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Juliet D French,
Maya Ghoussaini,
Stacey L Edwards,
Kerstin B Meyer,
Kyriaki Michailidou,
Shahana Ahmed,
Sofia Khan,
Mel J Maranian,
Martin O'Reilly,
Kristine M Hillman, [......],
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Bruce A J Ponder,
Heli Nevanlinna,
Melissa A Brown,
Georgia Chenevix-Trench,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
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Christian R Loehberg,
Katrin Almstedt,
Sebastian M Jud,
Lothar Haeberle,
Peter A Fasching,
Carolin C Hack,
Michael P Lux,
Falk C Thiel,
Michael G Schrauder,
Michaela Brunner,
Christian M Bayer,
Alexander Hein,
Katharina Heusinger,
Jutta Heimrich,
Mayada R Bani,
Stefan P Renner,
Arndt Hartmann,
Matthias W Beckmann,
David L Wachter
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ABSTRACT: Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer.
Breast Cancer Research and Treatment 03/2013; · 4.43 Impact Factor
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Falk C Thiel,
Anton Scharl,
Thomas Hildebrandt,
Efstratios Kotziabassis,
Michael G Schrauder,
Mayada R Bani,
Andreas Müller,
Tanja Hauzenberger, Christian R Loehberg,
Sebastian M Jud,
Peter A Fasching,
Arndt Hartmann,
Rüdiger Schulz-Wendtland,
Vratislav Strnad,
Matthias W Beckmann,
Michael Patrick Lux
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ABSTRACT: INTRODUCTION: Although care in certified breast centers is now established throughout Germany, numerous services are still not being reimbursed. This also affects other centers involved in the specialty of gynecology such as gynecological cancer centers, perinatal centers, and endometriosis centers. Although a certified center is entitled to charge additional fees, these are in most cases not reimbursed. Calculation of additional costs is limited by the fact that data from the Institute for the Hospital Reimbursement System (Institut für das Entgeltsystem im Krankenhaus, InEK) do not reflect interdisciplinary services and procedures. For decision-makers, society's willingness to pay is an important factor in guiding decisions on the basis of social priorities. A hypothetical maximum willingness to pay can be calculated using a willingness-to-pay analysis, making it possible to identify deficiencies in the arbitrary setting of health budgets at the macro-level. MATERIALS AND METHODS: In a multicenter study conducted between November 2009 and December 2010, 2,469 patients at a university hospital and at a non-university hospital were asked about the extent of their awareness of certified centers, the influence of centers on hospital presentation, and about personal attitudes toward quality-oriented reimbursement. A subjective assessment of possible additional charges was calculated using a willingness-to-pay analysis. RESULTS: In the overall group, 53.4 % of the patients were aware of what a certified center is and 27.4 % had specific information (obstetrics 40.0/32.3 %; mastology 66.8/23.2 %; gynecological oncology 54.7/27.3 %; P < 0.001). For 43.8 %, a certified center was one reason or the major reason for presentation (obstetrics 26.2 %; mastology 66.8 %; gynecological oncology 46.6 %; P < 0.001). A total of 72.6 % were in favor of quality-oriented reimbursement and 69.7 % were in favor of an additional charge for a certified center amounting to 538.56 (mastology 643.65, obstetrics 474.67, gynecological oncology 532.47). In all, 33.9 % would accept an increase in health-insurance fees (averaging 0.3865 %), and 28.3 % were in favor of reduced remuneration for non-certified centers. CONCLUSIONS: The existence of certified centers is being increasingly recognized by patients. Additional charges for certified centers are generally supported. There is therefore a clear demand for them-from patients as well. This may be useful when negotiations are being conducted.
