient mammary tumor formation, we examined tumor formation in cohorts of <i>Brca1<sup>co/co</sup></i> (<i>n</i> = 28), <i>Brca1<sup>co/co</sup>Mtor<sup>co/co</sup></i> (<i>n</i> = 30), <i>Brca1<sup>co/co</sup>MMTV-Cre</i> (<i>n</i> = 24), and <i>Brca1<sup>co/co</sup>Mtor<sup>co/co</sup>MMTV-Cre</i> (<i>n</i> = 29) mice (Top left of Figure 1A). <i>Brca1<sup>co/co</sup></i> and <i>Brca1<sup>co/co</sup>Mtor<sup>co/co</sup></i> mice showed no signs of mammary abnormalities, including tumors, up to 24 months of age. In contrast, <i>Brca1<sup>co/co</sup>MMTV-Cre</i> mutant mice developed breast cancer, reaching a high incidence (37.5%; 9/24) by 24 months of age. During the s","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"486-490"},"PeriodicalIF":20.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000618","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":"Efficacy and safety of KN026 and docetaxel for HER2-positive breast cancer: a phase II clinical trial","authors":"Jianli Ma,&nbsp;Jingxuan Wang,&nbsp;Ting Xu,&nbsp;Quchang Ouyang,&nbsp;Xiaojia Wang,&nbsp;Jingfen Wang,&nbsp;Lu Gan,&nbsp;Zhong Ouyang,&nbsp;Daren Lin,&nbsp;Tao Sun,&nbsp;Changping Shan,&nbsp;Herui Yao,&nbsp;Baochun Zhang,&nbsp;Zhengguang Li,&nbsp;Zhixiang Zhuang,&nbsp;Ying Lu,&nbsp;Hongwei Yang,&nbsp;Jian Huang,&nbsp;Xingwang Yang,&nbsp;Hongmei Sun,&nbsp;Qingyuan Zhang","doi":"10.1002/cac2.12662","DOIUrl":"10.1002/cac2.12662","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic breast cancer currently includes pertuzumab plus trastuzumab and docetaxel. This study aimed to evaluate the effectiveness of KN026, an anti-HER2 bispecific antibody, plus docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This open-label, single-arm, phase II study enrolled patients with HER2-positive recurrent/metastatic breast cancer in 19 centers across China from December 30, 2019 to May 27, 2021. Patients were administered KN026 (30 mg/kg) plus docetaxel (75 mg/m²) in 21-day cycles. Primary endpoints included the objective response rate (ORR) and duration of response (DOR). In addition, overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety profile were examined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 57 patients were included. In the efficacy analysis set of 55 patients, the ORR was 76.4% (95% confidence interval [CI], 63.0%-86.8%), and the CBR was 85.5% (95% CI, 73.3%-93.5%). The median DOR was not reached (95% CI, 20.7 months-not reached). In the safety set of 57 patients, the median PFS was 27.7 months (95% CI, 18.0 months-not reached). The median OS was not reached, with OS rates at 12, 24 and 30 months of 93.0%, 84.1% and 78.5%, respectively. Grade ≥3 treatment-emergent adverse events (AEs) were detected in 36 (63.2%) patients. No deaths were attributed to KN026 or docetaxel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>KN026 plus docetaxel showed promising efficacy and a manageable safety profile in first-line treatment of HER2-positive recurrent/metastatic breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"476-485"},"PeriodicalIF":20.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000555","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":"Bioequivalence of alternative pembrolizumab dosing regimens: current practice and future perspectives","authors":"Ruben Malmberg,&nbsp;Bram C. Agema,&nbsp;Maaike M. Hofman,&nbsp;Stefani Oosterveld,&nbsp;Sander Bins,&nbsp;Daphne W. Dumoulin,&nbsp;Arjen Joosse,&nbsp;Joachim G. J. V. Aerts,&nbsp;Reno Debets,&nbsp;Birgit C. P. Koch,&nbsp;Astrid A. M. van der Veldt,&nbsp;Roelof W. F. van Leeuwen,&nbsp;Ron H. J. Mathijssen","doi":"10.1002/cac2.12661","DOIUrl":"10.1002/cac2.12661","url":null,"abstract":"&lt;p&gt;Immune checkpoint inhibitors (ICIs), including humanized anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) monoclonal antibodies (mAbs), such as pembrolizumab, have transformed cancer treatment. Pembrolizumab was initially approved as a three-weekly (Q3W) 2 mg/kg weight-based dose by the Food and Drug Administration (FDA), which was later replaced by a 200 mg Q3W fixed-dose, mainly based on in silico simulations. Later, a