Breast Cancer Research : BCR最新文献

{"title":"Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).","authors":"Judith M Bliss, Holly Tovey, Abigail Evans, Chris Holcombe, Kieran Horgan, Elizabeth Mallon, Raghavan Vidya, Anthony Skene, Andrew Dodson, Margaret Hills, Simone Detre, Lila Zabaglo, Jane Banerji, Lucy Kilburn, James P Morden, John F R Robertson, Ian Smith, Mitch Dowsett","doi":"10.1186/s13058-023-01626-3","DOIUrl":"10.1186/s13058-023-01626-3","url":null,"abstract":"<p><strong>Purpose: </strong>Ki67 assessed at diagnosis (Ki67_baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67_2week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67_2week) with recurrence-free survival. The aim was to define the association between Ki67_baseline and after aromatase inhibitor (AI) exposure ∆Ki67_2week and Ki67_2week with key prognostic and biologic factors utilising data from the POETIC study.</p><p><strong>Patients and methods: </strong>In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression.</p><p><strong>Results: </strong>Established associations of Ki67_baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67_baseline. In control group Ki67_2week was 18% lower than Ki67_baseline (p < 0.001) when Ki67_2week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki67_2week) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type.</p><p><strong>Conclusions: </strong>The magnitude of this study allowed characterisation of relationships between Ki67_baseline, ∆Ki67_2week and Ki67_2week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki67_2week or Ki67_2week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9374036","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":"PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-β1 overcomes radiotherapy resistance in breast cancer.","authors":"Fayun Zhang,&nbsp;Zifeng Zheng,&nbsp;Luoyang Wang,&nbsp;Wenfeng Zeng,&nbsp;Wenjing Wei,&nbsp;Chunling Zhang,&nbsp;Ziran Zhao,&nbsp;Wei Liang","doi":"10.1186/s13058-023-01641-4","DOIUrl":"https://doi.org/10.1186/s13058-023-01641-4","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1_EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1_EV will pave a way for overcoming the radiotherapy resistance in cancer treatment.</p><p><strong>Methods: </strong>The superoxide-Zinc-PKC-ζ-TGF-β1_EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups.</p><p><strong>Results: </strong>The radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1_EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1_EV pathway.</p><p><strong>Conclusions: </strong>The superoxide-zinc-PKC-ζ-TGF-β1_EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1_EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers.</p><p><strong>Trial registration: </strong>The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10082517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722096","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":"Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer.","authors":"Slavica Janeva,&nbsp;Ellen Krabbe,&nbsp;Toshima Z Parris,&nbsp;Salmir Nasic,&nbsp;Marie Sundquist,&nbsp;Per Karlsson,&nbsp;Riccardo A Audisio,&nbsp;Roger Olofsson Bagge,&nbsp;Anikó Kovács","doi":"10.1186/s13058-023-01632-5","DOIUrl":"https://doi.org/10.1186/s13058-023-01632-5","url":null,"abstract":"<p><strong>Background: </strong>When ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC.</p><p><strong>Methods: </strong>Patients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with ≥ 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci.</p><p><strong>Results: </strong>Discordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6).