Breast Cancer Research最新文献

{"title":"Ultrasound-based quantitative microvasculature imaging for early prediction of response to neoadjuvant chemotherapy in patients with breast cancer.","authors":"Soroosh Sabeti, Nicholas B Larson, Judy C Boughey, Daniela L Stan, Malvika H Solanki, Robert T Fazzio, Mostafa Fatemi, Azra Alizad","doi":"10.1186/s13058-025-01978-y","DOIUrl":"10.1186/s13058-025-01978-y","url":null,"abstract":"<p><strong>Background: </strong>Angiogenic activity of cancerous breast tumors can be impacted by neoadjuvant chemotherapy (NAC), thus potentially serving as a marker for response monitoring. While different imaging modalities can aid in evaluation of tumoral vascular changes, ultrasound-based approaches are particularly suitable for clinical use due to their availability and noninvasiveness. In this paper, we make use of quantitative high-definition microvasculature imaging (qHDMI) based on contrast-free ultrasound for assessment of NAC response in breast cancer patients.</p><p><strong>Methods: </strong>Patients with invasive breast cancer recommended treatment with NAC were included in the study and ultrafast ultrasound data were acquired at pre-NAC, mid-NAC, and post-NAC time points. Data acquisitions also took place at two additional timepoints - at two and four weeks after NAC initiation in a subset of patients. Ultrasound data frames were processed within the qHDMI framework to visualize the microvasculature in and around the breast tumors. Morphological analyses on the microvasculature structure were performed to obtain 12 qHDMI biomarkers. Pathology from surgery classified response using residual cancer burden (RCB) and was used to designate patients as responders (RCB 0/I) and non-responders (RCB II/III). Distributions of imaging biomarkers across the two groups were analyzed using Wilcoxon rank-sum test. The trajectories of biomarker values over time were investigated and linear mixed effects models were used to evaluate interactions between time and group for each biomarker.</p><p><strong>Results: </strong>Of the 53 patients included in the study, 32 (60%) were responders based on their RCB status. The results of linear mixed effects model analysis showed statistically significant interactions between group and time in six out of the 12 qHDMI biomarkers, indicating differences in trends of microvascular morphological features by responder status. In particular, vessel density (p-value: 0.023), maximum tortuosity (p-value: 0.049), maximum diameter (p-value: 0.002), fractal dimension (p-value: 0.002), mean Murray's deviation (p-value: 0.034), and maximum Murray's deviation (p-value: 0.022) exhibited significantly different trends based on responder status.</p><p><strong>Conclusions: </strong>We observed microvasculature changes in response to NAC in breast cancer patients using qHDMI as an objective and quantitative contrast-free ultrasound framework. These finding suggest qHDMI may be effective in identifying early response to NAC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"24"},"PeriodicalIF":7.4,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442426","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-low status as a distinct breast cancer subtype: myth or truth? Analysis of the WSG trials WSG-ADAPT-HR+/HER2-, WSG-PlanB, and WSG-ADAPT-TN.","authors":"Gilda Schmidt, Oleg Gluz, Matthias Christgen, Mattea Reinisch, Sherko Kümmel, Ulrike Nitz, Michael Braun, Bahriye Aktas, Kerstin Lüdtke-Heckenkamp, Helmut Forstbauer, Eva-Maria Grischke, Claudia Schumacher, Rolf Mahlberg, Wolfram Malter, Toralf Reimer, Benno Nuding, Andrea Stefek, Rachel Wuerstlein, Monika Graeser, Katarzyna Jóźwiak, Sandy Burmeister, Christine Zu Eulenburg, Michael Lauseker, Cornelia Kolberg-Liedtke, Aleix Prat, Peter Schmid, Rick Baehner, Hans Heinrich Kreipe, Erich-Franz Solomayer, Nadia Harbeck","doi":"10.1186/s13058-025-01969-z","DOIUrl":"10.1186/s13058-025-01969-z","url":null,"abstract":"<p><strong>Background: </strong>New data show that not only HER2-overexpressing breast cancer (BC) tumors but also HER2-low tumors, classically considered as HER2-negative, respond to HER2-targeting antibody-drug-conjugates. Our objective was to analyze the prevalence of HER2-low BC in a pooled analysis of contemporary early BC trials and to evaluate its role as a prognostic factor in terms of survival in comparison to HER2-zero BC.