Breast Cancer Research : BCR最新文献

{"title":"The impact of cardiovascular disease on all-cause and cancer mortality: results from a 16-year follow-up of a German breast cancer case-control study.","authors":"Annika Möhl,&nbsp;Sabine Behrens,&nbsp;Fabian Flaßkamp,&nbsp;Nadia Obi,&nbsp;Annika Kreienbrinck,&nbsp;Bernd Holleczek,&nbsp;Kathleen Gali,&nbsp;Jenny Chang-Claude,&nbsp;Heiko Becher","doi":"10.1186/s13058-023-01680-x","DOIUrl":"https://doi.org/10.1186/s13058-023-01680-x","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease (CVD) is the leading cause of death worldwide. The aim of this study was to examine if CVD affects the mortality of women after a breast cancer diagnosis and population controls differently.</p><p><strong>Methods: </strong>The analysis included a total of 3,555 women, diagnosed with primary stage 1-3 breast cancer or in situ carcinoma between 2002 and 2005 and 7,334 controls breast cancer-free at recruitment, all aged 50-74 years, who were followed-up in a German breast cancer case-control study until June, 30 2020. Kaplan-Meier and cumulative incidence function were calculated for all-cause mortality and mortality from any cancer, stratified for case-control status and CVD, separately for women aged < 65 and ≥ 65 years. Cox regression and Fine-Gray subdistribution hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between case-control-status, CVD and mortality from all causes/any cancer.</p><p><strong>Results: </strong>The median follow-up was 16.1 years. In total, 1,172 cases (33.0%) and 1,401 initial controls (19.1%) died. CVD prevalence at recruitment was 15.2% in cases and controls. Cases with CVD had the highest and controls without CVD the lowest mortality during the entire observation period in both age groups (< 65 and ≥ 65 years). CVD was identified as a risk factor for all-cause mortality in both cases and controls aged < 65 years (HR 1.22, 95%CI 0.96-1.55 and HR 1.79, 95%CI 1.43-2.24) as well as at ages of ≥ 65 years (HR 1.44, 95%CI 1.20-1.73 and HR 1.59, 95%CI 1.37-1.83). A significant association of CVD and cancer mortality was found only for cases aged ≥ 65 years.</p><p><strong>Conclusion: </strong>CVD was significantly associated with all-cause mortality of both cases and controls and CVD was identified as a risk factor for cancer mortality of cases aged ≥ 65 years at recruitment. Therefore, attention should be paid on monitoring and preventing CVD in breast cancer patients, especially in those diagnosed at older ages.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10281781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.","authors":"Chanjuan Zheng,&nbsp;Xi Xu,&nbsp;Muyao Wu,&nbsp;Lian Xue,&nbsp;Jianyu Zhu,&nbsp;Hongzhuo Xia,&nbsp;Siyu Ding,&nbsp;Shujun Fu,&nbsp;Xinyu Wang,&nbsp;Yian Wang,&nbsp;Guangchun He,&nbsp;Xia Liu,&nbsp;Xiyun Deng","doi":"10.1186/s13058-023-01676-7","DOIUrl":"https://doi.org/10.1186/s13058-023-01676-7","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferation and metastasis. In the tumor microenvironment, neutrophils modulate the immune milieu through polarization between the anti-tumor and the pro-tumor phenotypes. Through a comprehensive review of recently published literature, it is evident that neutrophils are an important player in TNBC immunobiology and can be used as an important prognostic marker of TNBC. Particularly, in their pro-tumor form, neutrophils facilitate TNBC metastasis through formation of neutrophil extracellular traps and the pre-metastatic niche. These findings will help advance the potential utilization of neutrophils as a therapeutic target in TNBC.