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  • 1
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    Keywords: CANCER ; BLOOD ; DISEASE ; RISK ; GENE ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; FAMILY ; FREQUENCY ; BREAST ; BREAST-CANCER ; family history ; OVARIAN-CANCER ; WOMEN ; MUTATION ; MUTATIONS ; PREVALENCE ; BRCA1/2 ; BRCA2 MUTATIONS ; early-onset breast cancer ; German population ; germline mutations ; POPULATION-BASED SAMPLE
    Abstract: This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high- risk populations
    Type of Publication: Journal article published
    PubMed ID: 12774040
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    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; proliferation ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; DISEASE ; NEW-YORK ; TISSUE ; PATIENT ; DNA ; RECEPTOR EXPRESSION ; INDEX ; primary ; ASSOCIATION ; chromosome ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; antibody ; hormone ; AMPLIFICATION ; immunohistochemistry ; AGE ; PROSTATE-CANCER ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; p53 ; REGION ; PROGNOSTIC-FACTORS ; tumor size ; REGIONS ; EVOLUTION ; BREAST-CARCINOMA ; CARCINOMAS ; INVOLVEMENT ; PROGNOSTIC FACTORS ; OVEREXPRESSION ; FLOW-CYTOMETRY ; S-PHASE ; PROGNOSTIC FACTOR ; SECTIONS ; MITOSIS ; GENETIC INSTABILITY ; protein expression ; DNA-PLOIDY ; POSSIBLE MECHANISM ; primary breast cancer,genetic instability,prognostic significance
    Abstract: Our purpose was to assess the presence of centrosomal aberrations as measured by immunohistochemistry in primary invasive breast cancer and their association with established and proposed prognostic factors. Tissue sections of 103 primary invasive breast cancers were examined using centrosome-specific antibodies to pericentrin and gamma-tubulin. At least 3 different tumor regions per case were examined to determine maximum centrosomal aberration levels, which represent the proportion of cells with abnormal centrosomes in the region with the highest percentage of cells with centrosomal aberrations. The chi(2) test was performed to evaluate the association of maximum centrosomal aberration levels with patient age; tumor size; nodal status; nuclear grade; hormone receptor and Her2/neu expression; proportion of Ki67-, p53- and Bcl-2-positive tumor cells; DNA index; S-phase fraction; and proliferation index. With pericentrin immunohistochemistry, maximum centrosomal aberration levels 〉35% were detectable in 92 of the 103 breast carcinomas (89%). We found a highly significant correlation of maximum centrosomal aberration levels above 3S% with axillary nodal tumor involvement (p 〈 0.0001) and the absence of hormone receptors (p 〈 0.0001). In addition, there was a borderline significant relationship with age 〈50 years (p = 0.00) and Her2/neu overexpression (p = 0.050). Among node-negative patients, maximum centrosomal aberration levels 〉35% were also associated with an increased DNA index (p = 0.006). In a subset of patients, additional staining of centrosomes with a monoclonal anti-gamma-tubulin antibody essentially confirmed these results. In primary invasive breast cancer, centrosomal aberrations are associated with those factors predicting a more aggressive course of disease. This might indicate a fundamental role of centrosomal dysfunction in disease evolution, possibly as a result of chromosome missegregation during mitosis. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14506732
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    Keywords: CANCER ; POPULATION ; PROTEINS ; COMPLEX ; RISK-FACTORS ; POLYMORPHISMS ; VARIANTS ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONSORTIUM ; CONFER SUSCEPTIBILITY ; BRCA2 MUTATION CARRIERS
    Abstract: Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 21844186
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    Keywords: POPULATION ; RISK ; MELANOMA ; BRCA1 MUTATION CARRIERS ; CONSORTIUM ; TUMOR SUBTYPES
    Abstract: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
    Type of Publication: Journal article published
    PubMed ID: 22976474