Archives of Gynecology 10/2012; · 0.91 Impact Factor
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Claudia Rauh,
Florian Faschingbauer,
Lothar Haeberle,
Sebastian M Jud,
Katharina Heusinger,
Peter A Fasching,
Tamme W Goecke,
Nadeeka Rajakaruna,
Franziska Voigt,
Mayada R Bani,
Michael P Lux,
Stefan P Renner, Christian R Loehberg,
Arndt Hartmann,
Ruediger Schulz-Wendtland,
Matthias W Beckmann,
Christian M Bayer
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ABSTRACT: Pregnancy and breastfeeding are major factors reducing breast cancer (BC) risk. A potential mechanism for this effect might be changes in mammographic density, but other factors might be involved. The aim of this study was to investigate factors influencing changes in breast size and breast stiffness after pregnancy. Of a consecutive cohort of 5991 women who gave birth between 1996 and 1999, 559 replied to a questionnaire including questions about breast changes. The women completed their own assessments of changes in breast size and stiffness since their last pregnancy. Factors being investigated regarding their predictive value for these changes were: BMI before pregnancy, weight gain, age at first full-term pregnancy (FFTP), number of pregnancies, breastfeeding, and BMI of the children's fathers. A decrease in breast size was reported in 21.8% of the participants and an increase in 35.1%. With regard to the breast stiffness, 66.4% reported a decrease and only 5% reported an increase. Independent predictors for increased breast size were age at FFTP, increase in BMI since last pregnancy, BMI before pregnancy, and time since FFTP. Factors predictive of greater breast stiffness included age at FFTP, BMI before FFTP, time since FFTP, breastfeeding status, and number of pregnancies. Breast changes after pregnancy depend on several variables, which are described as BC-risk factors. Individual reaction of the female breast to a pregnancy leads to different outcomes with regard to breast size and stiffness. Further studies are needed to clarify whether these individual responses interact with the effect of pregnancy on the BC risk.
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 09/2012; · 2.21 Impact Factor
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Katharina Heusinger,
Sebastian M Jud,
Lothar Häberle,
Carolin C Hack,
Peter A Fasching,
Martina Meier-Meitinger,
Michael P Lux,
Carsten Hagenbeck, Christian R Loehberg,
Thomas Wittenberg,
Claudia Rauh,
Florian Wagner,
Michael Uder,
Arndt Hartmann,
Rüdiger Schulz-Wendtland,
Matthias W Beckmann,
David L Wachter
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ABSTRACT: There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.
Breast Cancer Research and Treatment 08/2012; 135(3):885-92. · 4.43 Impact Factor
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Lothar Häberle,
Florian Wagner,
Peter A Fasching,
Sebastian M Jud,
Katharina Heusinger, Christian R Loehberg,
Alexander Hein,
Christian M Bayer,
Carolin C Hack,
Michael P Lux,
Katja Binder,
Matthias Elter,
Christian Münzenmayer,
Rüdiger Schulz-Wendtland,
Martina Meier-Meitinger,
Boris R Adamietz,
Michael Uder,
Matthias W Beckmann,
Thomas Wittenberg
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ABSTRACT: Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design.
A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model.
Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model.
Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy.
Breast cancer research: BCR 04/2012; 14(2):R59. · 5.24 Impact Factor
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Katharina Heusinger,
Sebastian M Jud,
Lothar Häberle,
Carolin C Hack,
Boris R Adamietz,
Martina Meier-Meitinger,
Michael P Lux,
Thomas Wittenberg,
Florian Wagner, Christian R Loehberg,
Michael Uder,
Arndt Hartmann,
Rüdiger Schulz-Wendtland,
Matthias W Beckmann,
Peter A Fasching
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ABSTRACT: For many breast cancer (BC) risk factors, there is growing evidence concerning molecular subtypes for which the risk factor is specific. With regard to mammographic density (MD), there are inconsistent data concerning its association with estrogen receptor (ER) and progesterone receptor (PR) expression. The aim of our study was to analyze the association between ER and PR expression and MD. In our case-only study, data on BC risk factors, hormone receptor expression and MD were available for 2,410 patients with incident BC. MD was assessed as percent MD (PMD) using a semiautomated method by two readers for every patient. The association of ER/PR and PMD was studied with multifactorial analyses of covariance with PMD as the target variable and including well-known factors that are also associated with MD, such as age, parity, use of hormone replacement therapy, and body mass index (BMI). In addition to the commonly known associations between PMD and age, parity, BMI and hormone replacement therapy, a significant inverse association was found between PMD and ER expression levels. Patients with ER-negative tumors had an average PMD of 38%, whereas patients with high ER expression had a PMD of 35%. A statistical trend toward a positive association between PMD and PR expression was also seen. PMD appears to be inversely associated with ER expression and may correlate positively with PR expression. These effects were independent of other risk factors such as age, BMI, parity, and hormone replacement therapy, possibly suggesting other pathways that mediate this effect.
