Breast Cancer Research最新文献

{"title":"The impact of a mainstream genetic testing pathway and socioeconomic factors on the uptake of germline genetic testing in breast cancer patients: results of the nationwide GENE-SMART study.","authors":"Chiem Leonardo de Jong, Sabine Siesling, Ghita Carola Wilhelmina Maria Puts, Agnes Jager, Margreet Geertruda Elia Maria Ausems","doi":"10.1186/s13058-025-02081-y","DOIUrl":"10.1186/s13058-025-02081-y","url":null,"abstract":"<p><strong>Background: </strong>Genetic testing in breast cancer patients is important for the patient's local and systemic treatment choices and follow-up, as well as for their family members. Not all eligible patients currently undergo genetic testing and disparities persist in genetic testing uptake. It is unknown on the large scale whether pre-test counselling by non-genetic healthcare professionals (HCPs)-mainstream genetic testing (MGT) - improves overall genetic testing uptake and reduces disparities. We examined the impact of MGT on germline genetic testing uptake in general and in subgroups of socioeconomic status (SES) in particular.</p><p><strong>Methods: </strong>In this retrospective nationwide cohort study, we selected all breast cancer patients from the Netherlands Cancer Registry who were eligible for genetic testing according to patient and tumour characteristics under the Dutch guidelines and who were diagnosed between 1-Jan-2017 and 31-Dec-2022. The primary outcome was genetic testing uptake. The influence of MGT and SES on overall uptake and uptake across different SES levels was evaluated using chi-squared tests and multivariable logistic regression analyses.</p><p><strong>Results: </strong>A total of 12,071 breast cancer patients were included. Overall genetic testing uptake was 67%: 78% for MGT versus 63% in referral to a genetics department (RGD) (p < 0.001) with significantly higher odds of receiving genetic testing for MGT versus RGD (OR 2.48, 95% CI 2.14-2.87). Patients with low SES showed significantly lower odds of receiving genetic testing compared to those with a high SES (OR 0.71, 95% CI 0.61-0.83). In MGT, no significant difference was found between low and high SES in the likelihood of receiving genetic testing (OR 0.75, 95% CI 0.50-1.13).</p><p><strong>Conclusions: </strong>MGT significantly increases genetic testing uptake among all eligible patients and across all SES subgroups, strongly encouraging further implementation of MGT. Educating HCPs about current disparities in genetic testing is essential to improve health equity in breast cancer care.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"129"},"PeriodicalIF":7.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627536","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":"Chemoresistant tumor cell secretome potentiates immune suppression in triple negative breast cancer.","authors":"Eleni Skourti, Kotryna Seip, Nadia Mensali, Shakila Jabeen, Siri Juell, Inger Øynebråten, Solveig Pettersen, Olav Engebraaten, Alexandre Corthay, Else Marit Inderberg, Helmut Dolznig, Gunhild Mari Mælandsmo, Eivind Valen Egeland, Lina Prasmickaite","doi":"10.1186/s13058-025-02082-x","DOIUrl":"10.1186/s13058-025-02082-x","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy is an integral part of the clinical management of triple negative breast cancer (TNBC), however, development of chemoresistance occurs frequently. Tumor sensitivity to treatment is known to be strongly influenced by the immune microenvironment, signifying the predictive potential of immune alterations. How tumor cells that acquire resistance may subsequently modulate the immune microenvironment it is still not well described. Here, we investigated immunomodulation in the context of acquired chemoresistance in TNBC, focusing on the role of the secretome.