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Breast Cancer Susceptibility and Pharmacogenomics

Breast cancer is the most frequent female cancer with more than one million newly diagnosed cases and more than 350.000 women dying from the disease each year worldwide. This is mainly attributed to the lack of known risk factors as well as lack of efficient and non-toxic anti-cancer drugs. My research employs strategies that might help to cut down the incidence of breast cancer by way of molecular epidemiological studies and to improve treatment outcomes of available therapies by way of pharmacogenomic approaches. My research team employs large patient collections (case-control and treatment cohorts) for the identification of susceptibility genes and treatment predictors by candidate gene, whole genome as well as epigenetic approaches. Candidates are further explored in mechanistic studies to establish biological evidence. This translational research involves a high degree of interdisciplinary collaboration among scientists with medical, epidemiological, laboratory and statistical expertises for the complex evaluation of clinical and laboratory data obtained via high-throughput molecular analyses. The overall goal is to provide the knowledge and diagnostic tools for future exploration and implementation of personalized treatment schemes.
 
 
Major projects
  • Candidate and genome wide search for breast cancer susceptibility genes
  • Genotype – phenotype correlations for the description of breast cancer subtypes
  • Tamoxifen pharmacogenomics and translation
  • Estrogen receptor regulation
  • Pharmacogenomics of anti cancer drugs
  • Epigenetic approaches for the identification of novel treatment predictors and drug targets
  • PhD Curriculum “Fighting Drug Failure”
Prof. Dr. Hiltrud B. Brauch

phone: ++49-711-8101 3705

Selected References
Original Articles
 
  • Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha et al.: Association analysis identifies 65 new breast cancer risk loci. In: Nature 551 (7678), S. 92–94, 2017
  • Hoppe, Reiner; Achinger-Kawecka, Joanna; Winter, Stefan; Fritz, Peter; Lo, Wing-Yee; Schroth, Werner; Brauch, Hiltrud: Increased expression of miR-126 and miR-10a predict prolonged relapse-free time of primary oestrogen receptor-positive breast cancer following tamoxifen treatment. In: European journal of cancer (Oxford, England : 1990) 49 (17), S. 3598–3608, 2013
  • Amaral S, Schroth W, Kugler S, et al. The Promoter C Specific ERa Isoform is Associated with Tamoxifen Outcome in Breast Cancer. Breast Cancer Research and Treatment 118:323-331, 2009
  • Ahmed S, Thomas G, Ghoussaini M, et al. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nature Genetics. 41(5):585-90, 2009
  • Jaremko M, Justenhoven C, Schroth W, et al. A Polymorphism of the DNA Repair enzyme XRCC1 is associated with treatment prediction in aqnthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of patients with primary invasive breast cancer. Pharmacogenetics and Genomics 17:529-538, 2007
  • Cox A, Dunning AM, Garcia-Closas M, et al. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics 39:352-358, 2007 Schroth W, Antoniadou L, Fritz P, et al. Breast Cancer Treatment Outcome with Adjuvant Tamoxifen in Relation to Patient CYP2D6 and CYP2C19 Genotypes. Journal of Clinical Oncology 33:5187-5193, 2007
  • Jaremko M, Justenhoven C, Abraham BK et al. MALDI-TOF MS and TaqMan assisted SNP genotyping of DNA isolated from formalin-fixed and paraffin embedded tissues (FFPET) Human Mutation 25:232-238, 2005
  • Schmidt, L.; Duh, F. M.; Chen, F.; Kishida, T.; Glenn, G.; Choyke, P. et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. In: Nature genetics 16 (1), S. 68–73, 1997
  • Brauch, H.; Johnson, B.; Hovis, J.; Yano, T.; Gazdar, A.; Pettengill, O. S. et al.: Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung. In: The New England journal of medicine 317 (18), S. 1109–1113 1987
  • Zbar, B.; Brauch, H.; Talmadge, C.; Linehan, M.: Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. In: Nature 327 (6124), S. 721–724, 1987


 
Reviews

  • Saladores PH, Precht JC, Schroth W, Brauch H, Schwab M. Impact of metabolizing enzymes on drug response of endocrine therapy in breast cancer. Expert Rev Mol Diagn. 13(4):349-65, 2013
  • Brauch H and Jordan VC Targeting of Tamoxifen to Enhance Antitumour Action for the Treatment and Prevention of Breast Cancer: the “Personalised” Approach? European Journal of Cancer 45: 2274-2283, 2009
Major Networks and Collaborations
Research Network Coordinator, Principle Investigator and International Network Collaborations The Interdisciplinary Study Group on Gene ENvironment Interactions and Breast CAncer in Germany (GENICA) for the identification of breast cancer susceptibility genes (funded by BMBF 1999-2010). This population-based case-control study recruited more than 2000 incident breast cancer cases and controls for the conduct of molecular epidemiological studies which have become an integral part of the research activities of the
  • Breast Cancer Association Consortium (BCAC: since 2005) - Global networks of more than 90 studies investigating more than 320.000 breast cancer cases and controls for the identification of novel breast cancer susceptibility loci based on GWAS.
  • Collaborative Oncological Gene-Environment Study (COGS: since 2010-2015) - Mega-Consortium for the identification of genetic determinates of breast, ovarian and prostate cancer as well as lifestyle factors that influence the risk of these cancers; Identification of the genetics influence on type of tumor and prognosis of the diseases.
  • OncoArray Network (ongoing): Mega Consortium to gain new insight into the genetic architecture and mechanisms underlying breast, ovarian, prostate, colorectal, and lung cancers. Focus is on the discovery of new cancer susceptibility variants. In addition, through fine mapping and high-density genotyping, this project offers an unprecedented opportunity to determine variants in known loci and to identify new – and rarer – variants.
  • B_CAST (ongoing): 20,000 tumors from a unique worldwide collection from large-scale epidemiological studies, clinical studies and biobanks are subjected to targeted sequencing towards risk and prognosis modelling of breast cancer (2016).
  • BRIDGES (ongoing): Existing datasets will be expanded by sequencing of all known breast cancer susceptibility genes in 20,000 breast cancer cases and 20,000 controls from population-based studies, and 10,000 cases from multiple case families towards the identification of women at high-risk of breast cancer

International Tamoxifen Pharmacogenomics Consortium, member of the Steering Committee (ITPC), (2009 - 2016). Established global evidence for the role of Tamoxifen CYP2D6 pharmacogenetics for breast cancer outcome of ER positive early breast cancer.
 