International Journal of Cancer 03/2012; 131(11):2643-9. · 5.44 Impact Factor
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Michael G Schrauder,
Reiner Strick,
Rüdiger Schulz-Wendtland,
Pamela L Strissel,
Laura Kahmann, Christian R Loehberg,
Michael P Lux,
Sebastian M Jud,
Arndt Hartmann,
Alexander Hein,
Christian M Bayer,
Mayada R Bani,
Swetlana Richter,
Boris R Adamietz,
Evelyn Wenkel,
Claudia Rauh,
Matthias W Beckmann,
Peter A Fasching
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ABSTRACT: MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls.
We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718).
Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA-expression were found for miR-202.
MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use.
PLoS ONE 01/2012; 7(1):e29770. · 4.09 Impact Factor
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Christian R Loehberg,
Pamela L Strissel,
Ralf Dittrich,
Reiner Strick,
Juergen Dittmer,
Angela Dittmer,
Ben Fabry,
Willi A Kalender,
Thorsten Koch,
David L Wachter, [......],
Ina Brandt,
Laura Lotz,
Inge Hoffmann,
Florentine Koppitz,
Sonja Oeser,
Andreas Mueller,
Peter A Fasching,
Michael P Lux,
Matthias W Beckmann,
Michael G Schrauder
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ABSTRACT: PI3K/Akt/mTOR and p53 signaling pathways are frequently deregulated in tumors. The anticancer drug RAD001 (everolimus) is a known mTOR-inhibitor, but mTOR-inhibition leads to phosphorylation of Akt inducing resistance against RAD001 treatment. There is growing evidence that conflicting signals transduced by the oncogene Akt and the tumorsuppressor p53 are integrated via negative feedback between the two pathways. We previously showed that the anti-malarial Chloroquine, a 4-alkylamino substituted quinoline, is a p53 activator and reduced the incidence of breast tumors in animal models. Additionally, Chloroquine is an effective chemosensitizer when used in combination with PI3K/Akt inhibitors but the mechanism is unknown. Therefore, our aim was to test, if Chloroquine could inhibit tumor growth and prevent RAD001-induced Akt activation. Chloroquine and RAD001 caused G1 cell cycle arrest in luminal MCF7 but not in mesenchymal MDA-MB-231 breast cancer cells, they significantly reduced MCF7 cell proliferation on a collagen matrix and mammospheroid formation. In a murine MCF7 xenograft model, combined treatment of Chloroquine and RAD001 significantly reduced mammary tumor growth by 4.6-fold (p = 0.0002) compared to controls. Chloroquine and RAD001 inhibited phosphorylation of mTOR and its downstream target, S6K1. Furthermore, Chloroquine was able to block the RAD001-induced phosphorylation of Akt serine 473. The Chloroquine effect of overcoming the RAD001-induced activation of the oncogene Akt, as well as the promising antitumor activity in our mammary tumor animal model present Chloroquine as an interesting combination partner for the mTOR-inhibitor RAD001.
Biochemical pharmacology 11/2011; 83(4):480-8. · 4.25 Impact Factor
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Martin C Koch,
Boris Adamietz,
Sebastian M Jud,
Peter A Fasching,
Lothar Haeberle,
Stefan Karbacher,
Klaus Veit,
Ruediger Schulz-Wendtland,
Michael Uder,
Matthias W Beckmann,
Mayada R Bani,
Katharina Heusinger, Christian R Loehberg,
Alexander Cavallaro
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ABSTRACT: Breast volume is a relevant measure for the prevention and prediction of diseases and for aesthetic surgery. This study evaluated a new technique to determine breast volume and compared measures using a three-dimensional (3D) body surface scanner and magnetic resonance imaging (MRI) scans, with the latter used as the standard method.
Both MRI scans and body surface 3D scans were obtained from 22 women. For each method, breast volumes were assessed. The MRI calculations of the breast volumes were performed by a specially trained radiologist using analysis software. A textured 3D image was generated by a calibrated digital texture camera after breast surface data acquisition. The volume assessment of the 3D photography was calculated using a software package after manual outlining of the breast and automated projection of a dorsal limit. Linear regression was used to predict the MRI volume assessment with the 3D image volume assessment.