fixed 400 mg six-weekly (Q6W) regimen was approved based on pharmacokinetic simulations [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Due to increasing ICI use and high costs per treatment, increasingly large portions of healthcare budgets are shifted to ICI treatment. Therefore, it is important to handle ICIs as efficiently and cost-effectively as possible. Hence, the Q6W regimen was introduced, lowering the total amount of ICI administrations per patient and the strain on healthcare capacity, and improving patient convenience. The cost-effectiveness of ICI treatment could be optimized further by using alternative dosing strategies (ADS) [&lt;span&gt;1&lt;/span&gt;]. Some of these ADS have already been tested for pembrolizumab in some countries [&lt;span&gt;2, 3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Recently, the FDA provided bioequivalence guidelines for ADS, specifically for anti-PD-1/PD-L1 mAbs [&lt;span&gt;4&lt;/span&gt;]. These guidelines support the use of pharmacokinetic-modeling to simulate steady-state trough concentrations (C&lt;sub&gt;trough,ss&lt;/sub&gt;) and area under the curve (AUC; exposure) to establish bioequivalence for anti-PD-1/PD-L1 mAbs. In these guidelines, ADS are considered bioequivalent when both C&lt;sub&gt;trough,ss&lt;/sub&gt; and exposure are at most 20% lower compared to the dosing regimen used while establishing efficacy in clinical trials (i.e. the reference dosing regimen). A maximum of 25% increase in the maximum concentration (C&lt;sub&gt;max&lt;/sub&gt;) is used as the upper boundary, unless adequate clinical evidence shows that increasing the C&lt;sub&gt;max&lt;/sub&gt; does not increase toxicity. For pembrolizumab, incidences of toxicities were generally consistent across a 2-10 mg/kg dose range in multiple trials [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To verify whether various ADS (Figure 1, Supplementary Table S1) are bioequivalent following the current FDA guidelines, we assessed bioequivalence using pharmacokinetic modelling. Using pharmacokinetic data from a real-world cohort, the best performing model was selected with which bioequivalence was assessed in extrapolations from this cohort (“extrapolation”) and also from a virtual (“simulation”) cohort. Details on both cohorts, as well as modelling procedures, are depicted in the Supplementary Material and Methods. As a reference, the Q3W 2 mg/kg dosing regimen was used, as this regimen was used in the original approval. Results of these analyses are shown in Figure 1. The simulated ADS for pembrolizumab given every 3 or 4 weeks (Q3/4W) were bioequivalent according to the FDA guidelines. Interestingly, despite meeting the criteria for e","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"471-475"},"PeriodicalIF":20.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12661","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000550","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":"Single-cell transcriptomics and epigenomics point to CD58-CD2 interaction in controlling primary melanoma growth and immunity","authors":"Antonia Stubenvoll,&nbsp;Maria Schmidt,&nbsp;Johanna Moeller,&nbsp;Max Alexander Lingner Chango,&nbsp;Carolyn Schultz,&nbsp;Olga Antoniadou,&nbsp;Henry Loeffler-Wirth,&nbsp;Stephan Bernhart,&nbsp;Florian Große,&nbsp;Beatrice Thier,&nbsp;Annette Paschen,&nbsp;Ulf Anderegg,&nbsp;Jan C. Simon,&nbsp;Mirjana Ziemer,&nbsp;Clara T. Schoeder,&nbsp;Hans Binder,&nbsp;Manfred Kunz","doi":"10.1002/cac2.12651","DOIUrl":"10.1002/cac2.12651","url":null,"abstract":"<p>Immunotherapy is currently one of the most promising treatment options for malignant melanoma [<span>1</span>]. To uncover new immunological targets for future treatment approaches, single-cell transcriptomic and epigenomic analyses were performed on human primary melanoma (MM) and melanocytic nevus (Nev) samples (Figure 1A). The detailed methods of this study are described in the Supplementary Material.