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99 Publications visible to you, out of a total of 99
Economic modeling of risk-adapted screen-and-treat strategies in women at high risk for breast or ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The ’German Consortium for Hereditary Breast and Ovarian Cancer’ (GC-HBOC) offers women with a family history of breast and ovarian cancer genetic counseling. The aim of this modeling study …y was to evaluate the cost-effectiveness of genetic testing for BRCA 1/2 in women with a high familial risk followed by different preventive interventions (intensified surveillance, risk-reducing bilateral mastectomy, risk-reducing bilateral salpingo-oophorectomy, or both mastectomy and salpingo-oophorectomy) compared to no genetic test. METHODS A Markov model with a lifelong time horizon was developed for a cohort of 35-year-old women with a BRCA 1/2 mutation probability of ≥ 10%. The perspective of the German statutory health insurance (SHI) was adopted. The model included the health states ’well’ (women with increased risk), ’breast cancer without metastases’, ’breast cancer with metastases’, ’ovarian cancer’, ’death’, and two post (non-metastatic) breast or ovarian cancer states. Outcomes were costs, quality of life years gained (QALYs) and life years gained (LYG). Important data used for the model were obtained from 4380 women enrolled in the GC-HBOC. RESULTS Compared with the no test strategy, genetic testing with subsequent surgical and non-surgical treatment options provided to women with deleterious BRCA 1 or 2 mutations resulted in additional costs of \text€7256 and additional QALYs of 0,43 (incremental cost-effectiveness ratio of \text€17,027 per QALY; cost per LYG: \text€22,318). The results were robust in deterministic and probabilistic sensitivity analyses. CONCLUSION The provision of genetic testing to high-risk women with a BRCA1 and two mutation probability of ≥ 10% based on the individual family cancer history appears to be a cost-effective option for the SHI.

Authors: Dirk Müller, Marion Danner, Rita Schmutzler, Christoph Engel, Kirsten Wassermann, Björn Stollenwerk, Stephanie Stock, Kerstin Rhiem

Date Published: 1st Jul 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Effects of lifestyle intervention in BRCA1/2 mutation carriers on nutrition, BMI, and physical fitness (LIBRE study): study protocol for a randomized controlled trial
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Women with highly penetrant BRCA mutations have a 55-60 % lifetime risk for breast cancer and a 16-59 % lifetime risk of developing ovarian cancer. However, penetrance differs interindividually, …, indicating that environmental and behavioral factors may modify this risk. It is well documented that the risk for sporadic breast cancer disease can be modified by changing lifestyle factors that primarily include physical activity, dietary habits, and body weight. It can thus be hypothesized that the modification of these lifestyle factors may also influence the incidence and progression of cancer in BRCA mutation carriers. METHODS/DESIGN This multicenter, interdisciplinary, prospective, two-armed, randomized (1:1) controlled trial aims to enroll a minimum of 600 BRCA1 and BRCA2 mutation carriers to partake in either a lifestyle intervention or usual care. The study primarily aims to demonstrate an improvement of nutritional behavior (adherence to the Mediterranean diet), body mass index, and physical fitness. Furthermore, the effects on quality of life, stress coping capacity, breast cancer incidence, and mortality will be investigated. The intervention group (IG) will receive a structured lifestyle intervention over 12 months, whereas the control group (CG) will only receive information regarding a healthy lifestyle. During the first 3 months, women in the IG will receive structured, individualized, and mainly supervised endurance training with a minimum of 18 MET-h physical activity per week and nutrition education based on the Mediterranean diet. Over the following 9 months, IG monthly group training sessions and regular telephone contacts will motivate study participants. The CG will receive one general training session about healthy nutrition in accordance with the recommendations of the German Society of Nutrition (standard of care in Germany) and the benefits of regular physical activity on health status. At randomization and subsequent time points (3 and 12 months), cardiopulmonary fitness will be assessed by spiroergometry, and nutritional and psychological status will be assessed by validated questionnaires, interviews, and clinical examinations. DISCUSSION As data on the role of lifestyle intervention in women with a hereditary risk for breast and ovarian cancer are currently lacking, this study will be of major importance from a scientific, as well as a practical advice viewpoint. It will investigate the optimal strategy to improve physical fitness, nutritional status, and psychological factors such as quality of life, perceived stress, optimism, as well as incidence and outcome of cancer in this selected group of women at high risk. If the study indicates a positive long-term outcome, a structured lifestyle intervention program could be added to health care prevention strategies for BRCA1 and BRCA2 mutation carriers. TRIAL REGISTRATION ClinicalTrials.gov: NCT02516540 . Registered on 22 July 2015.