The mean breast volume according to MRI volumetry was 442.8 ml on the left side and 471.8 ml on the right side. The mean breast volume using a 3D body surface volume assessment method was 273.8 ml (observer A) and 226.2 ml (observer B) on the left side and 284.4 ml (observer A) and 234.9 ml (observer B) on the right side. The use of linear regression models showed R (2) values of 0.59-0.77. The mean time for MRI recording and volume assessment was 68.0 ± 14.1 min for both sides and 11.6 ± 1.5 min for 3D recording and volume assessment.
The 3D surface-based volume measurements are feasible in terms of time and can predict the MRI breast volume with sufficient accuracy. This might facilitate the broad use of such an assessment technique in a large-scale epidemiologic study using breast volume as a study aim. Additionally, further development of volume assessments could help to implement this technique in breast surgery procedures.
Aesthetic Plastic Surgery 04/2011; 35(5):847-55. · 1.41 Impact Factor
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Xiaohong R Yang,
Jenny Chang-Claude,
Ellen L Goode,
Fergus J Couch,
Heli Nevanlinna,
Roger L Milne,
Mia Gaudet,
Marjanka K Schmidt,
Annegien Broeks,
Angela Cox, [......],
John L Hopper,
Fleur Hammet,
Helen Tsimiklis,
Letitia D Smith,
Melissa C Southey,
Manjeet K Humphreys,
Douglas Easton,
Paul Pharoah,
Mark E Sherman,
Montserrat Garcia-Closas
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ABSTRACT: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
CancerSpectrum Knowledge Environment 02/2011; 103(3):250-63. · 14.07 Impact Factor
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Katharina Heusinger, Christian R Loehberg,
Lothar Haeberle,
Sebastian M Jud,
Peter Klingsiek,
Alexander Hein,
Christian M Bayer,
Claudia Rauh,
Michael Uder,
Alexander Cavallaro,
Matthias S May,
Boris Adamietz,
Ruediger Schulz-Wendtland,
Thomas Wittenberg,
Florian Wagner,
Matthias W Beckmann,
Peter A Fasching
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ABSTRACT: Mammographic percent density (MD) is recognized as one of the strongest risk factors associated with breast cancer. This matched case-control study investigated whether MD represents an independent risk factor. Mammograms were obtained from 1025 breast cancer patients and from 520 healthy controls. MD was measured using a quantitative computer-based threshold method (0-100%). Breast cancer patients had a higher MD than healthy controls (38 vs. 32%, P<0.01). MD was significantly higher in association with factors such as age over 60 years, body mass index (BMI) of 25-30 kg/m², nulliparity or low parity (one to two births). Average MD was inversely associated with age, BMI, parity and positively associated with age at first full-term pregnancy. MD was higher in women with at least one first-degree relative affected, but only among patients and not in the group of healthy controls (P<0.01/P=0.61). In women with an MD of 25% or more, the risk of breast cancer was doubled compared with women with an MD of less than 10% (odds ratio: 2.1; 95% confidence interval: 1.3-3.4; P<0.01); in the postmenopausal subgroup, the risk was nearly tripled (odds ratio: 2.7; 95% confidence interval: 1.6-4.7; P<0.001). This study provides further evidence that MD is an important risk factor for breast cancer. These results indicate strong associations between MD and the risk of breast cancer in a matched case-control study in Germany.
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 01/2011; 20(1):1-8. · 2.21 Impact Factor
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Michael G Schrauder,
Peter A Fasching,
Lothar Häberle,
Michael P Lux,
Claudia Rauh,
Alexander Hein,
Christian M Bayer,
Katharina Heusinger,
Arndt Hartmann,
Johanna D Strehl,
David L Wachter,
Rüdiger Schulz-Wendtland,
Boris Adamietz,
Matthias W Beckmann, Christian R Loehberg
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological studies indicated that type 2 diabetes mellitus may increase breast cancer risk and mortality. The aim of this retrospective cohort study was to examine the effect of diabetes on the clinical course and the prognosis of early stage breast cancer in relation to tumour and patient characteristics.