</p><p><strong>Methods: </strong>We evaluated 5598 patients with locally HR + /HER2- BC from the screening cohort of WSG-ADAPT-HR + /HER2-, 2592 patients with HR + /HER2- or HR-/HER2- from the adjuvant WSG-PlanB trial, and 336 patients from the WSG-ADAPT-TN trial. Central HER2 testing was performed prospectively in WSG-ADAPT and retrospectively in WSG-PlanB. Following ASCO/CAP guidelines, HER2-low status was defined as immunohistochemistry (IHC) 1 + or 2 + and in situ hybridization (ISH)-negative, and HER2-zero was defined as IHC 0. Agreement between HER2 assessments was evaluated with Cohen's kappa coefficient, and effects of HER2 status on pathological complete response (pCR) and on survival were analyzed with logistic regression and Cox proportional hazards models, respectively.</p><p><strong>Findings: </strong>In WSG-ADAPT-HR + /HER2-, 3198 (64.6%) tumors were HER2-low by the central and 3096 (55.6%) by the local histology (agreement for HER2-low status was 61.0%). In HR + /HER2- cases from WSG-PlanB, 601 tumors (28.7%) were HER2-low. In both cohorts, HER2-low status was significantly associated with higher ERBB2 mRNA expression by Oncotype DX test in comparison to HER2-zero: mean 9.3 vs. 9.1 (p < .001) by local HER2 assessment in WSG-ADAPT and mean 9.2 vs. 8.8 (p < .001) in WSG-PlanB. Furthermore, patients with HER2-low tumors in WSG-ADAPT-HR + /HER2- significantly less often had a pCR compared to the HER2-zero tumors (p = .015). No significant difference was observed in (invasive and/or distant) disease-free survival (DFS) between centrally HER2-low and HER2-zero tumors in both HR + /HER2- cohorts (WSG-ADAPT-HR + /HER2- distant DFS: unadjusted HR = 1.06, 95%CI 0.83-1.36, similar results for local assessment; WSG-PlanB DFS: unadjusted HR = 1.28, 95%CI 0.91-1.82). In the HR-/HER2- WSG-PlanB cohort, centrally HER2-low tumors (10.5%) were associated with better DFS (unadjusted HR = 0.21, 95%CI 0.05-0.83), this association was not observed in the WSG-ADAPT-TN.</p><p><strong>Conclusion: </strong>The prevalence of HER2-low status varied between the analyzed trials. Our results show that survival does not differ between HER2-low and HER2-zero tumors in HR + /HER2- cohorts; however, HER2-low status appears to have an inconsistent impact on survival in TNBC. Therefore, our findings do not support the characterization of HER2-low status as a distinct BC subtype.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"22"},"PeriodicalIF":7.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426542","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":"Clinical efficacy and therapy response prediction of neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR+/HER2- stage II-III breast cancer (DARLING 01): a single-arm, open-label, exploratory study.","authors":"Lina Zhang, Yueping Liu, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Jiajie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng","doi":"10.1186/s13058-025-01976-0","DOIUrl":"10.1186/s13058-025-01976-0","url":null,"abstract":"<p><strong>Background: </strong>Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer, yet its response to traditional chemotherapy remains limited, posing a challenge in achieving optimal therapeutic outcomes. In this study, we aimed to evaluate the clinical efficacy and safety of dalpiciclib, a novel CDK4/6 inhibitor, combined with letrozole as neoadjuvant therapy (NAT) in postmenopausal patients with HR+/HER2- stage II-III breast cancer. Additionally, we explored potential predictive biomarkers for treatment response using gene analysis.</p><p><strong>Methods: </strong>This single-arm, open-label, exploratory phase II trial involved 35 postmenopausal women with HR+/HER2- breast cancer (ClinicalTrials.gov identifier NCT05512780). Patients received four cycles of dalpiciclib (125 mg/day for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg/day). The primary endpoint was objective response rate (ORR), and secondary endpoints included changes in Ki-67 expression, complete cell cycle arrest (CCCA) rate, residual cancer burden (RCB), and safety profiles. Gene expression profiling and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify biomarkers predictive of response to NAT.