</p><p><strong>Methods: </strong>Bulk RNA sequencing and multiplex cytokine profiling were performed on paclitaxel-resistant and -sensitive isogenic variants of TNBC cells to reveal resistance-associated secretome alterations. The immunomodulatory influence of the tumor cell secretome was investigated by exploring its effect on monocytes, macrophages (MΦs) and T cells derived from healthy blood donors. The influence on the immune cell phenotype and activity was evaluated by measuring molecular markers and performing functional assays. To validate the clinical relevance, we utilized longitudinal -omics data from breast cancer patients refractory to standard chemotherapy in the NeoAva clinical trial. CIBERSORT was applied to transcriptomics data to infer MΦ and T cell abundance in individual tumors upon treatment. To evaluate their association with the secretome profiles, patient-matched serum cytokine data were used.</p><p><strong>Results: </strong>The acquisition of chemoresistance was accompanied by enhanced secretion of cytokines. Subsequently, the resistant cell secretome affected the abundance, phenotype and activity of immune cells. Specifically, it potentiated the recruitment of monocytes, facilitated the polarization of MΦs towards the immunosuppressive M2-like phenotype, and attenuated the activation of CD8⁺ T cells. Data from the NeoAva clinical cohort validated the enrichment of M2 MΦs and/or the depletion of M1 MΦs after treatment in the majority of residual tumors. The MΦ-associated changes counteracted CD8⁺ T cell abundance and were partially associated with the cytokine-enriched secretome.</p><p><strong>Conclusion: </strong>Development of chemoresistance in BC is associated with alterations in the tumor secretome, which impairs immune activation and facilitates immunosuppression. Knowledge on the immune microenvironment in residual tumors after standard chemotherapy could aid in selecting rational treatment options for this group of patients.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"131"},"PeriodicalIF":7.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638564","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":"The association between body mass index and neoadjuvant chemotherapy response in patients with breast cancer.","authors":"Jonas Busk Holm, Stine Blaabjerg Skovbjerg, Hanne Melgaard Nielsen, Peer Christiansen, Jens Meldgaard Bruun, Jan Alsner, Deirdre Cronin-Fenton, Signe Borgquist","doi":"10.1186/s13058-025-02083-w","DOIUrl":"10.1186/s13058-025-02083-w","url":null,"abstract":"<p><strong>Background: </strong>Obesity, defined as Body Mass Index (BMI) ≥ 30 kg/m², is associated with inferior breast cancer prognosis, but its effect on neoadjuvant chemotherapy response is uncertain. We hypothesized that obesity decreases the odds of pathological complete response (pCR) after neoadjuvant chemotherapy.</p><p><strong>Methods: </strong>We assembled a cohort of women with breast cancer who underwent neoadjuvant chemotherapy and subsequent surgery between January 1, 2016, and December 31, 2020, in Denmark. Patients received six or eight series of EC-TAX (epirubicin, cyclophosphamide, and paclitaxel) based on disease stage. Trastuzumab and pertuzumab were also used for patients with HER2+ disease. BMI was assessed as a categorical variable (normal weight (BMI = 18.5-<25 kg/m²), overweight (BMI = 25-<30 kg/m²), and obesity (BMI ≥ 30 kg/m²)) and as a continuous variable. We used multivariable logistic regression models to compute odds ratios (ORs) for pCR after neoadjuvant chemotherapy according to BMI groups, using normal weight as reference, and stratified by menopausal, estrogen receptor (ER), and HER2 status. We adjusted for age and menopausal status based on a directed acyclic graph.</p><p><strong>Results: </strong>Among 1819 patients, 417 had pCR. Patients with overweight (N = 585) or obesity (N = 450) had 22% and 27% lower odds, respectively, of pCR (OR_adj=0.78 [95%CI = 0.60-1.00] and OR_adj=0.73 [95%CI = 0.55-0.97]) compared with patients with normal weight (N = 784). In ER/HER2-stratified analyses, we observed lower pCR odds among women with obesity and HER2+ tumors (OR_adj=0.72 [95%CI = 0.47-1.12]) compared with their normal weight counterparts, but no notable association appeared for ER+/HER2- (OR_adj=0.97 [95%CI = 0.49-1.96]) and ER-/HER2- tumors (OR_adj=0.88 [95%CI = 0.49-1.57]). In analyses stratified by menopausal status, obesity was associated with lower pCR odds among postmenopausal women (OR_adj=0.62 [95%CI = 0.41-0.94]), and, to a lesser extent, premenopausal women (OR_adj=0.86 [95%CI = 0.58-1.27]).