The cohort analyzed in this study consisted of 4,056 patients with invasive primary breast cancer. We compared overall survival, distant metastasis-free survival and local recurrence free survival between breast cancer patients with and without diabetes.
In our cohort 276 breast cancer patients (6.8%) were affected by diabetes compared to 3,780 patients (93.2%) without diabetes. Women with diabetes were significantly older, had larger tumours, and a higher rate of lymph node involvement. After a follow-up period of 5 years, stratification for age and adjustment for other prognostic factors, overall mortality following breast cancer was significantly higher in diabetic breast cancer patients (hazard ratio, HR 1.92; 95% confidence interval, CI 1.49-2.48). We found no significant differences in distant metastasis-free survival and local recurrence free survival between the two groups, but we found a slightly significant higher rate of distant metastasis in the group of patients with diabetes and oestrogen receptor negative tumours (HR 2.28; CI 1.31-3.97).
In this study, patients with diabetes and oestrogen receptor negative breast cancer had a more than 2-fold higher risk for distant metastasis compared to patients without diabetes. Diabetes was also associated with an almost 2-fold increase in mortality within the 5 years follow-up period.
Journal of Cancer Research and Clinical Oncology 12/2010; 137(6):975-83. · 2.56 Impact Factor
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Christian R Loehberg,
Katharina Heusinger,
Sebastian M Jud,
Lothar Haeberle,
Alexander Hein,
Claudia Rauh,
Mayada R Bani,
Michael P Lux,
Michael G Schrauder,
Christian M Bayer,
Cosima Helbig,
Ronald Grolik,
Boris Adamietz,
Ruediger Schulz-Wendtland,
Matthias W Beckmann,
Peter A Fasching
[show abstract]
[hide abstract]
ABSTRACT: Mammographic density (MD) has consistently been found as one of the strongest breast cancer risk factors. In our study, both qualitative and quantitative density measurements were performed in a hospital-based group of premenopausal women before and after first full-term pregnancy providing an opportunity for direct evaluation of the effects of one pregnancy on MD. Mammograms were obtained from 23 women before and after first full-term pregnancy and from 28 nulliparous controls. MD was determined by a standard qualitative assessment method using the Breast Imaging Reporting and Data System, and a quantitative computer-based threshold method (0-100%). The mean age at mammography before and after pregnancy was 31 and 34 years, respectively, with a mean difference of 40 months between mammographies. The quantitative density assessment showed a significant reduction in relative MD after pregnancy of 12 percentage points (8.6-15.4), compared with 3.1 (0.0-6.2) in the nulliparous control group (P<0.001). A reduction in MD of more than 10% was seen in 52% of the patients, compared with 18% of the controls. The qualitative density assessment confirmed a reduction in MD after pregnancy by one Breast Imaging Reporting and Data System category (P=0.02). This longitudinal study showed that MD can be influenced by one full-term pregnancy. This effect was seen with both quantitative and qualitative assessment methods. It may be hypothesized that breast cancer risk reduction associated with pregnancy is mediated through a direct reduction of MD, and MD assessment might be incorporated in individualizing risk assessment and prevention.
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 11/2010; 19(6):405-12. · 2.21 Impact Factor
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[show abstract]
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ABSTRACT: Serotonin (5-hydroxytryptamine 3; 5-HT(3)) receptors are involved in chemotherapy-induced nausea and vomiting (CINV), and 5-HT(3) antagonists are part of the 'gold standard' antiemetic treatment during chemotherapy. We investigated the correlation of common variants in 5-HT(3) receptor subunit genes with the occurrence of CINV.
A total of 110 previously characterized chemotherapy-naive women with primary breast cancer treated with anthracycline-containing chemotherapy served as a study group for mutational analysis by direct sequencing. Eight common SNPs in the 5-HT(3) receptor genes, HTR3A, HTR3B, HTR3D and HTR3E, were selected for association analysis.
A nonsynonymous variant in HTR3D, p.G36A (rs6443930), was found to be over-represented in nonresponders, assuming a log-additive inheritance model (p = 0.048). Cox proportional regression analysis resulted in a hazards ratio of 0.36 for homozygous carriers of the C allele to vomit within 24 h after first chemotherapy administration (p = 0.049).