</p><p><strong>Results: </strong>Among the 35 enrolled patients, 31 completed the full treatment course. Of the 29 patients with evaluable response data after 4 cycles, 16 achieved partial response (PR), resulting in an ORR of 55.2%. Following two weeks of treatment, the mean Ki-67 expression significantly decreased from a baseline of 17.5-1.8%, and CCCA was observed in 75% of patients. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were mainly decreased neutrophil count (45.7%), with a median duration of 3 days. The NAT predictive model, developed using gene expression analysis and clinicopathological factors, achieved an area under the curve (AUC) of 0.928, indicating that TFRC, SCUBE2, and MMP11A could serve as novel predictive biomarkers for response to NAT.</p><p><strong>Conclusions: </strong>Dalpiciclib combined with letrozole demonstrated promising antitumor activity and an acceptable safety profile in postmenopausal patients with HR+/HER2- breast cancer. The identification of TFRC, SCUBE2, and MMP11A as predictive biomarkers provides insights into the potential for personalized neoadjuvant treatment strategies.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"21"},"PeriodicalIF":7.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415972","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":"SMYD4 promotes MYH9 ubiquitination through lysine monomethylation modification to inhibit breast cancer progression.","authors":"Jin-Shuo Yang, Jun-Ming Cao, Rui Sun, Xue-Jie Zhou, Zhao-Hui Chen, Bo-Wen Liu, Xiao-Feng Liu, Yue Yu, Xin Wang","doi":"10.1186/s13058-025-01973-3","DOIUrl":"10.1186/s13058-025-01973-3","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer is the leading cause of female mortality worldwide. (SET And MYND Domain Containing 4) SMYD4 has been reported to be a tumour suppressor. However, the molecular mechanism of SMYD4 remains unclear.</p><p><strong>Methods: </strong>The expression level of SMYD4 in breast cancer cells was detected by qRT-PCR and western blot. The effect of SMYD4 was verified in vitro and in vivo. The interaction between SMYD4 and MYH9 was investigated by co‑IP assay. The regulation of SMYD4 on WNT signaling pathway was detected by luciferase reporter assay and ChIP analysis.</p><p><strong>Results: </strong>This study found that SMYD4 downregulation was associated with poor prognosis. SMYD4 was performed as a tumor suppressor both in vitro and in vivo. SMYD4 was found to interact with the downstream protein MYH9 and impede WNT signaling pathway. Further studies revealed that SMYD4 impeded the binding of MYH9 to the CTNNB1 promoter region by promoting lysine monomethylation and ubiquitination degradation of MYH9.</p><p><strong>Conclusions: </strong>These findings reveal the emerging character of SMYD4 in Wnt/β‑catenin signaling and bring new sights of gene interaction. The discovery of this SMYD4/MYH9/CTNNB1/WNT/β-Catenin signalling pathway axis suggests that SMYD4 is a potential therapeutic target for breast cancer.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"20"},"PeriodicalIF":7.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11812198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392328","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":"Exploring the role of ESR1 mutations in metastatic hormone receptor-positive breast cancer T cell immune surveillance disruption.","authors":"Morgane Lopez, Laurie Spehner, Fabrice André, Julien Viot, Evan Seffar, Amélie Marguier, Elsa Curtit, Guillaume Meynard, Erion Dobi, Sylvain Ladoire, Romain Boidot, Romain Loyon, Valentin Derangere, François-Clément Bidard, Christophe Borg, Laura Mansi, Marie Kroemer","doi":"10.1186/s13058-025-01962-6","DOIUrl":"10.1186/s13058-025-01962-6","url":null,"abstract":"<p><strong>Background: </strong>Breast Cancer (BC) is the most common type of cancer in women around the world and 70% of cases are hormone-receptor positive (HR+). In 40% of cases, a key mechanism of endocrine resistance to the standard first line is a mutation of the ligand-binding domain (LBD) of Estrogen Receptor 1 (ESR1) encoding estrogen receptor α (ER). Most common ESR1 mutations that occur at positions 537 and 538 have been associated with poor clinical outcomes. ESR1 mutations have the potential to provide neoantigens. This study aims to identify if ESR1 mutations generate specific T cell responses against ESR1 neoantigens in patients with HR⁺ HER2^- BC, and to investigate if ESR1 mutations might correlate with a gene expression profile related to immune surveillance disruption.