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 (<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.

Women's features and inter-/intra-rater agreement on mammographic density assessment in full-field digital mammograms (DDM-SPAIN).

Measurement of mammographic density (MD), one of the leading risk factors for breast cancer, still relies on subjective assessment. However, the consistency of MD measurement in full-digital mammograms has yet to be evaluated. We studied inter- and intra-rater agreement with respect to estimation of breast density in full-digital mammograms, and tested whether any of the women's characteristics might have some influence on them. After an initial training period, three experienced radiologists estimated MD using Boyd scale in a left breast cranio-caudal mammogram of 1,431 women, recruited at three Spanish screening centres. A subgroup of 50 randomly selected images was read twice to estimate short-term intra-rater agreement. In addition, a reading of 1,428 of the images, performed 2 years before by one rater, was used to estimate long-term intra-rater agreement. Pair-wise weighted kappas with 95% bootstrap confidence intervals were calculated. Dichotomous variables were defined to identify mammograms in which any rater disagreed with other raters or with his/her own assessment, respectively. The association between disagreement and women's characteristics was tested using multivariate mixed logistic models, including centre as a random-effects term, and taking into account repeated measures when required. All quadratic-weighted kappa values for inter- and intra-rater agreement were excellent (higher than 0.80). None of the studied women's features, i.e. body mass index, brassiere size, menopause, nulliparity, lactation or current hormonal therapy, was associated with higher risk of inter- or intra-rater disagreement. However, raters differed significantly more in images that were classified in the higher-density MD categories, and disagreement in intra-rater assessment was also lower in low-density mammograms. The reliability of MD assessment in full-field digital mammograms is comparable to that for original or digitised images. The reassuring lack of association between subjects' MD-related characteristics and agreement suggests that bias from this source is unlikely.

Evaluation of mammographic density patterns: reproducibility and concordance among scales.

BACKGROUND: Increased mammographic breast density is a moderate risk factor for breast cancer. Different scales have been proposed for classifying mammographic density. This study sought to assess intra-rater agreement for the most widely used scales (Wolfe, Tabár, BI-RADS and Boyd) and compare them in terms of classifying mammograms as high- or low-density. METHODS: The study covered 3572 mammograms drawn from women included in the DDM-Spain study, carried-out in seven Spanish Autonomous Regions. Each mammogram was read by an expert radiologist and classified using the Wolfe, Tabár, BI-RADS and Boyd scales. In addition, 375 mammograms randomly selected were read a second time to estimate intra-rater agreement for each scale using the kappa statistic. Owing to the ordinal nature of the scales, weighted kappa was computed. The entire set of mammograms (3572) was used to calculate agreement among the different scales in classifying high/low-density patterns, with the kappa statistic being computed on a pair-wise basis. High density was defined as follows: percentage of dense tissue greater than 50% for the Boyd, "heterogeneously dense and extremely dense" categories for the BI-RADS, categories P2 and DY for the Wolfe, and categories IV and V for the Tabár scales. RESULTS: There was good agreement between the first and second reading, with weighted kappa values of 0.84 for Wolfe, 0.71 for Tabár, 0.90 for BI-RADS, and 0.92 for Boyd scale. Furthermore, there was substantial agreement among the different scales in classifying high- versus low-density patterns. Agreement was almost perfect between the quantitative scales, Boyd and BI-RADS, and good for those based on the observed pattern, i.e., Tabár and Wolfe (kappa 0.81). Agreement was lower when comparing a pattern-based (Wolfe or Tabár) versus a quantitative-based (BI-RADS or Boyd) scale. Moreover, the Wolfe and Tabár scales classified more mammograms in the high-risk group, 46.61 and 37.32% respectively, while this percentage was lower for the quantitative scales (21.89% for BI-RADS and 21.86% for Boyd). CONCLUSIONS: Visual scales of mammographic density show a high reproducibility when appropriate training is provided. Their ability to distinguish between high and low risk render them useful for routine use by breast cancer screening programs. Quantitative-based scales are more specific than pattern-based scales in classifying populations in the high-risk group.

Impact of a mammography screening programme on the breast cancer population of the Region of Valencia (Spain).

OBJECTIVE: Randomised clinical trials with a control arm of non-screened patients are nowadays ethically impossible. The aim of this study was to establish the impact of mammography screening on a non-selected population. PATIENTS AND METHODS: Between January 1993 and December 2002, 3662 patients were included, 2313 in the screened group and 1349 in the unscreened group. RESULTS: 55.3% of the screened patients were diagnosed in stage I vs. 26.1% in the non-screened group. The proportion of stage III-IV was 4.6% and 19.8% for the screened and unscreened groups respectively (p<0.001). 48.8% in the screening group were submitted to mastectomy vs. 66.4% of the unscreened patients (p<0.001). Overall survival was superior for the prevalent cases in the screening group, with a relative risk of 0.49, and was not significant for the incident cases. CONCLUSIONS: Diagnosis of breast cancer in the mammography screening programme of the Region of Valencia significantly increases conservative surgery rates and suggests an improvement in survival in prevalent cases. The increased rate of early stages in these patients could be the main reason of this benefit.