</p><p><strong>Conclusions: </strong>Our findings suggest that breast cancer patients with overweight or obesity have lower odds of pCR compared with patients with normal weight. As the results varied by ER and HER2 status, the observed association may depend on subtype. In summary, our results are consistent with earlier studies that propose BMI as a potential prognostic marker of pCR.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"130"},"PeriodicalIF":7.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144620998","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":"Erdafitinib inhibits the tumorigenicity of MDA-MB-231 triple-negative breast cancer cells by inducing TRIM25/ubiquitin-dependent degradation of FGFR4.","authors":"Qing Luo, Li Zhang, Yue Hao, Chunwei Xu, Xiaojia Wang, Zhen Jia, Xiandong Xie, Zhihong Huang, Xiaomin Gao, Yu Chen, Xue Zhu, Jing Fang, Ke Wang, Yongxiang Yin","doi":"10.1186/s13058-025-02086-7","DOIUrl":"10.1186/s13058-025-02086-7","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implicated in TNBC; however, the therapeutic potential of targeting FGFRs for TNBC treatment remains unclear. This study investigated the anti-cancer activity of the selective pan-FGFR inhibitor Erdafitinib and its underlying mechanisms using both in vitro and in vivo models. The results demonstrated that Erdafitinib suppressed TNBC tumorigenicity by promoting FGFR1/4 degradation, generating reactive oxygen species (ROS), inducing DNA damage, and ultimately triggering cell death. Mechanistic analyses revealed that Erdafitinib facilitated FGFR1/4 degradation through ubiquitination, enhanced interaction between TRIM25 and FGFR1/4, and subsequent lysosomal degradation. Furthermore, RNA-seq data from the TCGA and GEO databases, along with paired tumor tissues from TNBC patients, indicated that FGFR4 was significantly upregulated in TNBC. Notably, co-knockdown of FGFR1 and FGFR4 induced cytotoxicity in MDA-MB-231 cells, highlighting the therapeutic relevance of FGFR1/4 degradation by Erdafitinib in TNBC. These findings provide novel insights into the mechanisms underlying the anti-cancer efficacy of Erdafitinib, supporting its potential as a promising therapeutic agent for TNBC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"128"},"PeriodicalIF":7.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602008","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":"Mutational landscape of pure ductal carcinoma in situ and associations with disease prognosis and response to radiotherapy.","authors":"Noor Rizvi, Eliseos J Mucaki, Emily L Salmini, Monica Zhang, Sabina Trebinjac, Ezra Hahn, Lawrence Paszat, Sharon Nofech-Mozes, Michael T Hallett, Eileen Rakovitch, Vanessa Dumeaux","doi":"10.1186/s13058-025-02080-z","DOIUrl":"10.1186/s13058-025-02080-z","url":null,"abstract":"<p><strong>Background: </strong>Managing Ductal Carcinoma in Situ (DCIS) remains challenging due to the lack of reliable biomarkers to predict radiotherapy (RT) response, leading to both overtreatment of indolent disease and undertreatment of aggressive cases.</p><p><strong>Results: </strong>Through whole-exome sequencing of 147 DCIS cases, we characterized the genomic landscape of pure DCIS and identified genetic alterations associated with the risk of recurrence, either in-situ or invasive. DCIS lesions harbored frequent mutations in established cancer drivers (PIK3CA, TP53) and genes regulating tissue architecture, which likely enhanced pre-invasive cell fitness but lacked prognostic value. A subset of younger patients exhibited distinct mutational processes characterized by high mutational burden, though these were not linked to recurrence risk. Across the cohort, five mostly mutually exclusive genes (SH2B2, PDZD8, MYO7A, MUCL3, DNASE2B), involved in cell adhesion, membrane organization, and DNA degradation, were significantly associated with 10-year risk of local recurrence. In RT-treated patients, we identified 27 additional mutated genes uniquely associated with recurrence, along with SH2B2 and MUCL3. Most of these genes were involved in cytoskeletal regulation, cell adhesion, and cell-environment interactions. Mutations in metabolic regulators (MGAM2 and AADACL3) and REV1, which mediates DNA damage tolerance, may impair