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9924377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning applications to breast cancer detection by magnetic resonance imaging: a literature review.","authors":"Richard Adam,&nbsp;Kevin Dell'Aquila,&nbsp;Laura Hodges,&nbsp;Takouhie Maldjian,&nbsp;Tim Q Duong","doi":"10.1186/s13058-023-01687-4","DOIUrl":"https://doi.org/10.1186/s13058-023-01687-4","url":null,"abstract":"<p><p>Deep learning analysis of radiological images has the potential to improve diagnostic accuracy of breast cancer, ultimately leading to better patient outcomes. This paper systematically reviewed the current literature on deep learning detection of breast cancer based on magnetic resonance imaging (MRI). The literature search was performed from 2015 to Dec 31, 2022, using Pubmed. Other database included Semantic Scholar, ACM Digital Library, Google search, Google Scholar, and pre-print depositories (such as Research Square). Articles that were not deep learning (such as texture analysis) were excluded. PRISMA guidelines for reporting were used. We analyzed different deep learning algorithms, methods of analysis, experimental design, MRI image types, types of ground truths, sample sizes, numbers of benign and malignant lesions, and performance in the literature. We discussed lessons learned, challenges to broad deployment in clinical practice and suggested future research directions.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10367400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9921449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancement of PD-L1-attenuated CAR-T cell function through breast cancer-associated fibroblasts-derived IL-6 signaling via STAT3/AKT pathways.","authors":"Nisa Chuangchot,&nbsp;Pranisa Jamjuntra,&nbsp;Supaporn Yangngam,&nbsp;Piriya Luangwattananun,&nbsp;Suyanee Thongchot,&nbsp;Mutita Junking,&nbsp;Peti Thuwajit,&nbsp;Pa-Thai Yenchitsomanus,&nbsp;Chanitra Thuwajit","doi":"10.1186/s13058-023-01684-7","DOIUrl":"https://doi.org/10.1186/s13058-023-01684-7","url":null,"abstract":"<p><strong>Background: </strong>Carcinoma-associated fibroblasts (CAFs) play a critical role in cancer progression and immune cell modulation. In this study, it was aimed to evaluate the roles of CAFs-derived IL-6 in doxorubicin (Dox) resistance and PD-L1-mediated chimeric antigenic receptor (CAR)-T cell resistance in breast cancer (BCA).</p><p><strong>Methods: </strong>CAF conditioned-media (CM) were collected, and the IL-6 level was measured by ELISA. CAF-CM were treated in MDA-MB-231 and HCC70 TNBC cell lines and siIL-6 receptor (IL-6R) knocked down (KD) cells to determine the effect of CAF-derived IL-6 on Dox resistance by flow cytometry and on increased PD-L1 through STAT3, AKT and ERK1/2 pathways by Western blot analysis. After pre-treating with CM, the folate receptor alpha (FRα)-CAR T cell cytotoxicity was evaluated in 2D and 3D spheroid culture assays.</p><p><strong>Results: </strong>The results showed a significant level of IL-6 in CAF-CM compared to that of normal fibroblasts (NFs). The CM with high IL-6 level significantly induced Dox resistance; and PD-L1 expression through STAT3 and AKT pathways in MDA-MB-231 and HCC70 cells. These induction effects were attenuated in siIL-6R KD cells. Moreover, the TNBC cell lines that were CM-treated with STAT3 and an AKT inhibitor had a reduced effect of IL-6 on PD-L1 expression. BCA cells with high IL-6 containing-CM treatment had resistance to cancer cell killing by FRα CAR-T cells compared to untreated cells.</p><p><strong>Conclusion: </strong>These results highlight CAF-derived IL-6 in the resistance of chemotherapy and T cell therapy. Using inhibitors of IL6-STAT3/AKT-PD-L1 axis may provide a potential benefit of Dox and CAR-T cell therapies in BCA patients.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9979018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer.","authors":"M G Muoio, M Pellegrino, V Rapicavoli, M Talia, G Scavo, V Sergi, V Vella, S Pettinato, M G Galasso, R Lappano, D Scordamaglia, F Cirillo, A Pulvirenti, D C Rigiracciolo, M Maggiolini, A Belfiore, E M De Francesco","doi":"10.1186/s13058-023-01686-5","DOIUrl":"10.1186/s13058-023-01686-5","url":null,"abstract":"<p><p>The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9961997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway.","authors":"Wenjie Xia,&nbsp;Wuzhen Chen,&nbsp;Chao Ni,&nbsp;Xuli Meng,&nbsp;Jun Wu,&nbsp;Qiong Yang,&nbsp;Hongchao Tang,&nbsp;Hongjun Yuan,&nbsp;Shan Fang","doi":"10.1186/s13058-023-01672-x","DOIUrl":"https://doi.org/10.1186/s13058-023-01672-x","url":null,"abstract":"<p><strong>Background: </strong>Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated.</p><p><strong>Methods: </strong>The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients.</p><p><strong>Results: </strong>CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration.</p><p><strong>Conclusions: </strong>These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10351125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9853506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of air pollution with postmenopausal breast cancer risk in UK Biobank.","authors":"Carmen Smotherman, Brian Sprague, Susmita Datta, Dejana Braithwaite, Huaizhen Qin, Lusine Yaghjyan","doi":"10.1186/s13058-023-01681-w","DOIUrl":"10.1186/s13058-023-01681-w","url":null,"abstract":"<p><strong>Background: </strong>We investigated the association of several air pollution measures with postmenopausal breast cancer (BCa) risk.</p><p><strong>Methods: </strong>This study included 155,235 postmenopausal women (of which 6146 with BCa) from UK Biobank. Cancer diagnoses were ascertained through the linkage to the UK National Health Service Central Registers. Annual exposure averages were available from 2005, 2006, 2007, and 2010 for NO₂, from 2007 and 2010 for PM₁₀, and from 2010 for PM_2.5, NO_X, PM_2.5-10 and PM_2.5 absorbance. Information on BCa risk factors was collected at baseline. Cox proportional hazards regression was used to evaluate the associations of year-specific and cumulative average exposures with BCa risk, overall and with 2-year exposure lag, while adjusting for BCa risk factors.</p><p><strong>Results: </strong>PM₁₀ in 2007 and cumulative average PM₁₀ were positively associated with BCa risk (2007 PM₁₀: Hazard ratio [HR] per 10 µg/m³ = 1.18, 95% CI 1.08, 1.29; cumulative average PM₁₀: HR per 10 µg/m³ = 1.99, 95% CI 1.75, 2.27). Compared to women with low exposure, women with higher 2007 PM₁₀ and cumulative average PM₁₀ had greater BCa risk (4th vs. 1st quartile HR = 1.15, 95% CI 1.07, 1.24, p-trend = 0.001 and HR = 1.35, 95% CI 1.25, 1.44, p-trend < 0.0001, respectively). No significant associations were found for any other exposure measures. In the analysis with 2-year exposure lag, both 2007 PM 10 and cumulative average PM10 were positively associated with BCa risk (4th vs. 1st quartile HR = 1.19, 95% CI 1.10, 1.28 and HR = 1.29, 95% CI 1.19, 1.39, respectively).</p><p><strong>Conclusion: </strong>Our findings suggest a positive association of 2007 PM₁₀ and cumulative average PM₁₀ with postmenopausal BCa risk.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10175429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring breast tissue microbial composition and the association with breast cancer risk factors.","authors":"Rana German,&nbsp;Natascia Marino,&nbsp;Chris Hemmerich,&nbsp;Ram Podicheti,&nbsp;Douglas B Rusch,&nbsp;Leah T Stiemsma,&nbsp;Hongyu Gao,&nbsp;Xiaoling Xuei,&nbsp;Pam Rockey,&nbsp;Anna Maria Storniolo","doi":"10.1186/s13058-023-01677-6","DOIUrl":"https://doi.org/10.1186/s13058-023-01677-6","url":null,"abstract":"<p><strong>Background: </strong>Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals, even relative to risk of developing breast cancer, remains unclear. Here, we performed a comprehensive analysis of the microbiota of the normal breast tissue, which was analyzed in relation to the microbial composition of the tumor and adjacent normal tissue.</p><p><strong>Methods: </strong>The study cohorts included 403 cancer-free women (who donated normal breast tissue cores) and 76 breast cancer patients (who donated tumor and/or adjacent normal tissue samples). Microbiome profiling was obtained by sequencing the nine hypervariable regions of the 16S rRNA gene (V1V2, V2V3, V3V4, V4V5, V5V7, and V7V9). Transcriptome analysis was also performed on 190 normal breast tissue samples. Breast cancer risk score was assessed using the Tyrer-Cuzick risk model.