Y-Box–Binding Protein YB-1 Identifies High-Risk Patients With Primary Breast Cancer Benefiting From Rapidly Cycled Tandem High-Dose Adjuvant Chemotherapy

2009 ◽  
Vol 27 (36) ◽  
pp. 6144-6151 ◽  
Author(s):  
Oleg Gluz ◽  
Karin Mengele ◽  
Manfred Schmitt ◽  
Ronald Kates ◽  
Raihana Diallo-Danebrock ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Binding Protein ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Tumor Grade ◽  
High Dose ◽  
Primary Tumors ◽  
Multifunctional Protein ◽  
Conventional Dose

Purpose To investigate the potential of Y-box–binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens. Patients and Methods YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (≥ 10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions. Results At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2×] epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 14 days, followed by 2× epirubicin 90 mg/m2, cyclophosphamide 3,000 mg/m2, and thiotepa 400 mg/m2 every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4× epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, followed by 3× cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS. Conclusion In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.

scholarly journals Protein Expression Profiling in High-Risk Breast Cancer Patients Treated with High-Dose or Conventional Dose–Dense Chemotherapy

2007 ◽  
Vol 13 (2) ◽  
pp. 488-497 ◽  
Author(s):  
Raihanatou Diallo-Danebrock ◽  
Evelyn Ting ◽  
Oleg Gluz ◽  
Alexander Herr ◽  
Svjetlana Mohrmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Expression Profiling ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Conventional Dose ◽  
Dose Dense ◽  
High Risk Breast Cancer ◽  
High Risk Breast ◽  
Risk Breast Cancer

scholarly journals Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer—results from the randomized phase III SUCCESS-A trial

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Amelie de Gregorio ◽  
Lothar Häberle ◽  
Peter A. Fasching ◽  
Volkmar Müller ◽  
Iris Schrader ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Breast Cancer ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Tumor Grade ◽  
Phase Iii ◽  
Primary Study ◽  
Breast Cancer Patients ◽  
Standard Chemotherapy

Abstract Background When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. Methods A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. Results No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. Conclusion Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. Trial registration Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

MamaPred: A new and innovative approach to determine recurrence risk in HR+/HER2- early-stage breast cancer using HTG EdgeSeq technology.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 558-558
Author(s):  
Jose Antonio Lopez Guerrero ◽  
Carlos Loucera ◽  
Marta Ramírez-Calvo ◽  
María Peña ◽  
Antonio Fernandez-Serra ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Adherens Junction ◽  
Disease Free Survival ◽  
Recurrence Risk ◽  
Glutathione Metabolism ◽  
Risk Allocation ◽  
Kegg Pathways

558 Background: Genomic platforms, such as Mammaprint (Agendia) (MP) and OncoType (Genomic Health) (OT), have been validated to determine the risk of relapse in therapeutic decision-making in early-stage hormone receptor positive (HR+), epidermal growth factor receptor 2 (HER2) negative breast cancer (BC). Discordances in risk allocation between these platforms affect up to 30% of patients. This study aims to develop the MamaPred test to improve the diagnostic performance of recurrence risk in HR+/HER2- early-stage BC. Methods: A total of 606 HR+/HER2- early-stage BC previously tested with OT [n = 287; Low Risk (LR) = 165, Intermediate Risk (IR) = 103 and High Risk (HR) = 19] and MP (n = 319; LR = 217 and HR = 102) were included. A retrospective independent series of 144 HR+/HER2- early-stage BC [median follow-up: 10.53 years (range: 3.1-23.1 yrs); age (median = 62.9 yrs (33-89 yrs); systemic relapse 10.5% (n = 15)] was used as validation set.The expression levels of 2560 cancer-related mRNAs were evaluated from one 5 μm thin-section of a FFPE block (15 mm2 tumor area) using the Oncology Biomarker Panel (OBP) and the HTG EdgeSeq System (HTG Molecular Diagnostics. Inc) and quantified by NGS on a NextSeq550 sequencer (Illumina). A predictive model was built from normalized and logarithmically transformed values (rescaled to [0, 1]) using as response a binary meta-variable constructed by taking the values -1 (for LR of MP and OT together the OT IR) and 1 (for HR MP and OT). Differential expression, GSEA and visualization were performed with DESeq2, gage and pathview packages respectively in R v4.0.1. Results: MamaPred consists of a logistic regression classifier with an elastic net penalty (mix of L1 and L2 priors as regularizer) where the mixing parameter is optimized along with regularization strength by selecting the ones that minimize the area under the precision and recall curve over a validation split for each training fold. Metrics of MamaPred were: balanced accuracy, 80.5%; Kappa, 0.562; specificity, 80.7%; and NPV, 91.4%. GSE analysis on differentially expressed genes (q < 0.1) showed four KEGG pathways overrepresented in HR (p < 0.05): adherens junction, tight junction, glutathione metabolism and focal adhesion; and two underrepresented: DNA replication (p = 0.0765) and pyrimidine metabolism (p = 0.086).The prognostic prediction of MamaPred was validated on the independent retrospective series, distant disease-free survival for HR and LR being 88.63% (95% IC: 78.72%-99.78%) and 98.1% (95% IC: 95.6%-100%) respectively (p = 0.00603). Correlation between the probabilities assigned to any given sample and its replicas was extremely high (r > 0.9 p < 1e-5). Conclusions: MamaPred identifies HR+/HER2- early-stage BC patients with high-risk of distant relapse improving the prognostic value of those studies that compare MP and OT, suggesting a more precise risk classification.