</p><p><strong>Methods: </strong>We identified candidate ESR1-derived peptides by predictive software (SYFPEITHI and NetMHCpan 3.0). Then the immunogenicity of ESR1-derived peptides was assessed in Peripheral-Blood-Mononuclear-Cells from 31 healthy donors (HD) and 25 patients with metastatic HR-positive BC by IFN-γ ELISpot assay. A vaccination assay on a humanized mouse model (HLA-A2/DR1) was used to validate the immunogenicity and the presentation of these peptides. Finally, we used Bulk RNA-Seq sequencing along with MCPcounter, a cellular deconvolution method, to investigate the immune contexture of ESR1-mutated BC.</p><p><strong>Results: </strong>Preliminary results showed recognition of ESR1-derived peptides by women HD lymphocytes but not in men. Frequencies and intensities of such immune responses were increased in patients with BC. Our results showed that 40% of patients had specific immune responses. In addition, we demonstrated the HLA-A2 ESR1 peptide immunogenicity in humanized HLA-A2/DR1 mice. In a data set generated from BC patients refractory to conventional therapy we showed that ESR1 mutations are correlated in advanced diseases with downregulation of molecules involved in antigen presentation and with loss HLA Class I gene expression. ESR1-mutated BC had a decrease in immune cell infiltration.</p><p><strong>Conclusion: </strong>These results support that common ESR1 mutations generate neoantigens in hormone-receptor positive metastatic breast cancers. If ESR1 peptides-restricted lymphocytes were detectable in BC patients, ESR1 mutations promote immune escape at advanced stages.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT02838381. Registered on June 2012.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"19"},"PeriodicalIF":7.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371132","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":"Quantifying the tumour vasculature environment from CD-31 immunohistochemistry images of breast cancer using deep learning based semantic segmentation.","authors":"Tristan Whitmarsh, Wei Cope, Julia Carmona-Bozo, Roido Manavaki, Stephen-John Sammut, Ramona Woitek, Elena Provenzano, Emma L Brown, Sarah E Bohndiek, Ferdia A Gallagher, Carlos Caldas, Fiona J Gilbert, Florian Markowetz","doi":"10.1186/s13058-024-01950-2","DOIUrl":"10.1186/s13058-024-01950-2","url":null,"abstract":"<p><strong>Background: </strong>Tumour vascular density assessed from CD-31 immunohistochemistry (IHC) images has previously been shown to have prognostic value in breast cancer. Current methods to measure vascular density, however, are time-consuming, suffer from high inter-observer variability and are limited in describing the complex tumour vasculature morphometry.</p><p><strong>Methods: </strong>We propose a method for automatically measuring a range of vascular parameters from CD-31 IHC images, which together provide a detailed description of the vasculature morphology. We first used a U-Net based convolutional neural network, trained and validated using 36 partially annotated whole slide images from 27 patients, to segment vessel structures and tumour regions from which the measurements are taken. The model also segments the vascular smooth muscle, benign epithelium, adipose tissue, stroma, lymphocyte clusters, nerves and CD-31 positive leukocytes, and we applied it to an additional 21 images from 15 patients. Using these segmentations, we investigated the relationship between the various tissue types and the vasculature and studied the relationship of various vascular parameters with clinical parameters. We also performed a 3D histology analysis on a separate tumour sample as a proof of principle, providing a more comprehensive visualization of vasculature morphology compared to the standard 2D cross-section of a tissue sample.