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Disease recurrence in patients undergoing mastectomy for ductal carcinoma in situ. 乳腺导管原位癌切除术患者的疾病复发。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 DOI: 10.1007/s10549-024-07530-4
Marissa C Kuo, Jessica Sims, Odette K Solis, Ingrid M Meszoely, Raeshell S Sweeting, Ana M Grau, Kelly C Hewitt, Rondi M Kauffmann, Mark C Kelley, Rachel L McCaffrey

Purpose: With DCIS incidence on the rise, up to 30% of patients undergo mastectomy for Ductal carcinoma in situ (DCIS) (Nash and Hwang, in: Ann Surg Oncol 30(6):3206-3214, 2023). Local recurrence rates after mastectomy for DCIS are reportedly low, but risk factors for recurrence are not known (Kim et al., in: J Cancer Res Ther 16(6):1197-1202, 2020). We aim to define risk factors associated with ipsilateral breast cancer recurrence in patients undergoing mastectomy for DCIS.

Methods: We aimed to identify risk factors that may contribute to recurrence of breast cancer following mastectomy for pure DCIS. We hypothesized that close or positive mastectomy margins, age at diagnosis, extent of breast disease and mutation carriers would be associated with increased risk of recurrence. We performed a retrospective chart review of patients who underwent unilateral or bilateral mastectomies for pure DCIS at a single academic tertiary referral center from 2013 to 2023.

Results: There were 165 patients who met inclusion criteria with an average length of follow-up of 39.9 months. On final surgical pathology, the average span of DCIS was 33.7 mm (± 24.6 mm). Hormone receptor positive disease was identified in 80.6% of the patient cohort. For margin status, 23 patients (14%) had < 1 mm margins on final pathology and of those, 1 received adjuvant radiation therapy and 4 returned to the OR for re-excision. Only 1 (0.6%) patient had ipsilateral disease recurrence during the study period.

Conclusion: Recurrence after mastectomy for pure DCIS is a rare event and in our study sample, only one recurrence occurred. Risk factors for recurrence appear unrelated to margin status, age, extent of DCIS, or pathogenic mutation (ElSherif et al., in Am J Surg 226(5):646-651, 2023).

目的:随着 DCIS 发病率的上升,多达 30% 的患者因乳腺导管原位癌 (DCIS) 而接受乳房切除术(Nash 和 Hwang,见《Ann Surg Oncol》30(6):3206-3214, 2023):Ann Surg Oncol 30(6):3206-3214, 2023)。据报道,DCIS 乳房切除术后的局部复发率很低,但复发的风险因素尚不清楚(Kim 等人,载于:J Cancer Res Reser Ther 16(6):3206-3214,2023):J Cancer Res Ther 16(6):1197-1202, 2020)。我们旨在确定因 DCIS 而接受乳房切除术的患者同侧乳腺癌复发的相关风险因素:我们旨在确定可能导致纯DCIS乳房切除术后乳腺癌复发的风险因素。我们假设,乳房切除边缘接近或呈阳性、确诊时的年龄、乳腺疾病的范围以及基因突变携带者与复发风险增加有关。我们对2013年至2023年在一家学术三级转诊中心接受单侧或双侧乳房切除术治疗纯DCIS的患者进行了回顾性病历审查:共有165名患者符合纳入标准,平均随访时间为39.9个月。最终手术病理结果显示,DCIS的平均跨度为33.7毫米(± 24.6毫米)。80.6%的患者确定为激素受体阳性。就边缘状态而言,23 名患者(14%)有结论:纯DCIS乳房切除术后复发是一种罕见情况,在我们的研究样本中,仅有一人复发。复发的风险因素似乎与边缘状态、年龄、DCIS 范围或致病基因突变无关(ElSherif 等人,载于 Am J Surg 226(5):646-651, 2023)。
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引用次数: 0
Influence of tumour grade on disease survival in male breast cancer patients: a systematic review. 肿瘤分级对男性乳腺癌患者生存期的影响:系统综述。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-02 DOI: 10.1007/s10549-024-07446-z
Stephen Kinsey-Trotman, Alain Nguyen, Suzanne Edwards, Adam Swalling, Pallave Dasari, David Walsh, Wendy V Ingman

Purpose: Histological grading of tumours is a well-established biomarker used to guide treatment in female breast cancer. However, its significance in male breast cancer remains unclear. This systematic review investigates the prognostic significance of tumour grade in relation to breast cancer-specific survival (BCSS) in male breast cancer patients undergoing surgery.