The Role of Irradiation of the Internal Mammary Lymph Nodes in High-Risk Stage II to IIIA Breast Cancer Patients After High-Dose Chemotherapy: A Prospective Sequential Nonrandomized Study

2003 ◽  
Vol 21 (14) ◽  
pp. 2713-2718 ◽  
Author(s):  
Salomon M. Stemmer ◽  
Shulamith Rizel ◽  
Izhar Hardan ◽  
Adamous Adamo ◽  
Avivit Neumann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Electron Beam ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Cox Regression ◽  
Disease Free Survival ◽  
High Dose Chemotherapy ◽  
Stage Ii ◽  
High Dose ◽  
Internal Mammary

Purpose: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation. Patients and Methods: 100 patients with high-risk stage II–III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years. Results: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P = .02). A trend was seen for overall survival (OS; 78% v 64%; P = .08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality. Conclusion: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.

Frühes Mammakarzinom: Hinzunahme von Gemcitabin zur adjuvanten Chemotherapie ohne Vorteil

2021 ◽  
pp. 1-3
Author(s):  
Maggie Banys-Paluchowski ◽  
Natalia Krawczyk
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Breast Cancer ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Tumor Grade ◽  
Primary Study ◽  
Breast Cancer Patients ◽  
Standard Chemotherapy ◽  
Frühes Mammakarzinom

<b>Background:</b> When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. <b>Methods:</b> A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. <b>Results:</b> No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. <b>Conclusion:</b> Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. <b>Trial registration:</b> Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005–000490–21. Registered September 2005.

Co-expression of ER-beta and HER2 associated with poorer prognosis in primary breast cancer

2009 ◽  
Vol 32 (3) ◽  
pp. 250 ◽  
Author(s):  
Wen-sheng Qui ◽  
Lu Yue ◽  
Ai-ping Ding ◽  
Jian Sun ◽  
Yang Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Differentiation ◽  
Primary Breast Cancer ◽  
Tumour Size ◽  
Univariate Analysis ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Er Alpha

Purpose: To assess the prognostic value of co-expression of estrogen receptor (ER)-beta and human epidermal growth factor receptor 2 (HER2) in primary breast cancer patients in China. Methods: Tumour specimens from 308 patients undergoing surgery for primary breast cancer were evaluated. Expression of ER-beta and HER-2 was investigated by the immunohistochemistry. Results: 123 patients (40%) were ER-beta positive and 58 (18.5 %) were HER2 positive. Among the 58 HER2 positive patients, 44 were ER-beta positive and 14 were ER-beta negative. ER-beta positive was associated with HER2 positive (75.9%, P=0.018) as well as ER-alpha positive (79.7%, P=0.023), poor cell differentiation (77.2% grade 2 or 3, P=0.010) and menopause age < 45 yr (55.3%, P=0.031). HER2 positive was associated with poor cell differentiation (93.1%, P=0.001), ?3cm tumour size (67.2%, P=0.011). Conclusion: Both ER-beta positive and HER2 positive status was associated with poorer overall survival (OS) by univariate analysis. In both HER2 positive and HER2 negative subgroups, ER-beta positive was associated with poorer distant disease free survival (DDFS) but not OS, which implied that ER-beta might relate to metastasis in breast cancer.

scholarly journals Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maitri Kalra ◽  
Yan Tong ◽  
David R. Jones ◽  
Tom Walsh ◽  
Michael A. Danso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Triple Negative ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Parp Inhibition ◽  
High Risk Population ◽  
Risk Population ◽  
The Impact

AbstractPatients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

scholarly journals CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Paulino Tallón de Lara ◽  
Héctor Castañón ◽  
Marijne Vermeer ◽  
Nicolás Núñez ◽  
Karina Silina ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Human Breast Cancer ◽  
Disease Free Survival ◽  
T Cell Response ◽  
Primary Breast Tumor ◽  
Human Breast ◽  
Primary Tumors ◽  
Metastatic Relapse ◽  
Discrete Population

AbstractSome breast tumors metastasize aggressively whereas others remain dormant for years. The mechanism governing metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identify a discrete population of CD39+PD-1+CD8+ T cells in primary tumors and in dormant metastasis, which is hardly found in aggressively metastasizing tumors. Using blocking antibodies, we find that dormancy depends on TNFα and IFNγ. Immunotherapy reduces the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevents metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not total CD8+ T cells correlates with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Thus, we suggest that a primary breast tumor could prime a systemic, CD39+PD-1+CD8+ T cell response that favors metastatic dormancy in the lungs.

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