Oligonucleotide Array CGH Profiles of Breast Cancer Patients Treated with High Dose or Conventional Chemotherapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50407 | GEO | 2014/12/22
SECONDARY ACCESSION(S): PRJNA217437
REPOSITORIES: GEO
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Project description:The aim of this study was to compare the gene expression profile changes breast tumors after the treatment with Anthracyclines and Taxanes. To this end, an oligonucleotide microarray was performed (AffymetrixM-bM-^@M-^Ys HG-U133 Plus 2.0 array). This gene expression study was carried out on the biopsied tumor samples previous being treated with chemotherapy, and subsequently compared with themselves once treatment schedule ended. The post-chemotherapy biopsy was obtained from the surgical piece. The goal of this study was the finding of several genes related to apoptosis, proliferation, differentiation, survival and transformation-related genes and correlating their differences in expression with the degree of response to chemotherapy, determined by the Miller and Payne histological grading system. After informed consent, patients with a histologically confirmed diagnosis of breast cancer and scheduled chemotherapy treatment based on Anthracyclines and Taxanes (Treatment A: Epirubicin 90 mg/m2-Cyclophosphamide 600 mg/m2, 3 cycles bi-weekly and Paclitaxel 150 mg/m2-Gemcitabine 2500 mg/m2, 6 cycles bi-weekly M-BM-1 weekly Herceptin 4 mg/Kg during the first week, 2 mg/Kg for the remaining 11 cycles; Treatment B: Doxorubicin 60 mg/m2-Pemetrexed 500 mg/m2, 4 cycles tri-weekly and Docetaxel 100 mg/m2, 4 cycles tri-weekly; Treatment C: Doxorubicin 60 mg/m2-Cyclophosphamide 600 mg/m2, 4 cycles tri-weekly and Docetaxel 100 mg/m2, 4 cycles tri-weekly ) were recruited for this study. Pre-chemotherapy and post-chemotherapy biopsies were examined by a pathologist who determined the Miller & Payne grade for each patient. Matching pairs of pre-chemotherapy and post-chemotherpy samples were divided into 3 groups according to Miller & Payne grade: group of bad response (Miller & Payne grades 1 and 2), group of mid response (Miller & Payne grade 3) and group of good response (Miller & Payne grades 4 and 5). Gene expression analysis was performed in paired samples as follows: mid response group post-chemotherapy biopsy vs pre-chemotherapy biopsy (Mid final vs initial). For this assay were necessary 20 samples being chosen according to histopathologic criteria (Miller & Payne grade 3). Other comparisons in which this group of samples was involved include: Initial Good vs Mid, Initial Bad vs Mid, Final Bad vs Mid and Final Good vs Mid. This gene expression profiling was carried out making use of AffymetrixM-bM-^@M-^Ys GeneChip technology, with the AffymetrixM-bM-^@M-^Ys HG-U133 Plus 2.0 array from this provider. All the protocols and apparatus were recommended by Affymetrix. Total RNA from frozen mammary tumors was directly extracted by a RNeasy Mini kit and homogenized by QIAshredder columns under manufacturerM-bM-^@M-^Ys instructions. The quality and quantity of the obtained RNA, was checked out through agarose electrophoresis and later spectrophotometry at 260/280 nm. Biotinylated cRNA was synthesized following the IVT labeling kit from Affymetrix and purified by the GeneChip Sample Cleanup Module from Affymetrix. Once again, the quality and quantity of the obtained cRNA, was checked out through agarose electrophoresis and posterior spectrophotometry at 260/280 nm. After hybridization, slides were washed and scanned following the manufacturerM-bM-^@M-^Ys standard protocol. Intensity values were normalized by Robust Multichip Average method and subsequently these were filtered for remove the control sequences and those with a hybridization signal near to background. The spike controls were: BioB, BioC, BioD and Cre; because BioB was the less presented in the samples, it was used to estimate the sensitivity of the experiment. The housekeeping control was GAPDH. After non-supervised PCA analysis and clustering, gene expression statistical significances were identified by two regression models taking into account the pathologic response to chemotherapy and if the sample was obtained before or after chemotherapy treatment. Supervised PCA analysis and clustering were performed with processed data. Partek Genomics Suite v7.3.1 (Partek) software was employed for the statistic analysis and clustering.