</p><p><strong>Results: </strong>The V1V2 amplicon sequencing resulted more suitable for the analysis of the normal breast microbiome and identified Lactobacillaceae (Firmicutes phylum), Acetobacterraceae, and Xanthomonadaceae (both Proteobacteria phylum) as the most abundant families in the normal breast. However, Ralstonia (Proteobacteria phylum) was more abundant in both breast tumors and histologically normal tissues adjacent to malignant tumors. We also conducted a correlation analysis between the microbiome and known breast cancer risk factors. Abundances of the bacterial taxa Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp. were associated with age (p < 0.0001), racial background (p < 0.0001), and parity (p < 0.0001). Finally, transcriptome analysis of normal breast tissues showed an enrichment in metabolism- and immune-related genes in the tissues with abundant Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp., whereas the presence of Ralstonia in the normal tissue was linked to dysregulation of genes involved in the carbohydrate metabolic pathway.</p><p><strong>Conclusions: </strong>This study defines the microbial features of normal breast tissue, thus providing a basis to understand cancer-related dysbiosis. Moreover, the findings reveal that lifestyle factors can significantly affect the normal breast microbial composition.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10332106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10212502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor.","authors":"Jian Zhang, Nicholas P McAndrew, Xiaojia Wang, Yiqun Du, Brian DiCarlo, Mei Wang, Kan Chen, Wenlei Yu, Xichun Hu","doi":"10.1186/s13058-023-01679-4","DOIUrl":"10.1186/s13058-023-01679-4","url":null,"abstract":"<p><strong>Background: </strong>Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable.</p><p><strong>Methods: </strong>The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.</p><p><strong>Results: </strong>DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean K_p,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.</p><p><strong>Conclusions: </strong>DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.</p><p><strong>Clinicaltrials: </strong>gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9806793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-progressive breast carcinomas detected at mammography screening: a population study.","authors":"Torunn Heggland,&nbsp;Lars Johan Vatten,&nbsp;Signe Opdahl,&nbsp;Harald Weedon-Fekjær","doi":"10.1186/s13058-023-01682-9","DOIUrl":"10.1186/s13058-023-01682-9","url":null,"abstract":"<p><strong>Background: </strong>Some breast carcinomas detected at screening, especially ductal carcinoma in situ, may have limited potential for progression to symptomatic disease. To determine non-progression is a challenge, but if all screening-detected breast tumors eventually reach a clinical stage, the cumulative incidence at a reasonably high age would be similar for women with or without screening, conditional on the women being alive.</p><p><strong>Methods: </strong>Using high-quality population data with 24 years of follow-up from the gradually introduced BreastScreen Norway program, we studied whether all breast carcinomas detected at mammography screening 50-69 years of age would progress to clinical symptoms within 85 years of age. First, we estimated the incidence rates of breast carcinomas by age in scenarios with or without screening, based on an extended age-period-cohort incidence model. Next, we estimated the frequency of non-progressive tumors among screening-detected cases, by calculating the difference in the cumulative rate of breast carcinomas between the screening and non-screening scenarios at 85 years of age.</p><p><strong>Results: </strong>Among women who attended BreastScreen Norway from the age of 50 to 69 years, we estimated that 1.1% of the participants were diagnosed with a breast carcinoma without the potential to progress to symptomatic disease by 85 years of age. This proportion of potentially non-progressive tumors corresponded to 15.7% [95% CI 3.3, 27.1] of breast carcinomas detected at screening.</p><p><strong>Conclusions: </strong>Our findings suggest that nearly one in six breast carcinomas detected at screening may be non-progressive.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9890589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}