Methods: MEDLINE, PUBMED Central and EMBASE databases were searched to identify randomised trials and observational studies related to male breast neoplasms, tumour grading, recurrence, and survival.

Results: A total of fifteen observational type studies were included in the review. A significant association between tumour grade and BCSS was reported in a majority of studies. This association was most evident with regard to high-grade (grade III) compared to low grade (grade I) tumours, with a significant relationship in 4 out of 4 studies. For intermediate-grade II tumours an association was demonstrated in a minority of studies.

Conclusions: This study confirms an association between high-grade male breast cancers and poorer disease-specific survival, however, the significance of intermediate-grade tumours remains unclear. Further research is required to investigate the biology of male breast cancer in relation to histological grade and optimally define intermediate-grade disease.

目的:肿瘤的组织学分级是用于指导女性乳腺癌治疗的成熟生物标志物。然而,它在男性乳腺癌中的意义仍不明确。本系统综述研究了肿瘤分级对接受手术的男性乳腺癌患者乳腺癌特异性生存率(BCSS)的预后意义:检索了MEDLINE、PUBMED Central和EMBASE数据库,以确定与男性乳腺肿瘤、肿瘤分级、复发和生存相关的随机试验和观察性研究:结果:共有 15 项观察性研究被纳入综述。大多数研究都报告了肿瘤分级与 BCSS 之间的重要关联。与低分级(I级)肿瘤相比,高分级(III级)肿瘤的这种关联最为明显,4项研究中有4项存在显著关联。结论:这项研究证实了高级别(III 级)肿瘤与低级别(I 级)肿瘤之间的关系:这项研究证实,高级别男性乳腺癌与较差的疾病特异性生存率之间存在关联,但中级肿瘤的重要性仍不清楚。需要进一步研究男性乳腺癌与组织学分级相关的生物学特性,并对中级肿瘤进行最佳定义。
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引用次数: 0
Baseline sLAG-3 levels in Caucasian and African-American breast cancer patients. 高加索人和非洲裔美国人乳腺癌患者的基线 sLAG-3 水平。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-09-04 DOI: 10.1007/s10549-024-07455-y
Helen Swede, Sharif M Ridwan, Jillian Strandberg, Andrew L Salner, Jonathan R Sporn, Lynn Kuo, Karen Ru, Henry M Smilowitz

Background: Worse survival persists for African-Americans (AA) with breast cancer compared to other race/ethnic groups despite recent improvements for all. Unstudied in outcomes disparities to date is soluble LAG-3 (sLAG-3), cleaved from the LAG-3 immune checkpoint receptor which is a proposed target for deactivation in emerging immunotherapies due to its prominent immunosuppressive function in the tumoral microenvironment. A prior study has found that lower sLAG-3 baseline level was associated with poor outcomes.

Methods: In a cross-sectional study of 95 patients with primary breast cancer (n = 58 Caucasian, n = 37 AA), we measured sLAG-3 (ELISA pg/ml) in pre-treatment blood samples using the non-parametric Mann-Whitney u-Test for independent samples, and, calculated Pearson r correlation coefficients of sLAG-3 with circulating cytokines by race.

Results: Mean sLAG-3 level was lower in AA compared to Caucasian patients (1377.6 vs 3690.3, P = .002), and in patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC malignancies (P = .02). When patients with TNBC tumors were excluded from analyses, the difference in sLAG-3 level between AA (n = 21) and Caucasian patients (n = 40) substantially remained (1937.4 vs 4182.4, P = .06). Among Caucasian patients, sLAG-3 was correlated with IL-6, IL-8 and IL-10 (r = .69, P < .001; r = .70, P < .001; and, r = .46, P = .01; respectively). For AA patients, sLAG-3 was correlated only with IL-6 (r = .37, P = .03).

Conclusions: We present the first report that African-American breast cancer patients might have comparatively low pre-treatment sLAG-3 levels, independent of TNBC status, along with reduced co-expression with circulating cytokines. The mechanistic and prognostic role of cleaved LAG-3, particularly in disparate outcomes, remains to be elucidated.