cellular responses to RT-induced stress. Notably, we identified distinct genes prognostic for in-situ versus invasive recurrence: nineteen genes predominantly involved in tissue structural maintenance in in-situ relapse, and thirteen genes primarily affecting cell-cycle and genome-stability pathways in invasive progression. Copy number analyses revealed that pure DCIS exhibits molecular subtype-specific patterns characteristic of invasive disease, with novel alterations associated with recurrence, including three non-adjacent gains and five losses in regions harboring oncogenes, tumor suppressor genes, and genes regulating structural integrity, cell-cell adhesion and interactions.</p><p><strong>Conclusions: </strong>While TP53, PIK3CA, and recurrent copy number alterations represent early events in tumorigenesis, they lack prognostic value in pure DCIS, underscoring the need for alternative biomarkers. Our findings identify key genetic alterations associated with local recurrence and RT resistance. We further uncovered distinct molecular programs underlying in-situ versus invasive recurrence, with mutations affecting tissue structural maintenance in in-situ relapse and cell-cycle/genome-stability pathways in invasive progression.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"127"},"PeriodicalIF":7.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592793","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":"Overexpression of TSG101 causes the development of adenosquamous mammary carcinoma.","authors":"Rayane Dennaoui, Patrick D Rädler, Madison N Wicker, Kerry Vistisen, Rosa-Maria Ferraiuolo, Aleata A Triplett, Hridaya Shrestha, Tessa A Liner, Karoline C Manthey, Hallgeir Rui, Robert D Cardiff, Teresa M Gunn, Charles M Perou, Kay-Uwe Wagner","doi":"10.1186/s13058-025-02007-8","DOIUrl":"10.1186/s13058-025-02007-8","url":null,"abstract":"<p><strong>Background: </strong>The mammalian Tumor Susceptibility Gene 101 (TSG101) encodes a protein with diverse functions that control the proliferation and survival of cells, but its role in malignant transformation and cancer development has remained enigmatic.</p><p><strong>Methods: </strong>To study the pro-tumorigenic functions of TSG101, we developed a bi-transgenic mouse model that expresses exogenous TSG101 along with a luciferase reporter in a ligand-controlled manner in the mammary gland epithelium. We performed a comprehensive histopathologic, biochemical, and molecular characterization of ductal hyperplasia and mammary tumors. Unsupervised hierarchical clustering based on 1,723 intrinsic genes of ten TSG101-overexpressing cancers alongside 251 tissue samples representing 31 reference mammary tumor models and normal mammary glands was conducted.</p><p><strong>Results: </strong>Females overexpressing TSG101 develop ductal hyperplasia, adenomyoepitheliomas, and palpable adenosquamous carcinomas at an average latency of approximately ten months. These metaplastic mammary tumors are comprised of transforming basal and luminal epithelial cells. Using a GFP reporter strain to monitor the transgene activation at the single-cell level, we determined that the epithelial heterogeneity within transforming ducts and ensuing carcinomas originated from the luminal epithelium. At the molecular level, TSG101-induced mammary tumors are triple-negative and exhibit gene expression signatures of Wnt and inflammatory cytokine signaling, which are key regulators of epithelial cell fate. The ligand-controlled downregulation of exogenous TSG101 in established carcinomas led to tumor regression. We demonstrated that the TSG101-mediated activation of PI3K/AKT signaling, as well as upregulation of Cyclin D1 and MDM2, are dependent on the perpetual expression of the TSG101 oncoprotein.</p><p><strong>Conclusions: </strong>The collective findings of this study provide in vivo evidence that TSG101 possesses pro-tumorigenic properties that extend to cancer progression and maintenance, suggesting that this protein could be a rational molecular target to prevent and treat a subset of mammary tumors.