</p><p><strong>Results: </strong>Using two-way cross-validation, we show that vessels were accurately segmented, with Dice scores of 0.875 and 0.856, and were accurately identified, with F1 scores of 0.777 and 0.748. All vascular parameters exhibit strong ( <math><mrow><mi>r</mi> <mo>></mo> <mn>0.7</mn></mrow> </math> ) and significant (p<0.001) correlations with measurements taken from the manual ground truth vessel segmentations. A significant relationship between the major/minor axis ratio, a measure of elongation, and the tumour grade was found.</p><p><strong>Conclusion: </strong>Our proposed method shows promise as a tool for studying the tumour vasculature and its relationship with surrounding cells and tissue types. Furthermore, the correlation with tumour grade highlights the clinical relevance of our approach. These findings suggest that our method could have substantial implications for improving prognostic assessments and personalizing therapeutic strategies in breast cancer treatment.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"17"},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191106","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":"Metabolites and lipid species mediate the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women.","authors":"Kayla R Getz, Myung Sik Jeon, Lili Liu, Lei Liu, Haixiang Zhang, Chongliang Luo, Jingqin Luo, Adetunji T Toriola","doi":"10.1186/s13058-025-01970-6","DOIUrl":"10.1186/s13058-025-01970-6","url":null,"abstract":"<p><strong>Background: </strong>Mammographic breast density (MBD), a strong predictor of breast cancer, is highly influenced by body mass index (BMI) in childhood and early adulthood, but the mechanisms underlying these associations are not fully understood. Our goal is to identify biomarkers that mediate the associations of BMI at ages 10 and 18 with MBD in premenopausal women.</p><p><strong>Methods: </strong>This study consists of 705 premenopausal women who had their screening mammogram at Washington University in St. Louis, MO, and provided a fasting blood sample. Our comprehensive metabolomic and lipidomic profiling yielded complete data for 828 metabolites and 857 lipid species after imputation. We used Volpara to determine volumetric measures of MBD. We performed high dimensional mediation analysis using the HIMA R package, adjusted for confounders, to determine whether lipid species and metabolites mediate the associations of BMI at 10 and 18 with MBD. We applied a false discovery rate (FDR) p-value < 0.1.</p><p><strong>Results: </strong>Four metabolites (glutamate, β-cryptoxanthin, cortolone glucuronide (1), phytanate) significantly mediated the association of BMI at 10 with volumetric percent density (VPD), and two (glutamate, β-cryptoxanthin) mediated the association of BMI at 18 with VPD. Glutamate was the strongest mediator across time points. Glutamate mediated 6.7% (FDR p-value = 0.06) and 9.3% (FDR p-value = 0.008) of the association between BMI at age 10 and 18, respectively. Four lipid species (CER(18:0), LCER(14:0), LPC(18:1), PC(18:1/18:1)), mediated the association of BMI at 10 with VPD, while five lipid species (CER(18:0), LCER(14:0), PC(18:1/18:1), TAG56:5-FA22:5, TAG52:2-FA16:0) mediated the association of BMI at 18 with VPD. The strongest mediator was PC(18:1/18:1), which mediated 9.7%, (FDR-p = 0.009) and 7.7%, (FDR-p = 0.04) of the association of BMI at age 10 and 18 with VPD, respectively.</p><p><strong>Conclusions: </strong>Metabolites in amino acid, lipid, cofactor/vitamin, and xenobiotic super-pathways as well as lipid species across the phospholipid, neutral complex lipid and sphingolipid super-pathways mediated the associations of BMI in early-life and MBD in premenopausal women. This study offers insight into the biological mechanisms underlying the link between early-life adiposity and MBD, which can support future research into breast cancer prevention.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"18"},"PeriodicalIF":7.