title: Mammographic density and breast cancer in women from high risk families.
abstract: BACKGROUND
  Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype.
  
  
  METHODS
  The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype.
  
  
  RESULTS
  We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes.
  
  
  CONCLUSIONS
  Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.
authors.affiliation: Medical Oncology Department, Hospital Santa Creu I Sant Pau, Barcelona, Spain. TRamon@santpau.cat.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón Y Cajal
authors.affiliation: Medical Oncology Department, Hospital Clinico Universitario de Valencia, Valencia, Spain. chirivella_isa@gva.es.
authors.forename: Isabel
authors.initials: I
authors.lastname: Chirivella
authors.affiliation: Foundation General Directorate Public Health and Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO - Public Health, Valencia, Spain. miranda_mjo@gva.es.
authors.forename: Josefa
authors.initials: J
authors.lastname: Miranda
authors.affiliation: Hereditary Cancer Program, Catalan Institue of Oncology-IDIBELL, Barcelona, Spain. ateule@iconcologia.net.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Teule
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology-IDIBGI, Girona, Spain. aizquierdo@iconcologia.net.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Izquierdo
authors.affiliation: Medical Oncology Deartment, Hospital Vall Hebron/Vall Hebron Institute of Oncology, Barcelona, Spain. jbalmana@vhio.net.
authors.forename: Judith
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authors.lastname: Balmaña
authors.affiliation: Medical Oncology Department, Hospital Universitario de Elche, Elche, Spain. sanchez_ana@gva.es.
authors.forename: Ana Beatriz
authors.initials: AB
authors.lastname: Sánchez-Heras
authors.affiliation: Genetic Counseling Unit, Corporació Sanitaria Parc tauli, Consorci Sanitari de Terrassa, Terrasa, Spain. gemllort@yahoo.es.
authors.forename: Gemma
authors.initials: G
authors.lastname: Llort
authors.affiliation: Medical Oncology Department, Hospital Santa Creu I Sant Pau, Barcelona, Spain. DFisas@santpau.cat.
authors.forename: David
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authors.lastname: Fisas
authors.affiliation: National Center for Epidemiology, Carlos III Institute of Health, Monforte de Lemos 5, 28029, Madrid, Spain. vicarvajal@isciii.es.|Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Carlos III Institute of Health, Madrid, Spain. vicarvajal@isciii.es.|Consortium Cancer Epidemiology Research Group, Oncology and Hematology Area, IIS Puerta de Hierro (IDIPHIM), Madrid, Spain. vicarvajal@isciii.es.
authors.forename: Virginia
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authors.lastname: Lope
authors.affiliation: Breast Cancer Unit, Clinical Research Programme, Spanish National Cancer Center (CNIO), Madrid, Spain. e_h_agudo@yahoo.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Hernández-Agudo
authors.affiliation: Medical Oncology Department, Foundation of the Valencian Oncologic Institute, Valencia, Spain. mjuanfi81@hotmail.com.
authors.forename: María José
authors.initials: MJ
authors.lastname: Juan-Fita
authors.affiliation: Medical Oncology Department, Hospital Provincial de Castellón, Castellón, Spain. tenagarcia.isabel@gmail.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tena
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. lrobles.hdoc@salud.madrid.org.
authors.forename: Luis
authors.initials: L
authors.lastname: Robles
authors.affiliation: Medical Oncology Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. carmenguillenponce@gmail.com.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guillén-Ponce
authors.affiliation: Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain. perezsegura09@gmail.com.
authors.forename: Pedro
authors.initials: P
authors.lastname: Pérez-Segura
authors.affiliation: Gynecological Department, Hospital Gregorio Marañón, Madrid, Spain. mluquem.hgugm@salud.madrid.org.
authors.forename: Mari Sol
authors.initials: MS
authors.lastname: Luque-Molina
authors.affiliation: Medical Department, Hospital Fundación Alcorcón, Alcorcón, Spain. shernando@fhalcorcon.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernando-Polo
authors.affiliation: Hereditary Cancer Program, Catalan Institue of Oncology-IDIBELL, Barcelona, Spain. msalinas@iconcologia.net.
authors.forename: Mónica
authors.initials: M
authors.lastname: Salinas
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology-IDIBGI, Girona, Spain. Jbrunet@iconcologia.net.|Medical Sciences Department, School of Medicine, University of Girona, Girona, Spain. Jbrunet@iconcologia.net.
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.affiliation: Foundation General Directorate Public Health and Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO - Public Health, Valencia, Spain. salas_dol@gva.es.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Salas-Trejo
authors.affiliation: Medical Oncology Department, Hospital Santa Creu I Sant Pau, Barcelona, Spain. ABarnadasM@santpau.cat.
authors.forename: Agustí
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authors.lastname: Barnadas
authors.affiliation: National Center for Epidemiology, Carlos III Institute of Health, Monforte de Lemos 5, 28029, Madrid, Spain. mpollan@isciii.es.|Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Carlos III Institute of Health, Madrid, Spain. mpollan@isciii.es.|Consortium Cancer Epidemiology Research Group, Oncology and Hematology Area, IIS Puerta de Hierro (IDIPHIM), Madrid, Spain. mpollan@isciii.es.
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mesh_terms: D000328:Adult; D000071060:Breast Density; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D005190:Family; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D042361:Mammary Glands, Human / Q000002:abnormalities*; D008327:Mammography; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D012307:Risk Factors