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"126"},"PeriodicalIF":7.4,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585473","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":"Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue.","authors":"Gaofeng Xiong, Daheng He, Dana Napier, Jing Chen, Haizhu Shi, Chun Li, Paula J Hurley, Chi Wang, Haining Zhu, Changcheng Zhou, Theresa J Bocklage, Ren Xu","doi":"10.1186/s13058-025-02076-9","DOIUrl":"10.1186/s13058-025-02076-9","url":null,"abstract":"<p><p>Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"125"},"PeriodicalIF":7.4,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576815","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":"THEM6 modulates carboplatin sensitivity by regulating ferroptosis through FDFT1 in triple-negative breast cancer.","authors":"Yuexiang Zeng, Zhijie Xu, Juan Huang, Qiaoli Yi, Xi Chen, Jiayu Wang, Zhihao Du, Jian Tian, Yuanliang Yan","doi":"10.1186/s13058-025-02078-7","DOIUrl":"10.1186/s13058-025-02078-7","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, as chemotherapy resistance leads to relapse in many patients. Carboplatin addition improves treatment response, but challenges persist.</p><p><strong>Methods: </strong>To identify novel targets for TNBC, we analyzed differentially expressed proteins in patients treated with neoadjuvant chemotherapy. Cell viability was assessed using CCK-8 and colony formation assays. In vivo effects were studied in an orthotopic xenograft model using THEM6 overexpression cells. ROS, iron levels, MDA, and mitochondrial ultrastructure were assessed. Protein expression was analyzed by Western blotting and RT-PCR, and FDFT1 ubiquitination was evaluated.</p><p><strong>Results: </strong>We identified THEM6 (co-downregulated) and PGRMC1 (co-upregulated) as survival-associated proteins. THEM6 overexpression enhanced carboplatin sensitivity in vitro and in vivo, reducing tumor weight and volume. THEM6-induced sensitivity was linked to ferroptosis, as the ferroptosis inhibitor Fer-1 reversed the effect, while apoptosis, necrosis, and autophagy inhibitors had no impact. THEM6 overexpression reduced GPX4 and SLC7A11, while increasing ACSL4. TEM revealed mitochondrial damage, and iron, MDA, and ROS levels were elevated in treated cells. Mechanistically, THEM6 stabilized FDFT1 by inhibiting its K48-linked ubiquitination, prolonging its protein half-life, and promoting ferroptosis. FDFT1 knockdown reversed THEM6-induced sensitivity to carboplatin.</p><p><strong>Conclusions: </strong>Our findings suggest that THEM6 enhances carboplatin sensitivity in TNBC by promoting ferroptosis through regulation of FDFT1. THEM6 may serve as a novel therapeutic target to improve TNBC treatment outcomes.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"124"},"PeriodicalIF":7.4,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576816","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":"Palazestrant, a novel oral Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), in patients with ER+/HER2- advanced or metastatic breast cancer: phase 1/2 study results.","authors":"Erika P Hamilton, Manish R Patel, Virginia F Borges, Jane L Meisel, Meena Okera, Carlos A Alemany, Timothy J Pluard, Robert Wesolowski, Dhanusha Sabanathan, Kathy D Miller, Alison K Conlin, Nicole McCarthy, Morena Shaw, Margaret Tonda, Mark Shilkrut, Nancy U Lin","doi":"10.1186/s13058-025-02049-y","DOIUrl":"10.1186/s13058-025-02049-y","url":null,"abstract":"<p><strong>Background: </strong>Endocrine resistance is a major challenge in treating patients with ER+ /HER2- metastatic breast cancer (MBC) necessitating a switch from endocrine therapy to more toxic therapies. Mutations in ESR1 constitute a key mechanism of resistance to endocrine therapy in ER+ /HER2- BC. Therapies that overcome endocrine resistance are needed. Palazestrant is a novel oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) belonging to a new class of ER-targeting agents that completely blocks estrogen-induced transcriptional activity, regardless of ESR1 mutation status. This first-in-human, open-label, multicenter, phase 1/2 dose-escalation/expansion study was designed to determine the recommended phase 2 dose (RP2D) and to evaluate safety, pharmacokinetics, and antitumor activity of palazestrant in patients with ER+ /HER2- MBC with disease progression on prior treatment.