</p><p>MM and Nev biopsies (Supplementary Figure S1; Supplementary Table S1) were analyzed by single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) (Supplementary Figure S2; Supplementary Tables S2 and S3). Using Uniform Manifold Approximation and Projection (UMAP), 28 distinct cellular clusters were identified and annotated based on scRNA-seq data from a previous report and manual curation (Figure 1B; Supplementary Figure S3A) [<span>2</span>]. Examples of gene expression patterns for individual cell types are provided in Supplementary Table S4. Lesional T lymphocytes were quantified using scRNA-seq data and anti-CD3 immunofluorescence staining, which revealed three distinct immune states: hot (&gt;25 % T cells), intermediate (&gt;6-25 % T cells), and cold (0-6 % T cells) (Supplementary Table S5).</p><p>Based on a previous study examining melanoma cell differentiation statuses, the melanoma cell cluster was divided into 8 distinct subclusters (Supplementary Figure S3B, C) [<span>3</span>]. Unsupervised clustering further refined these findings, predicting 11 cellular subclusters of melanoma cells (Figure 1C, Supplementary Table S6) [<span>3</span>].</p><p>To investigate the molecular mechanisms underlying melanoma cell dedifferentiation, RNA velocity and latent time (LT) analyses were performed (Supplementary Material and Methods). These analyses measure developmental processes based on the gene expression patterns of spliced and unspliced genes [<span>4</span>], with LT more directly reflecting transcriptional dynamics. As shown in Figure 1C, RNA velocity arrows indicate a trajectory from the melanoma subcluster of undifferentiated, neural crest (nc)-like cells on the left toward the more differentiated Mel_trans-melan_c7 and Mel_trans-melan_c8 subclusters at the right edge. LT analysis (Figure 1C) and the latent time heatmap (Figure 1D) revealed an opposing trajectory toward a more dedifferentiated state, exemplified by the Mel_trans subcluster. Here, melanoma cell dedifferentiation was linked to gene sets enriched in antigen presentation and the induction of T cell receptor signaling (Figure 1D). This aligns with the known association between high immune cell infiltrates and dedifferentiated tumors. Notably, Serpin Family E Member 2 <i>(SERPINE2)</i> has been identified as a mediator of melanoma metastasis and tumor progression [<span>5</span>].</p><p>Next, we performed regulon analysis (https://github.com/aertslab/pySCENIC) of the melanoma cell clusters, which refers to a ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"465-470"},"PeriodicalIF":20.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982600","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 ferroptosis resistance resensitizes metastatic HR+HER2− breast cancer cells to palbociclib-hormone therapy","authors":"Charles Pottier,&nbsp;Laetitia Montero-Ruiz,&nbsp;Robin Jehay,&nbsp;Coline Wery,&nbsp;Dominique Baiwir,&nbsp;Gabriel Mazzucchelli,&nbsp;Sophie Bekisz,&nbsp;Romain Thissen,&nbsp;Claire Josse,&nbsp;Andrée Rorive,&nbsp;Stéphanie Gofflot,&nbsp;Ahmed Dahmani,&nbsp;Ludivine Morisset,&nbsp;Joëlle Collignon,&nbsp;Philipe Delvenne,&nbsp;Elisabetta Marangoni,&nbsp;Agnès Noël,&nbsp;Guy Jerusalem,&nbsp;Nor Eddine Sounni","doi":"10.1002/cac2.12646","DOIUrl":"10.1002/cac2.12646","url":null,"abstract":"&lt;p&gt;Metastatic hormone receptor-positive (HR&lt;sup&gt;+&lt;/sup&gt;), human epidermal growth factor receptor 2-negative (HER2&lt;sup&gt;−&lt;/sup&gt;) breast cancer often develops resistance to first-line treatment, typically combining cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with hormone therapy (HT) [&lt;span&gt;1, 2&lt;/span&gt;]. After an initial response, most patients become resistant, and compensatory mechanisms are not fully uncovered [&lt;span&gt;3&lt;/span&gt;]. To address this, we analyzed HR&lt;sup&gt;+&lt;/sup&gt; resistant CAMA1 and 747D cells using whole-exome and RNA sequencing, supplemented by proteomics and target validation with human samples. Additionally, we conducted combination therapy trials using xenografts and patient-derived xenografts (PDXs). Detailed study designs and methods are provided in the Supplementary file.