背景:与其他种族/族裔群体相比,非裔美国人(AA)乳腺癌患者的生存率一直较低,尽管最近所有种族/族裔群体的生存率都有所提高。可溶性 LAG-3(sLAG-3)是由 LAG-3 免疫检查点受体裂解而成,由于其在肿瘤微环境中具有显著的免疫抑制功能,因此被认为是新兴免疫疗法中的失活靶点。之前的一项研究发现,较低的sLAG-3基线水平与较差的预后有关:在一项针对 95 名原发性乳腺癌患者(n = 58 名白种人,n = 37 名 AA 人)的横断面研究中,我们使用非参数 Mann-Whitney u 检验法测量了治疗前血液样本中的 sLAG-3(ELISA pg/ml),并按种族计算了 sLAG-3 与循环细胞因子的 Pearson r 相关系数:结果:与白种人相比,AA 患者的平均 sLAG-3 水平较低(1377.6 vs 3690.3,P = .002);与非 TNBC 恶性肿瘤患者相比,三阴性乳腺癌(TNBC)患者的平均 sLAG-3 水平较低(P = .02)。如果将 TNBC 肿瘤患者排除在分析之外,AA 患者(21 人)和白种人患者(40 人)之间的 sLAG-3 水平差异仍然很大(1937.4 vs 4182.4,P = .06)。在白种人患者中,sLAG-3 与 IL-6、IL-8 和 IL-10 存在相关性(r = .69,P 结论:sLAG-3 与 IL-6、IL-8 和 IL-10 存在相关性:我们首次报告了非裔美国人乳腺癌患者治疗前的 sLAG-3 水平可能相对较低,与 TNBC 状态无关,同时与循环细胞因子的共表达也较低。裂解 LAG-3 的机理和预后作用,尤其是在不同结果中的作用,仍有待阐明。
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引用次数: 0
Enhanced cancer cell proliferation and aggressive phenotype counterbalance in breast cancer with high BRCA1 gene expression. 在 BRCA1 基因高表达的乳腺癌中,癌细胞增殖和侵袭性表型相互抵消。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-07 DOI: 10.1007/s10549-024-07421-8
Kohei Chida, Masanori Oshi, Arya Mariam Roy, Takumi Sato, Maya Penelope Takabe, Li Yan, Itaru Endo, Kenichi Hakamada, Kazuaki Takabe

Purpose: While comprehensive research exists on the mutation of the DNA repair gene BRCA1, limited information is available regarding the clinical significance of BRCA1 gene expression. Given that cancer cell proliferation is aggrevated by DNA repair, we hypothesized that high BRCA1 gene expression breast cancer (BC) might be linked with aggressive tumor biology and poor clinical outcomes.

Methods: The cohorts: The Cancer Genome Atlas (TCGA, n = 1069), METABRIC (n = 1903), and SCAN-B (n = 3273) were utilzed to obtain data of 6245 BC patients.

Results: BC patients without BRCA1 mutation exhibited higher BRCA1 expression, which was associated with DNA repair functionality. However, no such correlation was observed with BRCA2 expression. The association of high BRCA1 expression with cancer cell proliferation was evidenced by significant enrichment of cell proliferation-related gene sets, higher histological grade, and proliferation score. Furthermore, increased levels of homologous recombination deficiency, intratumoral heterogeneity, and altered fractions were associated with high BRCA1 expression. Moreover, BC with high BRCA1 expression exhibited reduced infiltration of dendritic cells and CD8 T-cells, while showing increased infiltration of Th1 cells. Surprisingly, BRCA1 expression was not associated with the survival of BC irrespective of the subtypes. Conversely, BC with low BRCA1 expression enriched cancer aggravating pathway gene sets, such as Cancer Stem Cell-related signaling (NOTCH and HEDGEHOG), Angiogenesis, Epithelial-Mesenchymal Transition, Inflammatory Response, and TGF-beta signaling.

Conclusion: Despite being linked to heightened proliferation of cancer cells and unassertive phenotype, BRCA1 expression did not show any association with survival in BC.