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    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; tumor ; human ; IN-VIVO ; MODEL ; THERAPY ; TISSUE ; TUMORS ; MICE ; TUMOR-NECROSIS-FACTOR ; RECEPTOR EXPRESSION ; INDEX ; primary ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; NOD/Scid mice ; PROGRESSION ; PATTERNS ; TUMOR PROGRESSION ; breast cancer xenotransplantation ; CELL THERAPY ; cellular adoptive transfer ; DUAL ROLE ; graft-vs.- host disease ; HUMAN-TUMORS ; IMMUNODEFICIENT MICE ; IMPLANTATION ; metastases ; NECROSIS-FACTOR-ALPHA ; NUDE-MICE ; SCID MOUSE ; tumor-infiltrating lymphocytes
    Abstract: We describe a new human tumor xenotransplant animal model that is highly efficient for engraftment, does not need host conditioning and is suitable for in vivo studies of human tumors. Pieces of 61 freshly operated primary breast tumors were implanted into 172 irradiated and 228 nonconditioned NOD/Scid mice. A high mortality was observed in irradiated but not in nonconditioned recipients. More than 90% of analyzed implanted breast cancer specimens engrafted in the NOD/Scid mice irrespective of pretreatment. The tumors were vascularized within 3 days of implantation and maintained original histomorphology as well as expression patterns of tumor markers (cytokeratin and MUCI) and cytokines (tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4) and IL-10) released by adjacent stromal cells. A majority of tumors grew slowly, locally infiltrating host tissue, whereas some grew aggressively, developing large, fatal tumor masses and metastases within regional lymph nodes. Tumor progression in mice correlated with stage, grade, proliferation index and hormone receptor status of primary tumors. The reproducible growth behavior and preservation of characteristic features suggest that this new xenotransplant model is relevant and can be recommended for testing new anticancer therapies. (C) 2003 Wiley-Liss. Inc
    Type of Publication: Journal article published
    PubMed ID: 12712433
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    Keywords: measurement ; CANCER ; tumor ; carcinoma ; MODEL ; THERAPY ; DISEASE ; TUMORS ; RESOLUTION ; SURGERY ; PATIENT ; MR ; MRI ; BREAST ; BREAST-CANCER ; score ; chemotherapy ; tumor size ; MAMMOGRAPHY ; CONSERVATION ; pathology ; neoadjuvant treatment ; breast neoplasms ; INDUCTION CHEMOTHERAPY ; PREOPERATIVE CHEMOTHERAPY
    Abstract: The aim of this study was to evaluate whether regressive changes after neoadjuvant chemotherapy for breast cancer affect the accuracy of preoperative MRI measurements of tumor size. Thirty-one patients with breast cancer underwent MRI before and after neoadjuvant treatment. Besides pre- and post-contrast T1- weighted MRI, dynamic MRI with high temporal resolution (turbo- FLASH) was performed. Contrast enhancement in dynamic MRI was quantified using a pharmacokinetic two-compartment model, where two parameters, amplitude and k(ep), were calculated and color code on transversal parameter maps. Considering the conventional MR images, tumor diameters were measured on the color maps and compared with histological tumor size. Histological regression was scored on a five-point scale regarding cytopathic effects, reactive changes, and tumor cell reduction. The correlation between tumor sizes measured by MRI and histopathology was 0.83 (p〈0.0007) in 12 tumors without regressive changes (score 0), and 0.48 (p〈0.051) in 17 tumors with regressive changes scored 1 or 2, without any tendency for systematic over- or underestimation. In two cases without residual tumor (score 4), MRI likewise showed no signs of persistent tumor. The decrease of the contrast enhancement parameters was significantly more marked in tumors with signs of histological regression than in those without. Whenever MRI is used to judge the response of breast cancer to chemotherapy, the reader must be aware that therapy-induced changes may cause significant over- or underestimation of tumor size. We saw a high precision only when there was either no response - according to histological criteria - or when the tumor had regressed completely
    Type of Publication: Journal article published
    PubMed ID: 12764635
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    Keywords: CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; tumor ; Germany ; PATHWAY ; PATHWAYS ; PHASE-I ; THERAPY ; CLASSIFICATION ; GENE ; GENE-EXPRESSION ; GENES ; RNA ; TISSUE ; PATIENT ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; IDENTIFICATION ; gene expression ; VECTOR ; PCR ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; CANCER-PATIENTS ; doxorubicin ; PREDICTION ; SELECTION ; sensitivity ; specificity ; CYCLOPHOSPHAMIDE ; OVEREXPRESSION ; expression profiling ; GUIDELINES ; PREOPERATIVE CHEMOTHERAPY ; signaling ; GEMCITABINE ; EPIRUBICIN ; docetaxel ; NEOADJUVANT CHEMOTHERAPY ; RECOMMENDATIONS ; PREDICTOR ; Phase I ; PREDICTS ; PHASE-I/II
