Abstract
E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
| Original language | English |
|---|---|
| Article number | 6574 |
| Journal | Scientific reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2018 Dec 1 |
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E-cadherin breast tumor expression, risk factors and survival : Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium. / Horne, Hisani N.; Oh, Hannah; Sherman, Mark E. et al.
In: Scientific reports, Vol. 8, No. 1, 6574, 01.12.2018.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - E-cadherin breast tumor expression, risk factors and survival
T2 - Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium
AU - Horne, Hisani N.
AU - Oh, Hannah
AU - Sherman, Mark E.
AU - Palakal, Maya
AU - Hewitt, Stephen M.
AU - Schmidt, Marjanka K.
AU - Milne, Roger L.
AU - Hardisson, David
AU - Benitez, Javier
AU - Blomqvist, Carl
AU - Bolla, Manjeet K.
AU - Brenner, Hermann
AU - Chang-Claude, Jenny
AU - Cora, Renata
AU - Couch, Fergus J.
AU - Cuk, Katarina
AU - Devilee, Peter
AU - Easton, Douglas F.
AU - Eccles, Diana M.
AU - Eilber, Ursula
AU - Hartikainen, Jaana M.
AU - Heikkilä, Päivi
AU - Holleczek, Bernd
AU - Hooning, Maartje J.
AU - Jones, Michael
AU - Keeman, Renske
AU - Mannermaa, Arto
AU - Martens, John W.M.
AU - Muranen, Taru A.
AU - Nevanlinna, Heli
AU - Olson, Janet E.
AU - Orr, Nick
AU - Perez, Jose I.A.
AU - Pharoah, Paul D.P.
AU - Ruddy, Kathryn J.
AU - Saum, Kai Uwe
AU - Schoemaker, Minouk J.
AU - Seynaeve, Caroline
AU - Sironen, Reijo
AU - Smit, Vincent T.H.B.M.
AU - Swerdlow, Anthony J.
AU - Tengström, Maria
AU - Thomas, Abigail S.
AU - Timmermans, A. Mieke
AU - Tollenaar, Rob A.E.M.
AU - Troester, Melissa A.
AU - Van Asperen, Christi J.
AU - Van Deurzen, Carolien H.M.
AU - Van Leeuwen, Flora F.
AU - Van'T Veer, Laura J.
AU - García-Closas, Montserrat
AU - Figueroa, Jonine D.
N1 - Funding Information: BCAC: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. ABCS: Blood bank Sanquin, The Netherlands. CNIO-BCS: Guillermo Pita, Charo Alonso, Nuria Álvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO). ESTHER: Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach. HEBCS: Sofia Khan, Johanna Kiiski, Kristiina Aittomäki, Rainer Fagerholm, KBCP: Eija Myöhänen, Helena Kemiläinen. kConFab/AOCS: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab) investigtaors: Morteza Aghmesheh, David Amor, Lesley Andrews, Yoland Antill, Shane Armitage, Leanne Arnold, Rosemary Balleine, Agnes Bankier, Patti Bastick, Jonathan Beesley, John Beilby, Barbara Bennett, Ian Bennett, Geoffrey Berry, Anneke Blackburn, Michael Bogwitz, Meagan Brennan, Melissa Brown, Michael Buckley, Matthew Burgess, Jo Burke, Phyllis Butow, Keith Byron, David Callen, Ian Campbell, Deepa Chauhan, Manisha Chauhan, Georgia Chenevix-Trench, Alice Christian, Christine Clarke, Paul Cohen, Alison Colley, Ashley Crook, James Cui, Bronwyn Culling, Margaret Cummings, Sarah-Jane Dawson, Anna deFazio, Martin Delatycki, Rebecca Dickson, Joanne Dixon, Alexander Dobrovic, Tracy Dudding, Ted Edkins, Stacey Edwards, Maurice Eisenbruch, Gelareh Farshid, Susan Fawcett, Andrew Fellows, Georgina Fenton, Michael Field, Frank Firgaira, James Flanagan, Jean Fleming, Peter Fong, John Forbes, Stephen Fox, Juliet French, Michael Friedlander, Clara Gaff, Mac Gardner, Mike Gattas, Peter George, Graham Giles, Grantley Gill, Jack Goldblatt, Sian Greening, Scott Grist, Eric