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191104","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":"Evaluating risk factors for Trastuzumab-Deruxtecan Pneumonitis in patients with metastatic breast cancer.","authors":"Jonathan Henricks, Tyler Haddad, Omair Ahmed, Jonathan Schoenhals, Pavnesh Kumar, Ryan Wilson, Jianing Ma, Jing Gennie Wang, Michael Wert, Vincent Esguerra, Ian Bentley, Kai Johnson, Daniel Stover, Sachin R Jhawar, Margaret Gatti-Mays, Kevin Ho","doi":"10.1186/s13058-025-01967-1","DOIUrl":"10.1186/s13058-025-01967-1","url":null,"abstract":"<p><strong>Background: </strong>Trastuzumab deruxtecan (T-DXd) is FDA-approved for treatment of patients with HER2 positive and HER2-low metastatic breast cancer. Currently, there is limited understanding of pre-treatment risk factors for pneumonitis associated with T-DXd.</p><p><strong>Methods: </strong>Consecutive breast cancer patients who received at least one dose of T-DXd at a single academic cancer study between January 1, 2019, and February 20, 2024, were identified for analysis. Pneumonitis was documented by the treating oncologist at the time of toxicity and retrospectively independently confirmed by a member of the study team through chart and radiologic review. Pre-treatment variables of interest were collected, including patient demographics, radiation dosimetry variables, and chest imaging abnormalities.</p><p><strong>Results: </strong>Of 179 total patients, 23 (12.8%) had pneumonitis after T-DXd exposure. Patients with pneumonitis had lower baseline oxygen saturation (98% vs. 97%, p = 0.02) and were more likely to have received abemaciclib (26.1% vs. 9.6%, p = 0.03) before T-DXd. Multiple pre-treatment variables were not found to be associated with T-DXd pneumonitis, including chest imaging abnormalities (41.9% vs. 47.8%, p = 0.59), prior immune checkpoint inhibitor treatment (16.0% vs. 8.7%, p = 0.50) and prior chest or breast radiation (61.5% vs. 47.8%, p = 0.20). On multivariate analysis, prior treatment with abemaciclib remained significantly associated with T-DXd pneumonitis (OR 3.25 [1.07-9.11], p = 0.04), while neither pre-treatment chest imaging abnormalities nor prior chest or breast radiation were associated (OR 1.60 [0.62-4.20], p = 0.33); OR 0.51 [0.20-1.33], p = 0.17).</p><p><strong>Conclusions: </strong>In this cohort, prior treatment with abemaciclib may be a risk factor for T-DXd pneumonitis. Conversely, pre-treatment chest imaging abnormalities, prior immune checkpoint inhibitor treatment, and prior chest or breast radiation did not increase the risk of T-DXd pneumonitis. Larger studies are warranted to validate these findings toward an improved understanding of risk factors for pneumonitis after T-DXd exposure.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"16"},"PeriodicalIF":7.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123879","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":"CXCR4 promotes tumor stemness maintenance and CDK4/6 inhibitors resistance in ER-positive breast cancer.","authors":"Qianfeng Shi, Wang Yang, Yiye Ouyang, Yujie Liu, Zijie Cai","doi":"10.1186/s13058-025-01965-3","DOIUrl":"10.1186/s13058-025-01965-3","url":null,"abstract":"<p><strong>Background: </strong>CDK4/6 inhibitors have significantly improved the survival of patients with HR-positive/HER2-negative breast cancer, becoming a first-line treatment option. However, the development of resistance to these inhibitors is inevitable. To address this challenge, novel strategies are required to overcome resistance, necessitating a deeper understanding of its mechanisms. Recent research has identified several dysregulated genes in CDK4/6 inhibitors-resistant breast cancer, but the underlying mechanism is complex due to tumor heterogeneity and warrants further investigation.</p><p><strong>Methods: </strong>RNA sequencing and KEGG pathway analysis was carried out to identify the mainly dysregulated genes in CDK4/6 inhibitors-resistant breast cancer cells. The effects of CXCR4 knockdown and overexpression via siRNAs and plasmids transfection were examined by mammosphere formation, RT-qPCR, flow cytometry, MTT and colony formation assays. The regulation mechanisms were analyzed by RT-qPCR, western blotting and immunofluorescence experiments. Mouse xenografts were used to analyze the role of CXCR4 in regulation palbociclib sensitivity in vivo. Additionally, we collected the clinical samples and performed immunohistochemistry to analyze the clinical significance of CXCR4.