</p><p><strong>Conclusion: </strong>Taken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10218058","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":"Cooperative NF-κB and Notch1 signaling promotes macrophage-mediated MenaINV expression in breast cancer.","authors":"Camille L Duran, George S Karagiannis, Xiaoming Chen, Ved P Sharma, David Entenberg, John S Condeelis, Maja H Oktay","doi":"10.1186/s13058-023-01628-1","DOIUrl":"10.1186/s13058-023-01628-1","url":null,"abstract":"<p><p>Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and frequently to patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin regulatory protein Mena, encoded by the ENAH gene, that endows tumor cells with transendothelial migration activity, allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. In this study, we discovered the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer, we further determined that for maximal induction of MenaINV in cancer cells, NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but it enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling activation and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10080980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9367645","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":"Lifetime changes in body fatness and breast density in postmenopausal women: the FEDRA study.","authors":"Giovanna Masala,&nbsp;Benedetta Bendinelli,&nbsp;Saverio Caini,&nbsp;Giacomo Duroni,&nbsp;Ilaria Ermini,&nbsp;Elisa Pastore,&nbsp;Miriam Fontana,&nbsp;Luigi Facchini,&nbsp;Andrea Querci,&nbsp;Maria Antonietta Gilio,&nbsp;Vincenzo Mazzalupo,&nbsp;Melania Assedi,&nbsp;Daniela Ambrogetti,&nbsp;Domenico Palli","doi":"10.1186/s13058-023-01624-5","DOIUrl":"https://doi.org/10.1186/s13058-023-01624-5","url":null,"abstract":"<p><strong>Background: </strong>High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). Body fatness conveys an increased BC risk in postmenopause but is associated with less dense breasts. Here, we studied the relationship between body fatness and breast composition within the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) longitudinal study.</p><p><strong>Methods: </strong>Repeated anthropometric data and MBD parameters (obtained through an automated software on BC screening digital mammograms) were available for all participants, as well as information on other BC risk factors. Multivariate linear regression and functional data analysis were used to longitudinally evaluate the association of body fatness, and changes thereof over time, with dense (DV) and non-dense (NDV) breast volumes and volumetric percent density (VPD).</p><p><strong>Results: </strong>A total of 5,262 women were included, with anthropometric data available at 20 and 40 years of age, at EPIC baseline (mean 49.0 years), and an average of 9.4 years thereafter. The mean number of mammograms per woman was 3.3 (SD 1.6). Body fatness (and increases thereof) at any age was positively associated with DV and NDV (the association being consistently stronger for the latter), and inversely associated with VPD. For instance, an increase by 1 kg/year between the age of 40 years and EPIC baseline was significantly associated with 1.97% higher DV, 8.85% higher NDV, and 5.82% lower VPD.</p><p><strong>Conclusion: </strong>Body fatness and its increase from young adulthood until midlife are inversely associated with volumetric percent density, but positively associated with dense and non-dense breast volumes in postmenopausal women.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9360767","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":"Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low.","authors":"Xi E Hu,&nbsp;Ping Yang,&nbsp;Songhao Chen,&nbsp;Gang Wei,&nbsp;Lijuan Yuan,&nbsp;Zhenyu Yang,&nbsp;Li Gong,&nbsp;Li He,&nbsp;Lin Yang,&nbsp;Shujia Peng,&nbsp;Yanming Dong,&nbsp;Xianli He,&nbsp;Guoqiang Bao","doi":"10.1186/s13058-023-01639-y","DOIUrl":"https://doi.org/10.1186/s13058-023-01639-y","url":null,"abstract":"<p><strong>Background: </strong>HER2-low could be found in some patients with triple-negative breast cancer (TNBC). However, its potential impacts on clinical features and tumor biological characteristics in TNBC remain unclear.</p><p><strong>Methods: </strong>We enrolled 251 consecutive TNBC patients retrospectively, including 157 HER2-low (HER2_low) and 94 HER2-negtive (HER2_neg) patients to investigate the clinical and prognostic features. Then, we performed single-cell RNA sequencing (scRNA-seq) with another seven TNBC samples (HER2_neg vs. HER2_low, 4 vs. 3) prospectively to further explore the differences of tumor biological properties between the two TNBC phenotypes. The underlying molecular distinctions were also explored and then verified in the additional TNBC samples.