目的:虽然对 DNA 修复基因 BRCA1 基因突变的研究很全面,但有关 BRCA1 基因表达的临床意义的信息却很有限。鉴于癌细胞增殖受 DNA 修复的影响,我们假设 BRCA1 基因高表达的乳腺癌(BC)可能与侵袭性肿瘤生物学和不良临床结局有关:队列:我们利用癌症基因组图谱(TCGA,n = 1069)、METABRIC(n = 1903)和 SCAN-B(n = 3273)获得了 6245 例 BC 患者的数据:结果:没有 BRCA1 基因突变的 BC 患者 BRCA1 表达较高,这与 DNA 修复功能有关。然而,BRCA2 的表达却没有这种相关性。BRCA1高表达与癌细胞增殖的关系表现在细胞增殖相关基因组的显著富集、较高的组织学分级和增殖评分。此外,同源重组缺陷、瘤内异质性和分化改变水平的增加也与 BRCA1 高表达有关。此外,BRCA1高表达的BC表现出树突状细胞和CD8 T细胞浸润减少,而Th1细胞浸润增加。令人惊讶的是,无论哪种亚型,BRCA1的表达与BC的存活率无关。相反,BRCA1表达量低的BC富集了癌症恶化通路基因集,如癌症干细胞相关信号转导(NOTCH和HEDGEHOG)、血管生成、上皮-间质转化、炎症反应和TGF-beta信号转导:结论:尽管BRCA1的表达与癌细胞的增殖和非侵袭性表型有关,但它与BC患者的存活率并无关联。
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引用次数: 0
CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer. 在ER阳性/HER2阴性乳腺癌中,CD133的表达与较少的DNA修复、较好的化疗反应和生存率有关。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-17 DOI: 10.1007/s10549-024-07434-3
Takumi Sato, Masanori Oshi, Jing Li Huang, Kohei Chida, Arya Mariam Roy, Itaru Endo, Kazuaki Takabe

Purpose: CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown.

Methods: The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data.

Results: Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts.

Conclusion: CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.

目的:据报道,CD133是癌症干细胞(CSC)标记物,它与三阴性乳腺癌(BC)的耐药性和生存率降低有关。然而,CD133在ER阳性/HER2-阴性(ER + /HER2-)乳腺癌(最常见的亚型)中的表达与临床的相关性仍然未知:方法:利用国际乳腺癌分子分类联盟(METABRIC,n = 1904)和癌症基因组图谱(TCGA,n = 1065)的BC队列获取生物变量和基因表达数据:结果:上皮细胞是大量 BC 中 CD133 基因表达的唯一来源。CD133 高 ER + /HER2- BC 与 CD24、NOTCH1、DLL1 和 ALDH1A1 基因表达以及 WNT/β-Catenin、Hedgehog 和 Notch 信号通路相关,这些都是 CSC 的特征。与 CSC 表型一致的是,CD133 低的 BC 富集了与细胞增殖相关的基因集,如 G2M 检查点、MYC 靶点 V1、E2F 靶点和 Ki67 基因表达。CD133 低水平 BC 还与 DNA 修复相关基因的富集有关,如 BRCA1、E2F1、E2F4、CDK1/2。另一方面,CD133高的肿瘤具有促炎症微环境,免疫细胞活性更高,与炎症和免疫反应相关的基因表达也更高。最后,在GSE25066队列中,CD133高的肿瘤在新辅助化疗后有更好的病理完全反应,在TCGA和METABRIC队列中,CD133高的肿瘤有更好的无病生存期和总生存期:CD133高的ER + /HER2- BC与CSC表型有关,如细胞增殖和DNA修复能力较弱,同时也与炎症反应增强、对新辅助化疗反应较好和预后较好有关。
{"title":"CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer.","authors":"Takumi Sato, Masanori Oshi, Jing Li Huang, Kohei Chida, Arya Mariam Roy, Itaru Endo, Kazuaki Takabe","doi":"10.1007/s10549-024-07434-3","DOIUrl":"10.1007/s10549-024-07434-3","url":null,"abstract":"<p><strong>Purpose: </strong>CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown.</p><p><strong>Methods: </strong>The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data.</p><p><strong>Results: </strong>Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts.</p><p><strong>Conclusion: </strong>CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141625961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer. 激素受体(HR)阳性、HER2阳性早期乳腺癌患者使用和耐受奈拉替尼辅助治疗的模式。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-17 DOI: 10.1007/s10549-024-07461-0
Julia Blanter, Elena Baldwin, Rima Patel, Tianxiang Sheng, Amy Tiersten

Purpose: One year of neratinib therapy is known to derive a significant invasive disease-free survival (iDFS) benefit in early-stage, hormone receptor-positive (HR +), HER2 + , node-positive breast cancer after trastuzumab-based adjuvant therapy. Limitations to neratinib use include significant gastrointestinal side effects, which often result in treatment discontinuation. In this study, we aimed to identify clinicopathologic features associated with adjuvant neratinib use and factors impacting treatment completion.