Our data supports the hypothesis that 5-HT(3) receptors play an important role in the pathogenesis of CINV. Along with previously identified HTR3 polymorphisms, the HTR3D p.G36A variant could also contribute to facilitating individual risk predictions.
Pharmacogenomics 07/2010; 11(7):943-50. · 3.97 Impact Factor
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Christian R Loehberg,
Sebastian M Jud,
Lothar Haeberle,
Katharina Heusinger,
Gerhard Dilbat,
Alexander Hein,
Claudia Rauh,
Peter Dall,
Nadine Rix,
Sabrina Heinrich,
Stefan Buchholz,
Benno Lex,
Barbara Reichler,
Boris Adamietz,
Ruediger Schulz-Wendtland,
Matthias W Beckmann,
Peter A Fasching
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ABSTRACT: It has been shown in several studies that antihormonal compounds can offer effective prophylactic treatment to prevent breast cancer. In view of the low participation rates in chemoprevention trials, the purpose of this study was to identify the characteristics of women taking part in a population-based mammography screening program who wished to obtain information about the risk of breast cancer and then participate in the the International Breast Cancer Intervention Study II (IBIS-II) trial, a randomized double-blind controlled chemoprevention trial comparing anastrozole with placebo. A paper-based survey was conducted in a population-based mammography screening program in Germany between 2007 and 2009. All women who met the criteria for the mammography screening program were invited to complete a questionnaire. A total of 2,524 women completed the questionnaire, and 17.7% (n = 446) met the eligibility criteria for the IBIS-II trial after risk assessment. The women who wished to receive further information about chemoprevention were significantly younger (P < 0.01) and had significantly more children (P = 0.03) and significantly more relatives with breast cancer (P < 0.001). There were no significant differences between the participants with regard to body mass index or hormone replacement therapy. Normal mammographic findings at screening were the main reason (42%) for declining to participate in the IBIS-II trial or attend risk counseling. The ultimate rate of recruitment to the IBIS-II trial was very low (three women). Offering chemoprevention to women within a mammography screening unit as part of a paper-based survey resulted in low participation rates for both, the survey and the final participation in the IBIS-II trial. More individualized approaches and communication of breast cancer risk at the time of the risk assessment might be helpful to increase the participation and the understanding of chemopreventive approaches.
Breast Cancer Research and Treatment 03/2010; 121(1):101-10. · 4.43 Impact Factor
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Tamme W Goecke,
Arif B Ekici,
Beate Niesler, Christian R Loehberg,
Christian Hammer,
Gudrun Rappold,
Denny Schanze,
Verica Straub,
Hans-Harald Altmann,
Pamela Strissel,
Reiner Strick,
Matthias W Beckmann,
Peter A Fasching
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ABSTRACT: To assess the association between pregnancy-associated symptoms and common single nucleotide polymorphisms (SNPs) in genes known to be involved in the pathogenesis of nausea and vomiting.
In a standardized, questionnaire-based interview, women selected from a control cohort for association studies were asked retrospectively about nausea and vomiting during their first pregnancy.
A total of 593 women who had completed at least one pregnancy and for whom germline DNA was available were selected.
Eight SNPs in the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, and NK1R (TACR1) were tested using polymerase chain reaction. The occurrence of nausea and vomiting was correlated with the patients' genotyping results and medical history parameters.
Both young age at first pregnancy and positive smoking status were significantly associated with vomiting and nausea during pregnancy. After adjustment for these two parameters, the two SNPs rs6806362 (odds ratio (OR) 1.38 per allele; 95% confidence interval (CI) 1.06-1.79; p = 0.017) and rs6807670 (OR 1.37; 95% CI 1.05-1.79 per allele; p = 0.023) were marginally associated with pregnancy-related nausea. None of the other polymorphisms showed any association.
Polymorphisms in the subunit gene HTR3C of the serotonin receptor may be involved in the pathogenesis of pregnancy-associated nausea.