Haan, Kate Hardie, Marion Harris, Stewart Hart, Nick Hayward, Sue Healey, Louise Heiniger, John Hopper, Evelyn Humphrey, Clare Hunt, Paul James, Mark Jenkins, Alison Jones, Rick Kefford, Alexa Kidd, Belinda Kiely, Judy Kirk, Jessica Koehler, James Kollias, Serguei Kovalenko, Sunil Lakhani, Amanda Leaming, Jennifer Leary, Jacqueline Lim, Geoff Lindeman, Lara Lipton, Liz Lobb, Graham Mann, Deborah Marsh, Sue Anne McLachlan, Bettina Meiser, Cliff Meldrum, Roger Milne, Gillian Mitchell, Beth Newman, Eveline Niedermayr, Sophie Nightingale, Shona O’Connell, Imelda O’Loughlin, Richard Osborne, Nick Pachter, Briony Patterson, Lester Peters, Kelly Phillips, Melanie Price, Lynne Purser, Tony Reeve, Jeanne Reeve, Robert Richards, Edwina Rickard, Bridget Robinson, Barney Rudzki, Mona Saleh, Elizabeth Salisbury, Joe Sambrook, Christobel Saunders, Jodi Saunus, Robyn Sayer, Elizabeth Scott, Rodney Scott, Clare Scott, Ram Seshadri, Adrienne Sexton, Raghwa Sharma, Andrew Shelling, Peter Simpson, Melissa Southey, Amanda Spurdle, Graeme Suthers, Pamela Sykes, Margaret Tassell, Donna Taylor, Jessica Taylor, Benjamin Thierry, Susan Thomas, Ella Thompson, Heather Thorne, Sharron Townshend, Alison Trainer, Lan Tran, Kathy Tucker, Janet Tyler, Jane Visvader, Logan Walker, Ian Walpole, Robin Ward, Paul Waring, Bev Warner, Graham Warren, Rachael Williams, Judy Wilson, Ingrid Winship, Kathy Wu, Mary Ann Young. ORIGO: We thank E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar. PBCS: Louise Brinton, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Jolanta Lisssowska, Pei Chao, Michael Stagner. POSH: The ethical approval for the POSH study is MREC /00/6/69, UKCRN ID: 1137. We thank staff in the Experimental Cancer Medicine Centre (ECMC) supported Faculty of Medicine Tissue Bank and the Faculty of Medicine DNA Banking resource. RBCS Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, Renée Foekens and Anita Trapman – Jansen.and the Erasmus MC Family Cancer Clinic. UKBGS: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. BCAC is funded by Cancer Research UK [C1287/A16563, C1287/A10118], the European Union’s Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European Community’s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The CNIO-BCS was supported by the Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923 and PI12/00070). The ESTHER study was supported by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. K.J.R. was supported by a training grant under the CTSA Grant Program Numbers UL1 TR000135 and KL2TR000136-09 from the National Center for Advancing Translational Sciences (NCATS) of the NIH. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official view of NIH. The ORIGO study was supported by the Dutch Cancer Society (RUL 1997-1505) and the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP16). The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The POSH study is funded by Cancer Research UK (grants C1275/A11699, C1275/C22524, C1275/A19187, C1275/A15956 and Breast Cancer Campaign 2010PR62, 2013PR044. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
AB - E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
UR - http://www.scopus.com/inward/record.url?scp=85045981399&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-23733-4
DO - 10.1038/s41598-018-23733-4
M3 - Article
C2 - 29700408
AN - SCOPUS:85045981399
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 6574
ER -