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Project description:<p>The SUCCESS-A Study (<a href="http://www.success-studie.de">http://www.success-studie.de</a>) is a randomized Phase III study of response to treatment of early primary breast cancer with adjuvant therapy after surgical resection. The primary outcome is disease-free survival and secondary outcomes are overall survival and toxicity. The study design includes comparison of two pairs of treatment regimes performed in sequence. The first randomization contrasts treatment with and without Gemcitabine (3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy). The second randomization contrasts treatment with Zoledronate for two versus five years. Patients were recruited from 2005 to 2007 and a total of 3754 patients were included from 250 study sites across Germany. Genome-wide SNP microarray data and phenotype outcomes for the first phase of the study (treatment with and without Gemcitabine) are included in the GARNET (Genomics and Randomized Trials Network) pharmacogenomic study in this dbGaP submission. (The Zoledronate treatments are still underway).</p> <p>SUCCESS-A is a an open-label, multicenter, 2x2 factorial design, randomized controlled, Phase III study comparing the disease free survival after randomization in patients treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC)-chemotherapy, followed by 3 cycles of Docetaxel(D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide(FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)-chemotherapy, and to compare the disease free survival after randomization in patients treated with 2 years of Zoledronate versus 5 years of Zoledronate in patients with early primary breast cancer. Patients were required to have histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as: pT>2 or histopathological grade 3, or age , ≤ 35 or negative hormone receptor, but were not allowed to have evidence of distant disease. Patients were entered into the study no later than 6 weeks after complete resection of the primary tumor. No antineoplastic treatment other than surgical treatment, the defined cytotoxic and endocrine treatment, and radiotherapy was allowed prior to study entry and during the course of the study. After surgery, leading to complete resection of the invasive and intraductal components of the primary tumor, patients were randomized to one of the following two treatments for the first phase of the project (which is included in this GARNET pharmacogenomics study):</p> <p><b>AA</b>: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 75 mg/m² body surface area i.v. (D), and Gemcitabine 1000 mg/m² i.v. (30 min infusion) (G), administered on day 1, followed by Gemcitabine 1000 mg/m² i.v. (30 min infusion) on day 8, repeated on day22</p> <p><b>AB</b>: 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 100 mg/m² body surface area i.v. (D), administered on day 1, repeated on day 22</p> <p>A second randomization was made for assigning patients to one of the following two subsequent treatments for the second phase of the project (NOT included in the pharmacogenetic study in this dbGaP submission):</p> <p><b>BA</b>: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years, subsequently followed by zoledronic acid 4 mg i.v., every 6 months for the duration of additional three years</p> <p><b>BB</b>: Zoledronic acid 4 mg i.v., every 3 months for the duration of two years</p> <p>Patients with positive hormone receptor status (≥10% positively stained cells for estrogen and/or progesterone) of the primary tumor were recommended to receive Tamoxifen treatment 20 mg p.o. per day for 2 years, after the end of chemotherapy . Subsequent to chemotherapy, postmenopausal patients with positive hormone receptor status were recommended to be treated with Anastrozole (Arimidex®) 1 mg p.o. for additional 3 years, premenopausal patients will continue Tamoxifen treatment for those additional 3 years. In addition to tamoxifen, all patients with positive hormone receptor status of the primary tumor and under the age of 40 or restart of menstrual bleeding within 6 months after the completion of cytostatic treatment or with premenopausal hormone levels as defined below were recommended to receive Goserelin (Zoladex®) 3.6 mg subcutaneously every 4 weeks over a period of 2 years following chemotherapy. Premenopausal endocrine status will be assumed, if the following serum levels are met: LH < 20 mIE/ml, FSH < 20 mIE/ml and E2 > 20 pg/ml. Endocrine therapy will start after the end of chemotherapy.</p> <p>All patients with breast conserving therapy or more than 3 axillary lymph node metastases or in the following cases after mastectomy will receive adjuvant radiotherapy: T3/T4-carcinoma, T2-carcinoma > 3 cm, multicentric tumor growth, lymphangiosis carcinomatosa or vessel involvement, involvement of the pectoralis fascia or a safety margin < 5 mm. Radiotherapy was usually performed after the chemotherapy and parallel to the beginning of the zoledronic acid therapy.