&lt;/p&gt;&lt;p&gt;In a cohort of 27 patients with metastatic breast cancer, we observed reduced progression-free survival in second- and third-line therapies following progression post palbociclib-HT treatment (Supplementary Figure S1A and Supplementary Table S1). Resistant tumors showed reduced estrogen receptor alpha (ERα) and progesterone receptor (PR) and increased proliferation rates (Supplementary Figure S1B-D). CAMA1 and T47D cells, treated with palbociclib and fulvestrant (PF) for 2 years, developed resistance (CAMA1-PFR and T47D-PFR) confirmed by proliferation assays and elevated half-maximal inhibitory concentrations. Resistant cells exhibited reduced levels of ERα and retinoblastoma protein (Supplementary Figure S2). Exome analysis revealed no drug resistance-related mutations (Supplementary Tables S2-S3), suggesting non-genetic factors.&lt;/p&gt;&lt;p&gt;RNA sequencing of T47D cells treated with DMSO or PF for 20 days and T47D-PFR cells revealed 1,172 upregulated genes and 824 downregulated genes in the resistant cells (Supplementary Figure S3A). Gene set enrichment analysis indicated increased fatty acid localization (Supplementary Figure S3B), with a heatmap showing elevated fatty acid uptake and metabolism-related genes, such as fatty acid binding protein-6 (FABP6), FABP7, cluster of differentiation-36 (CD36), and proteasome proliferator-activated receptor-gamma (PPARγ) in T47D-PFR cells (Figure 1A). Lipid droplets accumulated in PF-treated parental and PF-resistant T47D and CAMA1 cells (Figure 1B and Supplementary Figure S3C). FABP6 levels were elevated in PF-treated parental and PF-resistant cells, with CD36 overexpression unique to T47D-PFR cells at both protein and mRNA levels (Figure 1C and Supplementary Figure S3D-E), suggesting that lipid uptake might be an adaptive response to oxidative stress [&lt;span&gt;4, 5&lt;/span&gt;]. This was supported by elevated reactive oxygen species (ROS) levels in PF-treated parental cells (Figure 1D). Furthermore, proteomic analysis in human biopsies revealed a functional network of 11 oxidative stress-triggered proteasomes (Supplementary Figure S4A and Supplementary Tables S4-S5) as indicators of oxidative stress [&lt;span&gt;6&lt;/span&gt;]. Im","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"460-464"},"PeriodicalIF":20.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12646","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968973","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":"Training the synergy between Bacillus Calmette-Guérin and immune checkpoint-blocking antibodies in bladder cancer","authors":"Renate Pichler,&nbsp;Martin Thurnher","doi":"10.1002/cac2.12647","DOIUrl":"10.1002/cac2.12647","url":null,"abstract":"&lt;p&gt;Fifty years after the introduction of Bacillus Calmette-Guérin (BCG), a live attenuated strain of &lt;i&gt;Mycobacterium bovis&lt;/i&gt; [&lt;span&gt;1&lt;/span&gt;], it is still the most effective and successful adjuvant immunotherapy of non-muscle invasive bladder cancer (NMIBC) [&lt;span&gt;2&lt;/span&gt;]. The guidelines of the European Association of Urology (EAU) suggest a 6-weekly induction phase followed by a maintenance schedule of BCG once weekly for 3 weeks and at 3, 6, 12, 18, 24, 30, and 36 months for 1 to 3 years [&lt;span&gt;2&lt;/span&gt;]. However, patients with BCG-unresponsive disease - defined as BCG-refractory tumors (T1 high-grade disease after at least 5 out of 6 doses of BCG induction, any high-grade disease during BCG maintenance, carcinoma in situ/Ta high-grade disease after induction, followed by recurrence after reinduction or one maintenance cycle) or early relapse including recurrence with any high-grade disease within 6 months or carcinoma in situ within 12 months after adequate BCG exposure - are unlikely to respond to further BCG alone (BCG reinduction), resulting in the necessity of radical cystectomy (RC) as a next therapeutic step [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Various ongoing studies with novel bladder-preserving strategies are therefore currently investigating whether RC can be prevented in BCG-unresponsive patients and whether the BCG-induced antitumor effect can be enhanced in BCG-naïve high-risk NMIBC by combining BCG with immune-enhancing agents, Supplementary Table S1.