</p><p><strong>Methods: </strong>Adults with ER+ /HER2‒ MBC who received ≥ 1 prior line of endocrine therapy for advanced disease and ≤ 2 prior chemotherapy regimens for metastatic disease were eligible. Patients received once-daily oral palazestrant (30-300 mg) in 28-day cycles until progression or intolerable toxicity.</p><p><strong>Results: </strong>This study enrolled 146 patients. No dose-limiting toxicities were observed at doses up to 300 mg/day palazestrant. Confirmed partial responses were observed with 60 and 120 mg/day palazestrant. Both doses showed similar and tolerable safety profiles, favorable pharmacokinetics, and steady-state plasma concentrations above the predicted threshold for complete ER inhibition. Greater clinical benefit at palazestrant 120 mg/day (46%) versus 60 mg/day (19%) led to selection of 120 mg/day as RP2D and study expansion dose. At 120 mg/day, the median progression-free survival was 4.8 months (95% CI, 3.5-7.1) overall and 5.6 months (95% CI, 4.8-NE) among patients with cancers with ESR1 mutations. Most treatment-emergent adverse events (TEAEs) were grade 1-2. The most common TEAEs were nausea (62.8%), vomiting (29.1%), and fatigue (25.6%). The most common grade ≥ 3 TEAE was transient neutropenia (10.5%) managed by dose interruption and reduction.</p><p><strong>Conclusions: </strong>Palazestrant demonstrated a manageable safety profile, with antitumor activity observed in patients with heavily pretreated cancers with wild-type and ESR1-mutated BC. These data support the ongoing phase 3 study evaluating palazestrant in patients with ER+ /HER2 - MBC.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT04505826 . Registered August 6, 2020.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"119"},"PeriodicalIF":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545767","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":"Prognosticating axillary lymph node metastasis in breast cancer through integrated photoacoustic imaging, ultrasound, and clinical parameters.","authors":"Zhibin Huang, Sijie Mo, Guoqiu Li, Hongtian Tian, Huaiyu Wu, Jing Chen, Mengyun Wang, Shuzhen Tang, Jinfeng Xu, Fajin Dong","doi":"10.1186/s13058-025-02073-y","DOIUrl":"10.1186/s13058-025-02073-y","url":null,"abstract":"<p><strong>Purpose: </strong>To develop and validate a predictive model for axillary lymph node metastasis (ALNM) in breast cancer (BC) by integrating clinicopathological factors, ultrasound features, and photoacoustic imaging-derived SO₂ measurements, aiming to improve diagnostic accuracy and provide comprehensive clinical insights.</p><p><strong>Methods: </strong>A total of 317 BC patients were included, with the cohort split into a training set (70%) and a testing set (30%). Univariate and multivariate logistic regression identified key predictive factors, leading to the creation of three models: ModA (clinicopathological factors only), ModB (clinicopathological and ultrasound features), and ModC (clinicopathological, ultrasound, and SO₂ measurements from photoacoustic imaging). De-Long test and ROC curve were used to evaluate and compare the diagnostic performance of the models.</p><p><strong>Results: </strong>Multivariate analysis showed that maximum diameter, Ki67 expression, AUS report and SO₂ levels were identified as significant risk factors for ALNM. ModA achieved an AUC of 0.776 (95% CI: 0.691-0.862), ModB improved to 0.824 (95% CI: 0.738-0.909), and ModC demonstrated the highest performance with an AUC of 0.882 (95% CI: 0.815-0.950) in the testing set. The results highlight that the comprehensive model (ModC), integrating clinical, ultrasound, and photoacoustic imaging data, provides superior predictive accuracy for ALNM.</p><p><strong>Conclusion: </strong>Integrating SO₂ measurements with traditional clinical and ultrasound data can substantially enhance the prediction of ALNM in BC patients. This combined model offers a comprehensive and reliable decision support tool for the preoperative risk assessment of axillary lymph nodes in BC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":"27 1","pages":"123"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545768","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}