Principle Investigator in German Research Networks

  • Improvement of Breast Cancer Diagnosis and Treatment Tübingen-Stuttgart (funded by BMBF), since 2005
  • MARIE-GENICA Consortium for the identification of constitutional factors predictive for the risk to develop breast cancer following hormone replacement therapy (MARIE: MAmmakarzinom RIsikofaktoren-Erhebung) (funded by BMBF), (2005-2010)
  • TAMENDOX: Innovation for Individualized Medicine: Genotype and phenotype guided supplementation of TAMoxifen standard therapy with ENDOXifen in breast cancer patients (Phase I/II clinical trial, funded by BMBF, since 2015 ongoing)

Lead Applicant and Coordinator of EU Training Site and Networks My personalized medicine oriented projects for innovative biomarker-guided clinical trial design and treatment concepts provide a platform for the training of national and international PhD students and post-doctoral fellows. Particularly the EU funded Marie Curie Programs FightingBreastCancer and the Innovative Training Network (ITN) FightingDrugFailure; www.fightingdrugfailure.net) provided an opportunity for the training of 20 PhD students from 12 countries.

  • 5FP: Marie Curie Training Site Stuttgart/Tübingen: “Fighting Breast Cancer” (European PhD Training Program (2001 to 2005)
  • 7FP PEOPLE-Initial Training Network (ITN) FightingDrugFailure (2009-2013) The network establishes the first European Curriculum in the field of Pharmacogenomics for young investigators. The program foresees pharmacogenomic research training of 15 international young investigators at nine specialized academic and industry sites in Germany, United Kingdom, Slovenia, Russia, and Switzerland, and is supported by US researchers from the Mayo Clinic-NIH Pharmacogenetics Research Network (PGRN) and Georgetown University Medical Center.

Curriculum Vitae Hiltrud Beatrix Brauch, PhD

Affiliation
Deputy Head Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Head Breast Cancer Susceptibility and Pharmacogenomics

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Auerbachstrasse 112
70376 Stuttgart, Germany
phone: ++49-711-8101 3705
fax: ++49-711-859295
email: hiltrud.brauch@ikp-stuttgart.de
Education and Professional Career
1975-1981 Study of Chemistry (Diploma), University Fridericiana Karlsruhe (TH), Germany
1981-1985 Dissertation: Regulation of Complement Lysis by a Membrane Glycoprotein (Glycophorin A), Institute of Immunology and Serology and Institute of Physical Chemistry, Ruprecht-Karls-University Heidelberg, Germany
1985-1988 Fogarty International Visiting Fellowship, Program of Collaborative Research Experience in the United States, The National Institutes of Health (NIH), USA
Visiting Fellow, Laboratory of Immunobiology (LIB)-National Cancer Institute (NCI)-National Institutes of Health (NIH), Frederick Cancer Research and Development Center(FCRDC), Frederick, MD, USA
1988-1990 Scientist, LIB, PRI-Inc. NCI-FCRDC, Frederick, MD, USA
1990-1992 Scientist, German Cancer Research Center (DKFZ), Germany
1992-1996 Head, Laboratory of Molecular Pathology, Institute of Pathology and Pathological Anatomy, Klinikum rechts der Isar, Technical University Munich, Germany
Habilitation and Venia Legendi in Molecular Pathology
1996-1999 Head Research Laboratory and Gynecological Diagnostics, Womens Hospital Eppendorf, University of Hamburg, Germany; Venia Legendi in Molecular Biology
1999-present Head Molecular Mechanisms of Origin and Treatment of Breast Cancer, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart
2000 Venia Legendi in Molecular Pathology University Tübingen
2006 Extraordinary Professorship at the University Tübingen Medical School
since 2008 Deputy Head of Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, Head Breast Cancer Susceptibility and Pharmacogenomics
Professional Memberships
1996-present: American Association of Cancer Research (AACR)
                            AACR-Molecular Epidemiology Group (MEG)
                            AACR-Women in Cancer Research (WICR)
1996-present: American Society of Human Genetics (ASHG)
2000-present: Gesellschaft für Biochemie und Molekularbiologie (GBM)
2007-present: Verein für von der von Hippel-Lindau (VHL) Erkrankung betroffene Familien e.V. (Board of Scientists of the VHL Family Alliance Germany)
Scientific Journal Editorial Board Memberships
2006-present: Pharmacogenetics and Genomics
Member of Organization Committees for Scientific Conferences
Cold Spring Harbor Laboratory Conference: Pharmacogenomics & Personalized Medicine (since 2009)

New Developments in the Endocrine Treatment of Breast Cancer, IKP Stuttgart, February 5, 2009
Awards and Honors
  • Fogarty International Fellowship, program of collaborative research experience in the United States, The National Institutes of Health (NIH), U.S.A. (1985-1989)
  • Susan G. Komen for the Cure Distinguished Lectureship, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (2012)
  • Tamoxifen Team Award, Wall of Honour, Royal Society of Medicine, London, UK (2013)