Methods: We performed a retrospective review of patients with early-stage HR + HER2 + breast cancer who were prescribed neratinib from 2017 to 2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical features, and treatment information. Patients were identified as high risk based on definitions adapted from the standard high-risk definition in HR + HER2- breast cancer combined with studies correlating high Ki67 or high tumor grade with lower recurrence-free survival. Statistical analysis was performed using two-sided T-tests and chi-square tests.

Results: We identified 62 eligible patients of whom 55% completed 1 year of neratinib and 45% did not. Sixty percent (N = 37) of patients offered neratinib were considered high risk at diagnosis. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by patients was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Patients who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 vs. 240 mg in those who did not (p = 0.016). Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 patients had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 patients developed metastatic disease and 57% (N = 4) had central nervous system metastases.

Conclusion: Patients are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven patients (11%) in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment.

目的:众所周知,对于激素受体阳性(HR +)、HER2 +、结节阳性的早期乳腺癌患者,在接受曲妥珠单抗辅助治疗后,接受一年的奈拉替尼治疗可获得显著的侵袭性无病生存期(iDFS)获益。使用奈拉替尼的局限性包括明显的胃肠道副作用,这通常会导致治疗中断。在这项研究中,我们旨在确定与使用奈拉替尼辅助治疗相关的临床病理特征以及影响治疗完成的因素:我们对本机构2017年至2023年期间处方奈拉替尼的早期HR + HER2 +乳腺癌患者进行了回顾性研究。我们使用电子病历提取了患者特征、临床特征和治疗信息。根据改编自HR + HER2-乳腺癌标准高风险定义的定义,结合高Ki67或高肿瘤分级与较低无复发生存率相关的研究,将患者确定为高风险患者。统计分析采用双侧 T 检验和卡方检验:我们确定了 62 名符合条件的患者,其中 55% 的患者完成了 1 年的奈拉替尼治疗,45% 的患者未完成治疗。在接受奈拉替尼治疗的患者中,60%(N = 37)在确诊时被认为是高危患者。停用奈拉替尼最常见的原因是无法忍受副作用(54%),其次是药片负担(18%)。患者最常见的副作用是在服用止泻药后仍出现腹泻(56%),其次是皮疹(8%)。与未接受纳拉替尼治疗的患者相比,接受纳拉替尼升级治疗的患者更有可能完成纳拉替尼的整个疗程(76% vs. 40.5% p = 0.013)。完成奈拉替尼治疗的患者起始剂量中位数为140毫克,而未完成治疗的患者起始剂量中位数为240毫克(p = 0.016)。两组患者均未出现统计学意义上的治疗中止或剂量减少。在治疗结果方面,10 名患者的病情出现进展,其中 7 人未完成奈拉替尼治疗(p = 0.169)。有趣的是,这7名患者出现了转移性疾病,其中57%(N = 4)出现了中枢神经系统转移:结论:通过剂量上调,患者更有可能完成1年的奈拉替尼辅助治疗。在我们的患者群体中,剂量减少和中断并不影响患者对奈拉替尼的依从性。在我们的研究中,有7名患者(11%)出现了转移性疾病,他们都没有完成奈拉替尼的辅助治疗。
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引用次数: 0
Contrast-enhanced mammography for surveillance in women with a personal history of breast cancer. 对有乳腺癌病史的妇女进行造影增强乳房 X 线照相术监测。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-07-04 DOI: 10.1007/s10549-024-07419-2
Julia Matheson, Kenneth Elder, Carolyn Nickson, Allan Park, Gregory Bruce Mann, Allison Rose

Purpose: Women with a personal history of breast cancer have an increased risk of subsequent breast malignancy and may benefit from more sensitive surveillance than conventional mammography (MG). We previously reported outcomes for first surveillance episode using contrast-enhanced mammography (CEM), demonstrating higher sensitivity and comparable specificity to MG. We now report CEM performance for subsequent surveillance.

Methods: A retrospective study of 1,190 women in an Australian hospital setting undergoing annual surveillance following initial surveillance CEM between June 2016 and December 2022. Outcome measures were recall rate, cancer detection rate, contribution of contrast to recalls, false positive rate, interval cancer rate and characteristics of surveillance detected and interval cancers.