</p> <p>Initially, DNA was extracted for performing SNP microarray assays using blood collected at baseline prior to the first randomization. However, the first set of SNP microarray results indicated a quality problem with approximately 50% of the DNA samples. A majority of the problematic samples were replaced with DNA extracted from redrawn blood. The remaining problematic samples were 'restored' using an Illumina FFPE Restoration procedure. A total of 3322 subjects (1638 from arm AA and 1684 from arm AB) were successfully genotyped. Among those, 1771 were from original blood samples, 1092 from redrawn blood samples and 459 from restored blood samples.</p> <p>The SUCCESS-A study is part of the Genomics and Randomized Trials Network (GARNET, <a href="http://www.garnetstudy.org">http://www.garnetstudy.org</a>) funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to disease-free survival for breast cancer patients using different forms of chemotherapy through large-scale genome-wide association studies of treatment response in randomized clinical trials. The study was conducted at the University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Germany. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington.</p>
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Project description:The aim of this study was to compare the gene expression profile changes breast tumors after the treatment with Anthracyclines and Taxanes. To this end, an oligonucleotide microarray was performed (AffymetrixM-bM-^@M-^Ys HG-U133 Plus 2.0 array). This gene expression study was carried out on the biopsied tumor samples previous being treated with chemotherapy, and subsequently compared with themselves once treatment schedule ended. The post-chemotherapy biopsy was obtained from the surgical piece. The goal of this study was the finding of several genes related to apoptosis, proliferation, differentiation, survival and transformation-related genes and correlating their differences in expression with the degree of response to chemotherapy, determined by the Miller and Payne histological grading system. After informed consent, patients with a histologically confirmed diagnosis of breast cancer and scheduled chemotherapy treatment based on Anthracyclines and Taxanes (Treatment A: Epirubicin 90 mg/m2-Cyclophosphamide 600 mg/m2, 3 cycles bi-weekly and Taxol 150 mg/m2-Gemcitabine 2500 mg/m2, 6 cycles bi-weekly M-BM-1 weekly Herceptin 4 mg/Kg during the first week, 2 mg/Kg for the remaining 11 cycles; Treatment B: Doxorubicin 60 mg/m2-Pemetrexed 500 mg/m2, 4 cycles tri-weekly and Taxotere 100 mg/m2, 4 cycles tri-weekly; Treatment C: Doxorubicin 60 mg/m2-Cyclophosphamide 600 mg/m2, 4 cycles tri-weekly and Taxotere 100 mg/m2, 4 cycles tri-weekly) were recruited for this study. Pre-chemotherapy and post-chemotherapy biopsies were examined by a pathologist who determined the Miller & Payne grade for each patient. Matching pairs of pre-chemotherapy and post-chemotherapy samples were divided into 3 groups according to Miller & Payne grade: group of bad response (Miller & Payne grades 1 and 2), group of mid response (Miller & Payne grade 3) and group of good response (Miller & Payne grades 4 and 5). Gene expression analysis was performed in paired samples as follows: bad response group post-chemotherapy biopsy vs pre-chemotherapy biopsy (Bad Final vs Initial). For this assay were necessary 13 samples being chosen according to histopathologic criteria (Miller & Payne grades 4 and 5). Of them, 10 samples were paired and 3 pre-chemotherapy samples from patients that experienced a good response to chemotherapy were also included in this experimental series. Other comparisons in which this group of samples was involved include: Initial Bad vs Good, Initial Good vs Mid, Final Mid vs Good and Final Bad vs Good. This gene expression profiling was carried out making use of AffymetrixM-bM-^@M-^Ys GeneChip technology, with the AffymetrixM-bM-^@M-^Ys HG-U133 Plus 2.0 array from this provider. All the protocols and apparatus were recommended by Affymetrix. Total RNA from frozen mammary tumors was directly extracted by a RNeasy Mini kit and homogenized by QIAshredder columns under manufacturerM-bM-^@M-^Ys instructions. The quality and quantity of the obtained RNA, was checked out through agarose electrophoresis and later spectrophotometry at 260/280 nm. Biotinylated cRNA was synthesized following the IVT labeling kit from Affymetrix and purified by the GeneChip Sample Cleanup Module from Affymetrix. Once again, the quality and quantity of the obtained cRNA, was checked out through agarose electrophoresis and posterior spectrophotometry at 260/280 nm. After hybridization, slides were washed and scanned following the manufacturerM-bM-^@M-^Ys standard protocol. Intensity values were normalized by Robust Multichip Average method and subsequently these were filtered for remove the control sequences and those with a hybridization signal near to background. The spike controls were: BioB, BioC, BioD and Cre; because BioB was the less presented in the samples, it was used to estimate the sensitivity of the experiment. The housekeeping control was GAPDH. After non-supervised PCA analysis and clustering, gene expression statistical significances were identified by two regression models taking into account the pathologic response to chemotherapy and if the sample was obtained before or after chemotherapy treatment. Supervised PCA analysis and clustering were performed with processed data. Partek Genomics Suite v7.3.1 (Partek) software was employed for the statistic analysis and clustering.
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