&lt;/p&gt;&lt;p&gt;A recently published clinical phase 1 trial (ADAPT-BLADDER) was able to show that the combination of the immune checkpoint inhibitor durvalumab and BCG is an effective therapy for BCG-unresponsive NMIBC [&lt;span&gt;3&lt;/span&gt;]. In detail, within the durvalumab + BCG cohort, the 3-, and 12-month complete response rate was high with 85% and 73%, respectively [&lt;span&gt;3&lt;/span&gt;]. Although this first encouraging preliminary data suggest that combinatory approaches synergistically improve antitumor response of BCG in patients with BCG-unresponsive NMIBC [&lt;span&gt;3&lt;/span&gt;], a better understanding of the immunological mechanisms underlying BCG activity and other combination agents is essential for patient selection, biomarker and future drug development.&lt;/p&gt;&lt;p&gt;BCG is a very special vaccine because of its ability to reprogram macrophages metabolically and epigenetically. As a result, repetitive administration of BCG increases macrophage responsiveness, a phenomenon referred to as “trained immunity”. BCG is an effective stimulus for inducing trained immunity. Upon detection of BCG by pattern recognition receptors [&lt;span&gt;4&lt;/span&gt;], activation of the Akt/mTOR pathway is crucial to shift cellular metabolism towards glycolysis and glutaminolysis, which - in turn - are required for the induction of trained immunity in human monocytes by BCG. Moreover, epigenetic mechanisms regulate the induction of these pathways at the level of chromatin organization. Specifically, an increase of H3K4me3, a histone mark denot","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"438-441"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12647","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963781","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":"To what extent is the association between obesity and colorectal cancer risk mediated by systemic inflammation?","authors":"Fatemeh Safizadeh,&nbsp;Marko Mandic,&nbsp;Michael Hoffmeister,&nbsp;Hermann Brenner","doi":"10.1002/cac2.12659","DOIUrl":"10.1002/cac2.12659","url":null,"abstract":"&lt;p&gt;Both overall and abdominal obesity are well-established risk factors for various cancer types, including colorectal cancer (CRC) [&lt;span&gt;1&lt;/span&gt;]. However, how adiposity impacts CRC development has been insufficiently investigated. Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC: alterations in insulin signaling, dysregulation of adipose tissue-derived inflammation, and sex hormone metabolism [&lt;span&gt;2, 3&lt;/span&gt;]. New mechanisms are also emerging, including altered gut microbiome and gut hormones, such as Ghrelin and nonalcoholic fatty liver disease (NAFLD). One of the key mechanisms proposed, and a common feature in most pathways, is inflammation [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Adiposity is associated with a systemic subclinical inflammation and higher levels of inflammatory biomarkers such as C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin‑1β (IL‑1β), IL‑6, and IL‑18 [&lt;span&gt;2&lt;/span&gt;]. Inflammation can contribute to cancer development through mechanisms, such as the production of free radicals, including reactive oxygen intermediates, by suppressing the immune system, causing abnormal cell signaling, which promotes proliferative and anti-apoptotic pathways, angiogenesis, and cell migration [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To quantify how much of the association between adiposity and CRC risk might be explained by inflammation, as reflected in increased serum levels of CRP —a nonspecific marker of systemic inflammation, we used body mass index (BMI) as a measure of general obesity, and waist circumference (WC) and waist-to-hip ratio (WHR) as measures of abdominal obesity, and we paid particular attention to a potential role of reverse causation due to cancer-related changes in body weight and CRP levels.