Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved outcome, not all patients benefit equally. We have evaluated the utility of an in vitro ...chemosensitivity assay in predicting response to neoadjuvant chemotherapy. Pre-therapeutic biopsies were obtained from 30 breast cancer patients assigned to neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Biopsies were subjected to a standardized ATP-based Epi/Doc chemosensitivity assay, and to gene expression profiling. Patients then received 3 cycles of chemotherapy, and response was evaluated by changes in tumor diameter and Ki67 expression. The efficacy of Epi/Doc in vitro was correlated with differential changes in tumor cell proliferation in response to Epi/Doc in vivo (p = 0.0011; r = 0.73670, Spearmans rho), but did not predict for changes in tumor size. While a pre-therapeutic gene expression signature identified tumors with a clinical response to Epi/Doc, no such signature could be found for tumors that responded to Epi/Doc in vitro, or tumors in which Epi/Doc exerted an antiproliferative effect in vivo. This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual biological response to chemotherapy in breast cancer.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Byline: Sharon E. Johnatty (1), Fergus J. Couch (2), Zachary Fredericksen (2), Robert Tarrell (2), Amanda B. Spurdle (1), Jonathan Beesley (1), Xiaoqing Chen (1), Daphne Gschwantler-Kaulich (6), ...Christian F. Singer (6), Christine Fuerhauser (6), Anneliese Fink-Retter (6), Susan M. Domchek (7), Katherine L. Nathanson (7), Vernon S. Pankratz (2), Noralane M. Lindor (2), Andrew K. Godwin (8), Maria A. Caligo (9), John Hopper (10), Melissa C. Southey (10), Graham G. Giles (11), Christina Justenhoven (12,13), Hiltrud Brauch (12,13), Ute Hamann (14), Yon-Dschun Ko (15), Tuomas Heikkinen (16), Kirsimari Aaltonen (16,18), Kristiina Aittomaki (17), Carl Blomqvist (18), Heli Nevanlinna (16), Per Hall (19), Kamila Czene (19), Jianjun Liu (20), Susan Peock (21), Margaret Cook (21), Radka Platte (21), D. Gareth Evans (22), Fiona Lalloo (22), Rosalind Eeles (23), Gabriella Pichert (24), Diana Eccles (25), Rosemarie Davidson (26), Trevor Cole (27), Jackie Cook (28), Fiona Douglas (29), Carol Chu (30), Shirley Hodgson (31), Joan Paterson (32), Frans B. L. Hogervorst (33), Matti A. Rookus (34), Caroline Seynaeve (35), Juul Wijnen (36), Maaike Vreeswijk (37), Marjolijn Ligtenberg (38), Rob B. Luijt (39), Theo A. M. Os (40), Hans J. P. Gille (41), Marinus J. Blok (42), Claudine Issacs (43), Manjeet K. Humphreys (21), Lesley McGuffog (21), Sue Healey (1), Olga Sinilnikova (44), Antonis C. Antoniou (21), Douglas F. Easton (21), Georgia Chenevix-Trench (1) Keywords: GATA3; Breast cancer; Polymorphism; BRCA1 and BRCA2; Risk GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (P .sub.trend = 0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours Garcia-Closas M et al. (2007) Cancer Epidemiol Biomarkers Prev 16:2269--2275. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (OR.sub.per-allele = 1.00, 95% CI 0.94--1.05), in ER negative BCAC cases (OR.sub.per-allele = 1.02, 95% CI 0.91--1.13), in BRCA1 mutation carriers RR.sub.per-allele = 0.99, 95% CI 0.90--1.09) or BRCA2 mutation carriers (RR.sub.per-allele = 0.93, 95% CI 0.80--1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women. Author Affiliation: (1) Cancer and Cell Biology, Queensland Institute of Medical Research, c/o Royal Brisbane Hospital Post Office, Herston, Brisbane, QLD, 4029, Australia (2) Mayo Clinic College of Medicine, Rochester, MN, USA (3) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (4) Lund University Hospital, Lund, Sweden (5) Karolinska University Hospital, Stockholm, Sweden (6) Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Vienna, Austria (7) University of Pennsylvania, Philadelphia, PA, USA (8) Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA (9) Section of Genetic Oncology Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy (10) Centre for MEGA Epidemiology, University of Melbourne, Melbourne, VIC, Australia (11) The Cancer Council of Victoria, Melbourne, VIC, Australia (12) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (13) University of Tubingen, Tubingen, Germany (14) Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany (15) Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (16) Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland (17) Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland (18) Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland (19) Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden (20) Human Genetics, Genome Institute of Singapore, Singapore, Singapore (21) Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (22) Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, UK (23) Translational Cancer Genetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK (24) Clinical Genetics, Guy's Hospital, London, UK (25) Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK (26) Ferguson-Smith Centre for Clinical Genetics, Glasgow, UK (27) West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK (28) Sheffield Clinical Genetics Service, Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK (29) Institute of Human Genetics, Centre for Life, Newcastle upon Tyne, UK (30) Yorkshire Regional Genetics Service, Leeds, UK (31) Department of Cancer Genetics, St Georges Hospital, University of London, London, UK (32) Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK (33) Department of Clinical Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands (34) Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands (35) Department of Medical Oncology, Erasmus University Medical Centre, Rotterdam, The Netherlands (36) Department of Clinical Molecular Genetics, Leiden University Medical Centre, Leiden, The Netherlands (37) Department of Molecular Genetics, Leiden University Medical Centre, Leiden, The Netherlands (38) Department of Clinical Molecular Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands (39) Department of Clinical Molecular Genetics, Utrecht University Medical Centre, Utrecht, The Netherlands (40) Department of Clinical Genetics, Amsterdam University Medical Centre, Amsterdam, The Netherlands (41) Department of Clinical Molecular Genetics, Free University Medical Centre, Amsterdam, The Netherlands (42) Department of Clinical Molecular Genetics, University Medical Centre Maastricht, Maastricht, The Netherlands (43) Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA (44) Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France, and Laboratoire de Genetique Moleculaire, Signalisation et Cancer, Universite de Lyon, Lyon, France (45) Brisbane, Australia Article History: Registration Date: 14/11/2008 Received Date: 12/11/2008 Accepted Date: 14/11/2008 Online Date: 11/12/2008 Article note: The authors S. E. Johnatty and F. J. Couch contributed equally to this work.
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