Acta Obstetricia Et Gynecologica Scandinavica 01/2010; 89(1):7-14. · 1.77 Impact Factor
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Folkward G Wiesner,
Achim Magener,
Peter A Fasching,
Julia Wesse,
Mayada R Bani,
Claudia Rauh,
Sebastian Jud,
Michael Schrauder, Christian R Loehberg,
Matthias W Beckmann,
Arndt Hartmann,
Michael P Lux
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ABSTRACT: The proliferation biomarker Ki-67 is a prognostic factor for breast cancer that has been investigated in several retrospective studies and a few prospective ones. The aims of the present study were to examine interactions between Ki-67 and other biomarkers in breast cancer patients and to assess the relationship of Ki-67 to histological grading.
Patients with uniform immunohistochemical staining of Ki-67 by MIB-1 were identified from the database of the University Breast Center for Franconia. Data were available for 1232 of 2523 patients with invasive breast cancer who had been treated between 1998 and 2005. Ki-67 index was determined during routine work-up of the breast cancers by several surgical pathologists according to a standardized procedure. The Ki-67 proliferation index was correlated with hormone receptor status, HER2/neu status, age, tumor staging, and prognosis. In routine clinical practice, the grading was assessed according to Elston and Ellis, along with all other parameters.
Ki-67 proliferation index>or=20% was found to be associated with all of the prognostic factors that were tested. However, it also maintained statistical significance relative to poor overall survival in a multivariate Cox proportional hazards model (hazards ratio 1.81; 95% CI, 1.17-2.78). The hazards ratio for disease-free survival did not reach statistical significance (HR 1.41; 95% CI, 0.95-2.09; P=0.086). However, in both models the grade was not an independent prognostic factor.
For routine clinical purposes, grading appears to add only limited information about the prognosis in comparison with Ki-67 expression. Further investigation of quality assurance for grading and of Ki-67 as a prognostic and predictive factor is warranted.
Breast (Edinburgh, Scotland) 03/2009; 18(2):135-41. · 2.09 Impact Factor
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ABSTRACT: The German health care system has entered an era of specialist centers and certification. Hospitals are required to introduce quality management with external monitoring, refining and improving their quality of treatment. These statutory requirements can only be met through specialization, centralization, and establishing centers and networks with internal and external interdisciplinary collaboration. The breast centers certified according to the criteria of the German Cancer Society (DKG) and German Society for Mastology (DGS) are pioneers here. Simultaneously, there are increasing demands for more cost-effective medical services despite limited resources - making economic analysis of health care provision necessary. Few economic studies of the centers and certification system have been conducted, however. General long-term quality data, particularly for results, are not yet available from certified breast centers. At present, a certified breast center is not itself a proven independent prognostic parameter for treatment results. However, the individual criteria required for breast center certification show a significant positive influence on clinical efficacy. Certified breast centers involve substantial extra costs that are not reimbursed by funding bodies, so the slightest potential benefit for patients from certified centers already appears cost-effective. When the actual costs, currently usually subsidized by other departments, are considered, it is unclear whether certified breast centers remain cost-effective.
Breast Care 01/2009; 4(4):245-250. · 0.45 Impact Factor
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ABSTRACT: The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. We have previously shown that the tumor-suppressor gene p53 is a potential mediator of hormone (estrogen/progesterone)-induced protection against chemical carcinogen-induced mammary carcinogenesis in animal models. Here, we show for the first time a breast cancer-protective effect of chloroquine in an animal model. Chloroquine significantly reduced the incidence of N-methyl-N-nitrosourea-induced mammary tumors in our animal model similar to estrogen/progesterone treatment. No protection was seen in our BALB/c p53-null mammary epithelium model, indicating a p53 dependency for the chloroquine effect. Using a human nontumorigenic mammary gland epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, chloroquine activates the tumor-suppressor p53 and the p53 downstream target gene p21, resulting in G(1) cell cycle arrest. p53 activation occurs at a posttranslational level via chloroquine-dependent phosphorylation of the checkpoint protein kinase, ataxia telangiectasia-mutated (ATM), leading to ATM-dependent phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, chloroquine does not induce G(1) cell cycle arrest compared with cells isolated from wild-type mice, also indicating a p53 dependency. Our results indicate that a short prior exposure to chloroquine may have a preventative application for mammary carcinogenesis.
Cancer Research 01/2008; 67(24):12026-33. · 7.86 Impact Factor