&lt;/p&gt;&lt;p&gt;Data from 499,926 UK Biobank study participants aged 40-69, collected from 22 UK Biobank assessment centers, were utilized. Detailed information on the study population and design, exposure and outcome assessments, and statistical analysis is provided in the Supplementary Materials and Methods. After excluding participants with previous cancer diagnosis (except non-melanoma skin cancer), missing BMI, WHR, WC, and CRP, 429,073 participants remained and were included in the analysis (Supplementary Figure S1). Of these, 5,544 were diagnosed with CRC during a median follow-up of 11.8 years (interquartile range: 11.0-12.5). Main characteristics of the cohort are shown in Supplementary Table S1. Median age at baseline was 57 years, 53.2% of participants were female, and 94.6% were white. Median BMI, WC, and WHR for the whole cohort population were 26.7 kg/m&lt;sup&gt;2&lt;/sup&gt;, 90.0 cm, and 0.87, respectively. Furthermore, approximately 22% of the population had CRP levels greater than or equal to 3 mg/L at baseline.&lt;/p&gt;&lt;p&gt;Individuals classified as overweight or obese exhibited elevated CRP levels compared to those with a normal BMI. Additionally, participants in higher quartiles for both ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"456-459"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12659","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945074","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":"Efficacy and safety of first-line sintilimab plus anlotinib versus chemotherapy for metastatic non-small cell lung cancer: a phase II, open-label, randomized controlled trial","authors":"Tianqing Chu,&nbsp;Hua Zhong,&nbsp;Zhuang Yu,&nbsp;Jing Wang,&nbsp;Yanqiu Zhao,&nbsp;Xiaoqian Mu,&nbsp;Xinmin Yu,&nbsp;Xun Shi,&nbsp;Qingming Shi,&nbsp;Maojing Guan,&nbsp;Cuimin Ding,&nbsp;Nan Geng,&nbsp;Jialin Qian,&nbsp;Baohui Han","doi":"10.1002/cac2.12654","DOIUrl":"10.1002/cac2.12654","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The prognosis for non-small cell lung cancer (NSCLC) patients treated with standard platinum-based chemotherapy was suboptimal, with safety concerns. Following encouraging results from a preliminary phase I study, this phase II trial investigated the efficacy and safety of first-line sintilimab and anlotinib in metastatic NSCLC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this open-label, randomized controlled trial (NCT04124731), metastatic NSCLC without epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or proto-oncogene tyrosine-protein kinase ROS (ROS1) mutations, and previous treatments for metastatic disease were enrolled. Participants were randomly assigned in a 1:1 ratio to either sintilimab (200 mg every 3 weeks) plus anlotinib (12 mg D1-14 every 3 weeks) or a standard platinum-based chemotherapy regimen. Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression. The primary endpoint was the objective response rate (ORR).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>From November 2019 to March 2023, 99 patients were randomized into the sintilimab plus anlotinib group (<i>n</i> = 49) and the chemotherapy group (<i>n</i> = 50). The ORR was significantly higher in the sintilimab plus anlotinib group (44.9%; 95% confidence interval [CI] = 30.7%-59.8%) compared to the chemotherapy group (18.0%; 95% CI = 8.6%-31.4%, <i>P</i> = 0.003). Progression-free survival (PFS) was also notably longer (median: 14.4 vs. 5.6 months; hazard ratio [HR] = 0.39; 95% CI = 0.23-0.67; <i>P</i> &lt; 0.001). The 24-month overall survival rate was 58.4% (95% CI = 40.4%-72.6%) and 43.2% (95% CI = 26.0%-59.2%), respectively. The rate of grade 3 or higher treatment-related adverse events was lower in the sintilimab plus anlotinib group (28.0%) than in the chemotherapy group (49.0%), especially for the hematological toxicities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>First-line sintilimab plus anlotinib showed improved ORR and PFS, alongside a superior safety profile, compared to the standard platinum-based chemotherapy for metastatic NSCLC patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"442-455"},"PeriodicalIF":20.