</p><p><strong>Results: </strong>Compared with HER2_neg TNBC, HER2_low TNBC patients exhibited malignant clinical features with larger tumor size (P = 0.04), more lymph nodes involvement (P = 0.02), higher histological grade of lesions (P < 0.001), higher Ki67 status (P < 0.01), and a worse prognosis (P < 0.001; HR [CI 95%] = 3.44 [2.10-5.62]). Cox proportional hazards analysis showed that neoadjuvant systemic therapy, lymph nodes involvement and Ki67 levels were prognostic factors in HER2_low TNBC but not in HER2_neg TNBC patients. ScRNA-seq revealed that HER2_low TNBC which showed more metabolically active and aggressive hallmarks, while HER2_neg TNBC exhibited signatures more involved in immune activities with higher expressions of immunoglobulin-related genes (IGHG1, IGHG4, IGKC, IGLC2); this was further confirmed by immunofluorescence in clinical TNBC samples. Furthermore, HER2_low and HER2_neg TNBC exhibited distinct tumor evolutionary characteristics. Moreover, HER2_neg TNBC revealed a potentially more active immune microenvironment than HER2_low TNBC, as evidenced by positively active regulation of macrophage polarization, abundant CD8⁺ effector T cells, enriched diversity of T-cell receptors and higher levels of immunotherapy-targeted markers, which contributed to achieve immunotherapeutic response.</p><p><strong>Conclusions: </strong>This study suggests that HER2_low TNBC patients harbor more malignant clinical behavior and aggressive tumor biological properties than the HER2_neg phenotype. The heterogeneity of HER2 may be a non-negligible factor in the clinical management of TNBC patients. Our data provide new insights into the development of a more refined classification and tailored therapeutic strategies for TNBC patients.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9252515","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":"Associations of alcohol consumption with breast tissue composition.","authors":"Lusine Yaghjyan,&nbsp;Yujing J Heng,&nbsp;Gabrielle M Baker,&nbsp;Bernard A Rosner,&nbsp;Rulla M Tamimi","doi":"10.1186/s13058-023-01638-z","DOIUrl":"https://doi.org/10.1186/s13058-023-01638-z","url":null,"abstract":"<p><strong>Background: </strong>We investigated the associations of alcohol with percentage of epithelium, stroma, fibroglandular tissue (epithelium + stroma), and fat in benign breast biopsy samples.</p><p><strong>Methods: </strong>We included 857 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII cohorts. Percentage of each tissue was measured on whole slide images using a deep-learning algorithm and then log-transformed. Alcohol consumption (recent and cumulative average) was assessed with semi-quantitative food frequency questionnaires. Regression estimates were adjusted for known breast cancer risk factors. All tests were 2-sided.</p><p><strong>Results: </strong>Alcohol was inversely associated with % of stroma and fibroglandular tissue (recent ≥ 22 g/day vs. none: stroma: β = - 0.08, 95% Confidence Interval [CI] - 0.13; - 0.03; fibroglandular: β = - 0.08, 95% CI - 0.13; - 0.04; cumulative ≥ 22 g/day vs. none: stroma: β = - 0.08, 95% CI - 0.13; - 0.02; fibroglandular: β = - 0.09, 95% CI - 0.14; - 0.04) and positively associated with fat % (recent ≥ 22 g/day vs. none: β = 0.30, 95% CI 0.03; 0.57; cumulative ≥ 22 g/day vs. none: β = 0.32, 95% CI 0.04; 0.61). In stratified analysis, alcohol consumption was not associated with tissue measures in premenopausal women. In postmenopausal women, cumulative alcohol use was inversely associated with % of stroma and fibroglandular tissue and positively associated with fat % (≥ 22 g/day vs. none: stroma: β = - 0.16, 95% CI - 0.28; - 0.07; fibroglandular: β = - 0.18, 95% CI - 0.28; - 0.07; fat: β = 0.61, 95% CI 0.01; 1.22), with similar results for recent alcohol use.</p><p><strong>Conclusion: </strong>Our findings suggest that alcohol consumption is associated with smaller % of stroma and fibroglandular tissue and a greater % of fat in postmenopausal women. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9252519","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":"The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy.","authors":"Pauline Wimberger,&nbsp;Jens-Uwe Blohmer,&nbsp;Petra Krabisch,&nbsp;Theresa Link,&nbsp;Marianne Just,&nbsp;Bruno Valentin Sinn,&nbsp;Eike Simon,&nbsp;Christine Solbach,&nbsp;Tanja Fehm,&nbsp;Carsten Denkert,&nbsp;Cristin Kühn,&nbsp;Kerstin Rhiem,&nbsp;Hans Tesch,&nbsp;Sherko Kümmel,&nbsp;Andrea Petzold,&nbsp;Oliver Stötzer,&nbsp;Cornelia Meisel,&nbsp;Jan Dominik Kuhlmann,&nbsp;Valentina Nekljudova,&nbsp;Sibylle Loibl","doi":"10.1186/s13058-023-01619-2","DOIUrl":"https://doi.org/10.1186/s13058-023-01619-2","url":null,"abstract":"<p><strong>Background: </strong>Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient's pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow.</p><p><strong>Methods: </strong>A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab.</p><p><strong>Results: </strong>At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00).</p><p><strong>Conclusion: </strong>This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9259357","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":"Impact of breast cancer care pathways and related symptoms on the return-to-work process: results from a population-based French cohort study (CONSTANCES).","authors":"Anne-Lise Rolland,&nbsp;Bertrand Porro,&nbsp;Sofiane Kab,&nbsp;Céline Ribet,&nbsp;Yves Roquelaure,&nbsp;Mélanie Bertin","doi":"10.1186/s13058-023-01623-6","DOIUrl":"https://doi.org/10.1186/s13058-023-01623-6","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) treatments and related symptoms may affect return to work (RTW). The objective of this study was to investigate the impact of BC care pathways (timing and sequence of treatments) and related symptoms on RTW.</p><p><strong>Methods: </strong>The study population included working-age women with BC who were enrolled in the French CONSTANCES cohort from 2012 to 2018. BC treatments, antidepressant/anxiolytic and antalgic drug deliveries (used as proxies of depression and pain, respectively) and statutory sick pay (used to estimate RTW and time to RTW) were assessed monthly using data from the French national healthcare system database. BC care pathways were identified with the sequence analysis method. Cox models with time-dependent covariates were used to investigate the impact of BC care pathways and related symptoms on RTW and time to RTW, after adjusting for age and socioeconomic characteristics.</p><p><strong>Results: </strong>73.2% (231/303) of women returned to work within 2 years after BC diagnosis. Five BC care pathway patterns were identified: (i) BC surgery only, (ii) BC surgery and radiotherapy, (iii) BC surgery and chemotherapy, (iv) BC surgery and chemotherapy and radiotherapy, and (v) BC surgery and long-term alternative chemotherapy/radiotherapy. The hazards ratios of non-RTW were significantly higher for women who received BC surgery and long-term alternative chemotherapy/radiotherapy and for > 55-year-old women. Time to RTW was significantly longer in women who received chemotherapy (patterns iii to v) and in women with antidepressant/anxiolytic and antalgic drug deliveries.</p><p><strong>Conclusion: </strong>This study highlights the value of considering the dynamic, cumulative and temporal features of BC care pathways and related symptoms to facilitate the RTW of women with BC.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10031867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9628098","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":"The WAVE3/β-catenin oncogenic signaling regulates chemoresistance in triple negative breast cancer.","authors":"Wei Wang, Priyanka S Rana, Vesna Markovic, Khalid Sossey-Alaoui","doi":"10.1186/s13058-023-01634-3","DOIUrl":"10.1186/s13058-023-01634-3","url":null,"abstract":"<p><strong>Background: </strong>Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization.</p><p><strong>Methods: </strong>The Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors.</p><p><strong>Results: </strong>Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo.</p><p><strong>Conclusion: </strong>We identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.</p>","PeriodicalId":9283,"journal":{"name":"Breast Cancer Research : BCR","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9613715","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}