</p><p><strong>Results: </strong>In our study, we focused on cancer stem cells, a critical contributor to cancer metastasis and therapy resistance, and detected an upregulation of stemness in our established palbociclib-resistant ER-positive breast cancer cells. Additionally, our research pinpointed CXCR4 as a pivotal gene responsible for maintaining cancer stemness and promoting palbociclib resistance. Mechanistically, CXCR4 activates the WNT5A/β-catenin signaling pathway by enhancing the expression of WNT5A and β-catenin, facilitating the nuclear translocation of β-catenin protein. Targeting CXCR4 using siRNAs or small molecular inhibitors effectively reduces cancer stemness and reverses palbociclib resistance both in vitro and in vivo. Clinical sample analysis further underscores the overactivation of the CXCR4/WNT5A/β-catenin axis in palbociclib-resistant breast cancer, suggesting CXCR4 as a potential biomarker for predicting resistance to CDK4/6 inhibitors.</p><p><strong>Conclusions: </strong>Collectively, our study demonstrates that CXCR4 overexpression plays a vital role in maintaining breast cancer stemness and promoting resistance to CDK4/6 inhibitors through the activation of the WNT5A/β-catenin pathway. Targeting CXCR4 may offer a promising therapeutic approach for advanced CDK4/6 inhibitor-resistant ER-positive breast cancer.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"15"},"PeriodicalIF":7.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143061282","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":"Prediction of pathological complete response after neoadjuvant chemotherapy for HER2-negative breast cancer patients with routine immunohistochemical markers.","authors":"Lothar Häberle, Ramona Erber, Paul Gass, Alexander Hein, Melitta Niklos, Bernhard Volz, Carolin C Hack, Rüdiger Schulz-Wendtland, Hanna Huebner, Chloë Goossens, Matthias Christgen, Thilo Dörk, Tjoung-Won Park-Simon, Andreas Schneeweiss, Michael Untch, Valentina Nekljudova, Sibylle Loibl, Arndt Hartmann, Matthias W Beckmann, Peter A Fasching","doi":"10.1186/s13058-025-01960-8","DOIUrl":"10.1186/s13058-025-01960-8","url":null,"abstract":"<p><strong>Background: </strong>Pathological complete response (pCR) is an established surrogate marker for prognosis in patients with breast cancer (BC) after neoadjuvant chemotherapy. Individualized pCR prediction based on clinical information available at biopsy, particularly immunohistochemical (IHC) markers, may help identify patients who could benefit from preoperative chemotherapy.</p><p><strong>Methods: </strong>Data from patients with HER2-negative BC who underwent neoadjuvant chemotherapy from 2002 to 2020 (n = 1166) were used to develop multivariable prediction models to estimate the probability of pCR (pCR-prob). The most precise model identified using cross-validation was implemented in an online calculator and a nomogram. Associations among pCR-prob, prognostic IHC3 distant recurrence and disease-free survival were studied using Cox regression and Kaplan-Meier analyses. The model's utility was further evaluated in independent external validation cohorts.</p><p><strong>Results: </strong>273 patients (23.4%) achieved a pCR. The most precise model had across-validated area under the curve (AUC) of 0.84, sensitivity of 0.82, and specificity of 0.71. External validation yielded AUCs between 0.75 (95% CI, 0.70-0.81) and 0.83 (95% CI, 0.78-0.87). The higher the pCR-prob, the greater the prognostic impact of pCR status (presence/absence): hazard ratios decreased from 0.55 (95% central range, 0.07-1.77) at 0% to 0.20 (0.11-0.31) at 50% pCR-prob. Combining pCR-prob and IHC3 score further improved the precision of disease-free survival prognosis.</p><p><strong>Conclusions: </strong>A pCR prediction model for neoadjuvant therapy decision-making was established. Combining pCR and recurrence prediction allows identification of not only patients who benefit most from neoadjuvant chemotherapy, but also patients with a very unfavorable prognosis for whom alternative treatment strategies should be considered.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"13"},"PeriodicalIF":7.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11759445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042993","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}