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12654","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945070","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":"Expression profiling of primary and metastatic oral squamous cell carcinoma identifies progression-associated transcriptome changes and therapeutic vulnerabilities","authors":"Jonas Pyko,&nbsp;Markus Glaß,&nbsp;Julia Rosemann,&nbsp;Matthias Kappler,&nbsp;Jana Macho,&nbsp;Sarah Qasem,&nbsp;Stefan Hüttelmaier,&nbsp;Alexander W. Eckert,&nbsp;Monika Haemmerle,&nbsp;Tony Gutschner","doi":"10.1002/cac2.12660","DOIUrl":"10.1002/cac2.12660","url":null,"abstract":"&lt;p&gt;Oral squamous cell carcinoma (OSCC), a major subgroup of head and neck squamous cell carcinoma (HNSCC), is an aggressive disease that preferentially spreads to cervical lymph nodes. Positive lymph node status is an important predictor of survival in OSCC [&lt;span&gt;1-3&lt;/span&gt;]. Hence, a better understanding of the molecular mechanisms underlying oral cancer metastasis and the identification of therapeutic vulnerabilities are needed to prevent and treat metastatic disease.&lt;/p&gt;&lt;p&gt;We collected 87 primary tumors and 21 lymph node metastasis (LNM) from 72 OSCC patients to conduct comprehensive transcriptome-wide expression and correlation analyses (Figure 1A). First, we performed expression-based clustering with all primary tumors and observed the best subdivision with &lt;i&gt;k&lt;/i&gt; = 3 using protein-coding and non-coding genes (Figure 1B). Of note, we observed transcriptional heterogeneity among multiregional tumor samples in about 30% of the cases, leading to the assignment of these patients and their respective tumors to different clusters. Intriguingly, Kaplan-Meier analysis of patients whose tumors were unambiguously assigned to only one cluster revealed that cluster 3 (C3) had the worst outcome, with a median survival of 15.6 months compared to 28.57 and 36.53 months for clusters 1 (C1) and 2 (C2), respectively (Figure 1C). Importantly, prognostic factors known to negatively affect survival, such as high T, N, and G status, were not enriched in C3 tumors (Supplementary Figure S1A-C). However, gene expression analysis identified 244 genes that were significantly changed in C3 compared to C1/2 tumors (Supplementary Figure S1D, Supplementary Table S1). Of note, cell cycle-related gene sets, including Early region 2 binding factor (&lt;i&gt;E2F&lt;/i&gt;) and Myelocytomatosis oncogene (&lt;i&gt;MYC&lt;/i&gt;) target genes, along with other oncogenic signaling pathways, showed a positive normalized enrichment score (NES), potentially explaining the poor outcomes of C3 tumors (Supplementary Figure S1E).&lt;/p&gt;&lt;p&gt;Next, we performed a gene expression-based overall survival (OS) analysis and identified two significant genes, namely Zinc Finger Protein 443 (&lt;i&gt;ZNF443&lt;/i&gt;) and Serine Hydroxymethyltransferase 2 (&lt;i&gt;SHMT2&lt;/i&gt;) (Figure 1D, Supplementary Table S2). Specifically, &lt;i&gt;ZNF443&lt;/i&gt; expression was associated with a reduced risk (Hazard ratio [HR] = 0.238), whereas expression of &lt;i&gt;SHMT2&lt;/i&gt; (HR = 4.028) suggested a higher risk of mortality. Thus, we further tested their prognostic relevance for OS and recurrence/disease-free survival (RFS/DFS) in our patient cohort (Figure 1E, Supplementary Figure S2A-C) as well as in The Cancer Genome Atlas (TCGA) HNSCC dataset (Supplementary Figure S2D-E) [&lt;span&gt;4&lt;/span&gt;]. These analyses indicated that &lt;i&gt;SHMT2&lt;/i&gt;, but not &lt;i&gt;ZNF443&lt;/i&gt;, might serve as an OSCC-specific biomarker for OS. In line with this, &lt;i&gt;SHMT2&lt;/i&gt; expression was higher in HNSCC tissues compared to normal tissues, as well as in T4 versus T1 tumors of the OSCC subtype, and its ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"433-437"},"PeriodicalIF":20.