Results: 2,592 incident surveillance episodes were analysed, of which 93% involved contrast-based imaging. Of 116 (4.5%) recall episodes, 40/116 (34%) recalls were malignant (27 invasive; 13 ductal carcinoma in situ), totalling 15.4 cancers per 1000 surveillance episodes. 55/116 (47%) recalls were contrast-directed including 17/40 (43%) true positive recalls. Tumour features were similar for contrast-directed recalls and other diagnoses. 8/9 (89%) of contrast-directed invasive recalls were Grade 2-3, and 5/9 (56%) were triple negative breast cancers. There were two symptomatic interval cancers (0.8 per 1000 surveillance episodes, program sensitivity 96%).

Conclusion: Routine use of CEM in surveillance of women with PHBC led to an increase in the detection of clinically significant malignant lesions, with a low interval cancer rate compared to previous published series. Compared to mammographic surveillance, contrast-enhanced mammography increases the sensitivity of surveillance programs for women with PHBC.

目的:有乳腺癌病史的女性罹患乳腺恶性肿瘤的风险会增加,因此可能会受益于比传统乳腺 X 射线照相术(MG)更灵敏的监测。我们曾报告过使用对比增强乳腺 X 光造影术(CEM)进行首次监测的结果,结果显示 CEM 的灵敏度更高,特异性与 MG 相当。现在我们报告 CEM 在后续监测中的表现:回顾性研究:2016 年 6 月至 2022 年 12 月期间,澳大利亚一家医院对 1190 名妇女进行了首次 CEM 监测后的年度监测。结果:分析了 2592 次事件监测,其中 93% 涉及造影剂成像。在 116 例(4.5%)召回病例中,40/116 例(34%)召回病例为恶性(27 例为浸润性;13 例为导管原位癌),每 1000 例监测病例中共有 15.4 例癌症。55/116(47%)次召回为造影剂导向召回,其中17/40(43%)次为真阳性召回。造影剂导向召回和其他诊断的肿瘤特征相似。8/9(89%)例造影剂引导的浸润性复查为 2-3 级,5/9(56%)例为三阴性乳腺癌。有两例无症状间期癌(每 1000 次监测中有 0.8 例,项目敏感性 96%):结论:在对患有 PHBC 的妇女进行监测时常规使用 CEM 可增加临床重大恶性病变的检出率,但与之前发表的系列研究相比,间期癌症的发生率较低。与乳腺X线照相监测相比,对比增强乳腺X线照相术提高了PHBC妇女监测项目的灵敏度。
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引用次数: 0
SGLT2 inhibition improves PI3Kα inhibitor-induced hyperglycemia: findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials. SGLT2 抑制可改善 PI3Kα 抑制剂诱发的高血糖:临床前动物模型以及 BYLieve 和 SOLAR-1 试验中患者的研究结果。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-23 DOI: 10.1007/s10549-024-07405-8
Manuel Ruiz Borrego, Yen-Shen Lu, Felipe Reyes-Cosmelli, Yeon Hee Park, Toshinari Yamashita, Joanne Chiu, Mario Airoldi, Nicholas Turner, Luis Fein, Farhat Ghaznawi, Jyotika Singh, Kristyn Pantoja, Christian Schnell, Murat Akdere, Stephen Chia

Purpose: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia.

Methods: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials.

Results: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%).

Conclusion: These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).