Authors: Marion Kiechle, Christoph Engel, Anika Berling, Katrin Hebestreit, Stephan C. Bischoff, Ricarda Dukatz, Michael Siniatchkin, Katharina Pfeifer, Sabine Grill, Maryam Yahiaoui-Doktor, Ellen Kirsch, Uwe Niederberger, Ute Enders, Markus Löffler, Alfons Meindl, Kerstin Rhiem, Rita Schmutzler, Nicole Erickson, Martin Halle

Date Published: 1st Dec 2016

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used … to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Authors: C. Fischer, K. Kuchenbacker, C. Engel, S. Zachariae, K. Rhiem, A. Meindl, N. Rahner, N. Dikow, H. Plendl, I. Debatin, T. Grimm, D. Gadzicki, R. Flottmann, J. Horvath, E. Schrock, F. Stock, D. Schafer, I. Schwaab, C. Kartsonaki, N. Mavaddat, B. Schlegelberger, A. C. Antoniou, R. Schmutzler

Date Published: 9th Apr 2013

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general …l population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Authors: A. Osorio, R. L. Milne, G. Pita, P. Peterlongo, T. Heikkinen, J. Simard, G. Chenevix-Trench, A. B. Spurdle, J. Beesley, X. Chen, S. Healey, S. L. Neuhausen, Y. C. Ding, F. J. Couch, X. Wang, N. Lindor, S. Manoukian, M. Barile, A. Viel, L. Tizzoni, C. I. Szabo, L. Foretova, M. Zikan, K. Claes, M. H. Greene, P. Mai, G. Rennert, F. Lejbkowicz, O. Barnett-Griness, I. L. Andrulis, H. Ozcelik, N. Weerasooriya, A-M Gerdes, M. Thomassen, D. G. Cruger, M. A. Caligo, E. Friedman, B. Kaufman, Y. Laitman, S. Cohen, T. Kontorovich, R. Gershoni-Baruch, E. Dagan, H. Jernström, M. S. Askmalm, B. Arver, B. Malmer, S. M. Domchek, K. L. Nathanson, J. Brunet, T. Ramón Y Cajal, D. Yannoukakos, U. Hamann, F. B. L. Hogervorst, S. Verhoef, E. B. Gómez García, J. T. Wijnen, A. van den Ouweland, D. F. Easton, S. Peock, M. Cook, C. T. Oliver, D. Frost, C. Luccarini, D. G. Evans, F. Lalloo, R. Eeles, G. Pichert, J. Cook, S. Hodgson, P. J. Morrison, F. Douglas, A. K. Godwin, O. M. Sinilnikova, L. Barjhoux, D. Stoppa-Lyonnet, V. Moncoutier, S. Giraud, C. Cassini, L. Olivier-Faivre, F. Révillion, J-P Peyrat, D. Muller, J-P Fricker, H. T. Lynch, E. M. John, S. Buys, M. Daly, J. L. Hopper, M. B. Terry, A. Miron, Y. Yassin, D. Goldgar, C. F. Singer, D. Gschwantler-Kaulich, G. Pfeiler, A-C Spiess, Thomas v. O. Hansen, O. T. Johannsson, T. Kirchhoff, K. Offit, K. Kosarin, M. Piedmonte, G. C. Rodriguez, K. Wakeley, J. F. Boggess, J. Basil, P. E. Schwartz, S. V. Blank, A. E. Toland, M. Montagna, C. Casella, E. N. Imyanitov, A. Allavena, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Ditsch, N. Arnold, D. Niederacher, H. Deissler, B. Fiebig, R. Varon-Mateeva, D. Schaefer, U. G. Froster, T. Caldes, M. de La Hoya, L. McGuffog, A. C. Antoniou, H. Nevanlinna, P. Radice, J. Benítez

Date Published: 1st Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of …f large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P \textless 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r^2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

Authors: Logan C. Walker, Zachary S. Fredericksen, Xianshu Wang, Robert Tarrell, Vernon S. Pankratz, Noralane M. Lindor, Jonathan Beesley, Sue Healey, Xiaoqing Chen, Dominique Stoppa-Lyonnet, Carole Tirapo, Sophie Giraud, Sylvie Mazoyer, Danièle Muller, Jean-Pierre Fricker, Capucine Delnatte, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Ines Schönbuchner, Helmut Deissler, Alfons Meindl, Frans B. Hogervorst, Martijn Verheus, Maartje J. Hooning, Ans Mw van den Ouweland, Marcel R. Nelen, Margreet Gem Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Monique M. Gerrits, Quinten Waisfisz, Csilla I. Szabo, Douglas F. Easton, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Patricia Harrington, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Carol Chu, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Tim Rebbeck, Katherine L. Nathanson, Susan M. Domchek, Christian F. Singer, Daphne Gschwantler-Kaulich, Anne-Catharina Dressler, Georg Pfeiler, Andrew K. Godwin, Tuomas Heikkinen, Heli Nevanlinna, Bjarni A. Agnarsson, Maria Adelaide Caligo, Håkan Olsson, Ulf Kristoffersson, Annelie Liljegren, Brita Arver, Per Karlsson, Beatrice Melin, Olga M. Sinilnikova, Lesley McGuffog, Antonis C. Antoniou, Georgia Chenevix-Trench, Amanda B. Spurdle, Fergus J. Couch

Date Published: 1st Dec 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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