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12660","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945072","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":"HER2 and HER3 expression during neoadjuvant treatment of HER2-negative early breast cancer: potential for biomarker-driven sequencing of T-DXd and HER3-DXd","authors":"Christian Fridolin Singer,&nbsp;Stephan Wenzel Jahn,&nbsp;Dominik Hlauschek,&nbsp;Ulrike Maria Heber,&nbsp;Charlotte Mang-Manger,&nbsp;Daniel Egle,&nbsp;Marija Balic,&nbsp;Angelika Pichler,&nbsp;Georg Pfeiler,&nbsp;Stephanie Kacerovsky-Strobl,&nbsp;Christoph Suppan,&nbsp;Magdalena Ritter,&nbsp;Edgar Petru,&nbsp;Richard Greil,&nbsp;Zsuzsanna Bago-Horvath,&nbsp;Christine Deutschmann,&nbsp;Günther Georg Steger,&nbsp;Michael Seifert,&nbsp;Florian Fitzal,&nbsp;Rupert Bartsch,&nbsp;Anu Santhanagopal,&nbsp;Jana Machacek-Link,&nbsp;Dalila Sellami,&nbsp;Magdalena Schwarz,&nbsp;Christian Fesl,&nbsp;Lidija Sölkner,&nbsp;Stephen Esker,&nbsp;Martin Filipits,&nbsp;Michael Gnant,&nbsp;the Austrian Breast and Colorectal Cancer Study Group","doi":"10.1002/cac2.12657","DOIUrl":"10.1002/cac2.12657","url":null,"abstract":"&lt;p&gt;With the development of novel antibody-drug conjugates (ADC) such as T-DXd (trastuzumab deruxtecan) and HER3-DXd (patritumab deruxtecan), global tumor cell targeting has become possible beyond the human epidermal growth factor receptor (HER) 2-positive setting [&lt;span&gt;1, 2&lt;/span&gt;]. Both drugs offer promising options for individualized treatment targeting HER2 and HER3 expression, potentially even in tumors which are currently considered “HER2-negative”. Relatively little is known about the efficacy of HER3-DXd in tumors with low HER3 expression, except for data from one recent study investigating its efficacy across different HER3 expression levels [&lt;span&gt;3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The DESTINY-Breast04 trial (NCT03734029) demonstrated that T-DXd-treated patients with HER2-low expressing metastatic breast cancer had significantly longer progression-free and overall survival than those who were treated with the physician's choice of chemotherapy [&lt;span&gt;4&lt;/span&gt;]. It is therefore important to understand whether neoadjuvant systemic therapy is able to induce or up-regulate HER2 and/or HER3 protein expression – raising the hope that neoadjuvant chemotherapy (NACT) and neoadjuvant endocrine therapy (NET) could be used to “prime” tumor cells for subsequent HER-targeting by adjuvant systemic therapy in case of non- pathologic complete remission (pCR). Therefore, we investigated the dynamics of HER2 and HER3 expression in HER2 non-amplified breast cancer by retrospectively analyzing the immunohistochemical HER2 and HER3 protein expression in pre- and post-treatment tumor samples, treated with neoadjuvant systemic chemo- and endocrine therapy, from the prospectively randomized ABCSG 34 trial.&lt;/p&gt;&lt;p&gt;The trial design, inclusion criteria, and main clinical results of this trial were reported previously [&lt;span&gt;5&lt;/span&gt;]. Briefly, in ABCSG 34, 400 pre- and post-menopausal women with HER2-negative early breast cancer received either standard-of-care (SoC) NACT (&lt;i&gt;n&lt;/i&gt; = 311) or NET (&lt;i&gt;n&lt;/i&gt; = 98), with or without the Mucin-1 (MUC1) directed vaccine tecemotide (Supplementary Methods). Immunohistochemical data on HER2 and HER3 expression were available from paired pre- and post-treatment samples of 183 of these patients (Supplementary Figure S1), which did not significantly differ from the overall study population regarding clinical-pathological parameters (Supplementary Table S1).&lt;/p&gt;&lt;p&gt;In tumors that had been subjected to SoC NACT, HER2 expression was detected at baseline in 57/134 (42.5%) tumors, with low expression (1+) in 39.6%, and equivocal expression (2+) in 3.0% of cases. HER2 expression in the post-treatment surgical samples was detected in 68/134 (50.7%) tumors, with a HER2 score of 1+ in 43.3%, and a HER2 score of 2+ in 7.5% of tumor samples (&lt;i&gt;p&lt;/i&gt; = 0.050 for marginal homogeneity). This corresponds to an increase of HER2 from baseline to surgery in 34/134 (25.4%; 95% CI, 18.8% to 33.4%) tumors, and a decrease in response to SoC NACT in 19/134 (14.2%; 95","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 4","pages":"428-432"},"PeriodicalIF":20.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930684","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}