目的:在PIK3CA突变的HR+ /HER2-晚期乳腺癌(ABC)(SOLAR-1)患者中,阿培利西布联合氟维司群与氟维司群相比具有显著的无进展生存期获益。高血糖是PI3Kα抑制的靶向不良反应,可导致剂量调整,从而可能影响alpelisib的疗效。我们报告了临床前模型和两项临床试验(SOLAR-1 和 BYLieve)中关于使用葡萄糖钠共转运体 2 抑制剂(SGLT2i)改善 PI3Kα 抑制剂相关高血糖的数据。方法:用二甲双胍和达帕利曲嗪(SGLT2i)以及阿来替尼的疗效分析健康棕色挪威鼠(BN)、轻度糖尿病扎克糖尿病脂肪鼠(ZDF)和接受阿来替尼治疗的Rat1-myr-p110α/HBRX3077肿瘤裸鼠的血糖和胰岛素控制情况。在这两项试验中,比较了接受SGLT2i与阿来替尼治疗的患者(n = 19)与未接受SGLT2i治疗的倾向得分匹配队列(n = 74)之间的高血糖不良事件(AEs):结果:用达帕格列净和二甲双胍治疗BN和ZDF大鼠后,阿来替尼能使血糖恢复正常并降低胰岛素水平。二甲双胍和达帕格列净与阿来替尼同时使用时,未观察到酮症或药物相互作用的迹象。在肿瘤大鼠体内与达帕利洛嗪同时使用时,阿来替尼的抗肿瘤疗效得以保持。与未使用SGLT2i的匹配患者相比,接受SGLT2i治疗的患者发生≥3级高血糖AEs和导致阿来替尼剂量调整、中断或停药的高血糖AEs的比例分别降低了4.9倍和6.4倍,发生这些AEs的风险也相对降低了(70.6%和35.7%):这些数据表明,添加 SGLT2i 可以有效控制高血糖,从而减少 PIK3CA 突变 HR+ /HER2- ABC 患者阿来利昔剂量调整和停药的次数(SOLAR-1:NCT02437318;BYLieve:NCT03056755)。
{"title":"SGLT2 inhibition improves PI3Kα inhibitor-induced hyperglycemia: findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials.","authors":"Manuel Ruiz Borrego, Yen-Shen Lu, Felipe Reyes-Cosmelli, Yeon Hee Park, Toshinari Yamashita, Joanne Chiu, Mario Airoldi, Nicholas Turner, Luis Fein, Farhat Ghaznawi, Jyotika Singh, Kristyn Pantoja, Christian Schnell, Murat Akdere, Stephen Chia","doi":"10.1007/s10549-024-07405-8","DOIUrl":"10.1007/s10549-024-07405-8","url":null,"abstract":"<p><strong>Purpose: </strong>Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia.</p><p><strong>Methods: </strong>Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials.</p><p><strong>Results: </strong>Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%).</p><p><strong>Conclusion: </strong>These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system. 综合医疗服务系统中 I-IIIA 期乳腺癌 NCCN 指南化疗方案的使用情况。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-08-16 DOI: 10.1007/s10549-024-07433-4
Jenna Bhimani, Kelli O'Connell, Sonia Persaud, Victoria Blinder, Rachael P Burganowski, Isaac J Ergas, Grace B Gallagher, Jennifer J Griggs, Narre Heon, Tatjana Kolevska, Yuriy Kotsurovskyy, Candyce H Kroenke, Cecile A Laurent, Raymond Liu, Kanichi G Nakata, Donna R Rivera, Janise M Roh, Sara Tabatabai, Emily Valice, Elisa V Bandera, Erin J Aiello Bowles, Lawrence H Kushi, Elizabeth D Kantor

Purpose: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time.

Methods: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time.

Results: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination.

Conclusion: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

目的:美国国立综合癌症网络(NCCN)指南推荐了多种药物组合和特定的给药计划用于早期乳腺癌的治疗,使医生能够根据患者的个体复杂性(包括合并症)和患者-医生的偏好提供治疗。虽然随着时间的推移,指导方案的使用也在发生变化,但很少有数据能说明早期乳腺癌的治疗随着时间的推移发生了怎样的变化:在北加州凯泽医疗集团和华盛顿凯泽医疗集团 2006-2019 年间接受 I-IIIA 期乳腺癌治疗的 34109 名女性队列中,我们介绍了化疗方案随时间推移而发生的变化,并探讨了 NCCN 指南方案(GR)的使用情况、在指南中未包含上述方案时使用的指南方案(称为时间不一致方案(TDR))以及非指南方案(NGR)的使用情况。研究结果按药物组合和时间顺序排列:在接受化疗的12506名妇女中,77.4%(n = 9681)接受了GR方案,9.1%(n = 1140)接受了TDR方案,13.5%(n = 1685)接受了NGR方案。2006年,AC-T(环磷酰胺-多柔比星-紫杉醇)是最常见的治疗方案,到2019年,TC(环磷酰胺-多西他赛)成为最普遍的治疗方案。NGR在环磷酰胺-甲氨蝶呤-5-氟尿嘧啶(CMF)、环磷酰胺-多柔比星-紫杉醇-曲妥珠单抗(ACTH)和紫杉醇-曲妥珠单抗(TH)中更为常见。随着时间的推移,GR 的使用有所增加(p-趋势 结论):随着时间的推移,化疗方式发生了显著变化,更多使用了GR。这些数据对于了解社区医疗机构的化疗情况非常重要。
{"title":"The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.","authors":"Jenna Bhimani, Kelli O'Connell, Sonia Persaud, Victoria Blinder, Rachael P Burganowski, Isaac J Ergas, Grace B Gallagher, Jennifer J Griggs, Narre Heon, Tatjana Kolevska, Yuriy Kotsurovskyy, Candyce H Kroenke, Cecile A Laurent, Raymond Liu, Kanichi G Nakata, Donna R Rivera, Janise M Roh, Sara Tabatabai, Emily Valice, Elisa V Bandera, Erin J Aiello Bowles, Lawrence H Kushi, Elizabeth D Kantor","doi":"10.1007/s10549-024-07433-4","DOIUrl":"10.1007/s10549-024-07433-4","url":null,"abstract":"<p><strong>Purpose: </strong>The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time.</p><p><strong>Methods: </strong>In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time.</p><p><strong>Results: </strong>Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination.</p><p><strong>Conclusion: </strong>Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436. 三阴性乳腺癌细胞系 MDA-MB-231 和 MDA-MB-436 中的 BET 定向 PROTACs。
IF 3 3区 医学 Q2 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-06-19 DOI: 10.1007/s10549-024-07403-w
Maryana Teufelsbauer, Sandra Stickler, Marie-Therese Eggerstorfer, Dennis Clyde Hammond, Gerhard Hamilton