    Abstract: Purpose Primary systemic therapy (PST) with gemcitabine (G), epirubicin (E), and docetaxel (Doc) has resulted in a pathologic complete response (pCR) in 26% of primary breast cancer patients. This study was aimed at the identification of a gene expression signature in diagnostic core biopsy tissue samples that predicts pCR. Patients and Methods Core biopsy samples from patients with operable primary breast cancer, T2-4N0-2M0, enrolled onto two phase I and II trials evaluating GEDoc (n = 48) and GE sequentially followed by Doc (GEsDoc; n = 52) as PST were snap frozen and subjected to RNA expression profiling. A signature predicting pCR was discovered in the training set (GEsDoc) applying a support vector machine algorithm, and performance of this classifier was validated on the independent test set (GEDoc) by receiver operator characteristics analysis. Results We identified a signature consisting of 512 genes, which was enriched in genes involved in transforming growth factor beta and RAS-mediated signaling pathways, that predicts pCR with a sensitivity of 78%, a specificity of 90%, and an overall accuracy of 88% (95% CI, 75% to 95%). Apart from our signature, only HER2 overexpression was an independent predictor of pCR in multivariate analysis. Conclusion In conclusion, our gene expression signature allows prediction of pCR to PST containing G, E, and Doc with unprecedented high overall accuracy and robustness
    Type of Publication: Journal article published
    PubMed ID: 16622258
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    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; BLOOD ; Germany ; THERAPY ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; TISSUE ; SURGERY ; PATIENT ; COMPLEX ; COMPLEXES ; MARKER ; LYMPH-NODES ; CYCLE ; treatment ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; IDENTIFICATION ; gene expression ; chemotherapy ; PCR ; SAFETY ; CYCLOPHOSPHAMIDE ; gene expression profiling ; PHASE-II ; PREOPERATIVE CHEMOTHERAPY ; SERUM ; ONCOLOGY ; analysis ; methods ; PHASE ; SIGNATURE ; USA ; docetaxel ; PREDICTOR ; SET ; gene expression signature ; pathologic complete response ; primary breast cancer ; response prediction ; GENE-EXPRESSION SIGNATURE ; prediction of response and resistance ; translational research
    Abstract: Background: Microarray gene expression profiling has indicated that complex molecular gene expression signatures might be predictive of outcome after systemic treatment for early breast cancer. Neoadjuvant systemic therapy (NST) with its assessment of pathologic complete response (pCR), so far the best surrogate parameter for cure, provides a unique opportunity to rapidly identify such molecular predictors. Patients and Methods: Currently, an International, randomized phase II study of 2 sequential regimens as NST is being conducted in patients with primary invasive breast cancer T2-4a-c N0-2 MO. Patients receive 4 cycles of doxorubicin/pemetrexed, followed by 4 cycles of docetaxel (AP-Doc) or 4 cycles of doxorubicin/cyclophosphamide, followed by 4 cycles of docetaxel (AC-Doc). Tumor, tissue, blood, and serum are collected at baseline and, if available, after 4 cycles of chemotherapy, and at surgery. The clinical objectives are to assess pCR rate, tumor response, rate of histologically negative axillary lymph nodes, disease-free survival, and safety after NST with AP-Doc or AC-Doc. Translational research objectives include the identification of differentially expressed genes predictive for the achievement of pCR after either treatment regimen. Results: As of January 2007, 178 of the 256 patients planned for this study had been enrolled at 12 European centers. The recommendation after a planned interim safety and efficacy analysis was to continue with the trial as planned. Conclusion: We anticipate this study will provide a better understanding of the treatment options with pemetrexed in primary breast cancer and give insight into the practical robustness of the new marker sets in response prediction
    Type of Publication: Journal article published
    PubMed ID: 17509164
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