Mammographic density and risk of breast cancer according to tumor characteristics and mode of detection: a Spanish population-based case-control study

Introduction: It is not clear whether high mammographic density (MD) is equally associated with all subtypes of breast cancer (BC). We investigated the association between MD and subsequent BC, considering invasiveness, means of detection, pathologic subtype, and the time elapsed since mammographic exploration and BC diagnosis. Methods: BC cases occurring in the population of women who attended screening from 1997 through 2004 in Navarre, a Spanish region with a fully consolidated screening program, were identified via record linkage with the Navarre Cancer Registry (n = 1,172). Information was extracted from the records of their first attendance at screening in that period. For each case, we randomly selected four controls, matched by screening round, year of birth, and place of residence. Cases were classified according to invasiveness (ductal carcinoma in situ (DCIS) versus invasive tumors), pathologic subtype (considering hormonal receptors and HER2), and type of diagnosis (screen-detected versus interval cases). MD was evaluated by a single, experienced radiologist by using a semiquantitative scale. Data on BC risk factors were obtained by the screening program in the corresponding round. The association between MD and tumor subtype was assessed by using conditional logistic regression. Results: MD was clearly associated with subsequent BC. The odds ratio (OR) for the highest MD category (MD >75%) compared with the reference category (MD <10%) was similar for DCIS (OR = 3.47; 95% CI = 1.46 to 8.27) and invasive tumors (OR = 2.95; 95% CI = 2.01 to 4.35). The excess risk was particularly high for interval cases (OR = 7.72; 95% CI = 4.02 to 14.81) in comparison with screened detected tumors (OR = 2.17; 95% CI = 1.40 to 3.36). Sensitivity analyses excluding interval cases diagnosed in the first year after MD assessment or immediately after an early recall to screening yielded similar results. No differences were seen regarding pathologic subtypes. The excess risk associated with MD persisted for at least 7 to 8 years after mammographic exploration. Conclusions: Our results confirm that MD is an important risk factor for all types of breast cancer. High breast density strongly increases the risk of developing an interval tumor, and this excess risk is not completely explained by a possible masking effect.