Purpose: This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.

Methods: Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.

Results: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.

Conclusion: The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.

目的:本研究旨在探讨溴基底域和末端外域(BET)抑制剂JQ1和BET蛋白靶向嵌合体(PROTACs)ARV-771和MZ1是否能减少三阴性乳腺癌(TNBC)细胞系的增殖和迁移:方法:采用细胞毒性试验、划痕迁移试验和Western印迹蛋白质组图谱阵列检测癌症相关蛋白质的表达,评估一种BET抑制剂和两种BET靶向PROTACs对细胞活力、迁移和蛋白质表达的影响:结果:JQ1以及PROTACs MZ1和ARV-771显著抑制了KRAS G13D突变的MDA-MB-231细胞的生长和迁移。在该细胞系中,PROTACs抑制了乳腺癌细胞增殖所必需的ERBB2/HER2、3和4的残余表达,证明该细胞系对HER2抑制剂敏感。相比之下,PROTACs 对 MDA-MB-436 细胞蛋白表达的影响主要涉及细胞因子及其同源受体:结论:PROTACs 对 BET 蛋白的降解具有显著的抗增殖作用。KRAS突变的MDA-MB-231细胞属于低HER2表达肿瘤,与HER2缺失患者相比预后较差。由于首个针对肿瘤激素受体的口服 PROTACs 已进入临床试验阶段,这种肿瘤治疗模式有望成为未来治疗 TNBC 的重要治疗策略。
{"title":"BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436.","authors":"Maryana Teufelsbauer, Sandra Stickler, Marie-Therese Eggerstorfer, Dennis Clyde Hammond, Gerhard Hamilton","doi":"10.1007/s10549-024-07403-w","DOIUrl":"10.1007/s10549-024-07403-w","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to find whether the proliferation and migration of triple negative breast cancer (TNBC) cell lines can be reduced by treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 and BET protein targeting chimeras (PROTACs) ARV-771 and MZ1.</p><p><strong>Methods: </strong>Cytotoxicity tests, scratch migration assays and western blot proteome profiler arrays for protein expression of cancer-related proteins were used to evaluate the impact of a BET-inhibitor and two BET-directed PROTACs on cell viability, migration and on protein expression.</p><p><strong>Results: </strong>JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs suppressed the residual expression of ERBB2/HER2, 3 and 4 that are essential for the proliferation of breast cancer cells and this cell line proved sensitive to HER2 inhibitors. In contrast, the effects of the PROTACs on the protein expression of MDA-MB-436 cells mostly affected cytokines and their cognate receptors.</p><p><strong>Conclusion: </strong>The degradation of BET-protein by PROTACs demonstrated significant anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells belong to the low-HER2 expressing tumors that have a poorer prognosis compared to HER2-null patients. Since first oral PROTACs against tumor hormone receptors are in clinical trials, this mode of tumor therapy is expected to become an important therapeutic strategy in the future treatment of TNBC.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Breast Cancer Research and Treatment
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