Mammographic density and breast cancer in women from high risk families
INTRODUCTION: 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 (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. ; This work was supported by three research grants, PS09/01006, PS09/01024 and PS09/01721, from Spain's Health Research Fund (Fondo de Investigación Sanitaria); and a grant from the Spanish Federation of Breast Cancer Patients (Federación Española de Cáncer de Mama) (FECMA 485 EPY 1170–10). The authors also acknowledge the contribution of the Asociación Española contra el Cáncer (AECC), Carlos III Health Institute; RTICC; and the Catalan Health Institute and Autonomous Government of Catalonia (grant numbers: RD06/0020/1051, RD06/0020/1050, RD12/0036/0008, RD12/0036/0031, PI10/01422, PI13/00285, PIE13/00022 and SGR290). This project was approved by the following ethical boards: Comité de Ética de la Investigación y de Bienestar Animal CEIyBA, Instituto de Salud Carlos III; Comité de Ética de la Investigación Clínica Hospital de la Santa Creu y Sant Pau, Barcelona; Comité de Ética de la Investigación Clínica Hospital Universitari de Girona Doctor Josep Trueta, Girona; Comité de Ética de la Fundación INCLIVA, Hospital Clínico Universitario, Valencia; Comité de Ética de la Investigación Clínica del Hospital Universitario 12 de Octubre, Madrid, and Comité de Ética de la Investigación Clínica del Hospital Ramón y Cajal, Madrid. ; Sí