Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages <55 years. To provide insight into these associations, we examined the components of PMD [dense area (DA) and nondense area (NDA)] with breast cancer subtypes.

Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression.

Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend <0.001] and NDA was associated with decreased risk [ORs for quartiles: 1.39, 1.00 (Ref), 0.88, 0.72; Ptrend <0.001] across all ages and invasive tumor characteristics. There were significant trends in the magnitude of associations of both DA and NDA with breast cancer by increasing tumor size (Ptrend < 0.001) but no differences by nodal status. Among women <55 years, DA was more strongly associated with increased risk of ER+ versus ER tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER versus ER+ tumors (Phet = 0.03).

Conclusions: DA and NDA have differential associations with ER+ versus ER tumors that vary by age.

Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

This article is featured in Highlights of This Issue, p. 767

Mammographic density (MD) represents the variability of breast tissue composition on the mammogram image. Radiographically, there are two main components of breast tissue: fat, which appears dark on a mammogram and is considered “nondense,” and fibroglandular tissue (i.e., epithelial cells and connective tissue), which appears white and is defined as “dense” tissue (1). Women in the highest quartile of percent mammographic density (PMD; i.e., proportion of dense fibroglandular tissue within the total area of the breast) have about 4 times the risk of developing breast cancer compared with women in the lowest quartile, even after adjusting for other known breast cancer risk factors (2). The biologic mechanism by which MD increases breast cancer risk, however, remains largely unknown.

We reported PMD to be a breast cancer risk factor across tumor characteristics and age groups (3). We noted stronger associations for tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women. Recent evidence from a large meta-analysis suggests that dense and nondense area may be independently associated with breast cancer risk (4–7). Few previous studies have evaluated the possible differential associations of dense and nondense breast area by breast cancer subtype or tumor characteristics. Therefore, we investigated the underlying associations of dense (fibroglandular) or nondense (adipose) area, or both, with tumor characteristics. Understanding these differential associations could provide insight into the mechanism by which percent density influences risk.

Study populations

Participating studies included the Mayo Mammography Health Study (MMHS; refs. 8, 9), Mayo Clinic Breast Cancer Study (MCBCS; refs. 10, 11), Nurses' Health Study (NHS), and NHSII (12–14), Mayo Clinic Mammography Study (MCMAM; ref. 15), and the San Francisco Bay Area Breast Cancer SPORE and San Francisco Mammography Registry (SFMR; refs. 16–18; Table 1). Details of the study populations are in Supplementary Table S1 and described in our earlier report (3); the current analysis includes additional cases and controls, primarily from the SFMR, which were not available at the time of our earlier analysis. Incident breast cancer cases were identified by self-report, linkage to clinic and/or statewide tumor registries, or death certificates with further confirmation by medical record review. Controls were selected from the underlying cohorts (MMHS, NHS, NHSII, SFMR) or from the source population (MCBCS, MCMAM) and typically matched to cases on age, menopausal status, and year of examination (MMHS, MCMAM, SFMR), blood draw (NHS, NHSII), or diagnosis (MCBCS) as described previously (3). From all studies, we excluded breast cancer cases diagnosed within 6 months of mammography and their matched controls, to minimize prevalent cancers at time of mammography. Covariate information was obtained from medical record review (MCMAM), self-administered questionnaires (NHS, NHSII), or both (MMHS, MCBCS) before (NHS, NHSII) or at the time of (MCBCS, MMHS, MCMAM, SFMR) mammography. In total, these analyses included 4,095 breast cancer cases and 8,558 controls.

Table 1.

Baseline characteristics of study population by age

Age < 55Age ≥ 55
CasesControlsCasesControls
N 1,884 4,072 2,211 4,486 
Standardized % PMD, median (IQR) 40.7 (30.2) 32 (30.8) 25 (26.1) 19 (23.2) 
Standardized dense area, cm2, median (IQR) 51.9 (44.4) 42.2 (41.8) 41.1 (43.0) 31.6 (37.3) 
Standardized nondense area, cm2, median (IQR) 79.6 (92.4) 98 (100.7) 130.7 (123.7) 138.6 (119.9) 
Mean age at mammogram (SD) 47.2 (4.6) 47.3 (4.5) 64.9 (7.4) 65.1 (7.4) 
Mean age at diagnosis (SD) 51.6 (5.5) — 69 (7.6) — 
Mean BMI (SD) 24.2 (6.5) 25.2 (6) 25.6 (7.8) 25.9 (5.5) 
Body mass index categories, kg/m2 
 <25 1,072 (56.9%) 2,352 (57.8%) 909 (41.1%) 2,213 (49.3%) 
 25–29 507 (26.9%) 1,007 (24.7%) 701 (31.7%) 1,422 (31.7%) 
 30–34 157 (8.3%) 399 (9.8%) 319 (14.4%) 553 (12.3%) 
 35+ 85 (4.5%) 275 (6.8%) 177 (8.0%) 275 (6.1%) 
 Unknown 63 (3.3%) 39 (1.0%) 105 (4.7%) 23 (0.5%) 
Menopausal status 
 Premenopausal 1,159 (61.5%) 2,629 (64.6%) 16 (0.7%) 44 (1.0%) 
 Postmenopausal 556 (29.5%) 1,220 (30.0%) 2,191 (99.1%) 4,434 (98.8%) 
 Unknown 169 (9.0%) 223 (5.5%) 4 (0.2%) 8 (0.2%) 
Parity 
 Nulliparous 419 (22.2%) 901 (22.1%) 330 (14.9%) 624 (13.9%) 
 Parous 1,315 (69.8%) 3,046 (74.8%) 1,675 (75.8%) 3,526 (78.6%) 
 Unknown 150 (8.0%) 125 (3.1%) 206 (9.3%) 336 (7.5%) 
Postmenopausal hormone therapya 
 Not current user 193 (41.1%) 498 (45.8%) 923 (51.6%) 2,403 (61.9%) 
 Current, estrogen 90 (19.1%) 256 (23.5%) 272 (15.2%) 561 (14.5%) 
 Current, estrogen + progestin 155 (33.0%) 290 (26.7%) 373 (20.9%) 574 (14.8%) 
 Unknown 32 (6.8%) 44 (4.0%) 220 (12.3%) 343 (8.8%) 
Family history 
 No 1,467 (77.9%) 3,588 (88.1%) 1,644 (74.4%) 3,745 (83.5%) 
 Yes 315 (16.7%) 466 (11.4%) 463 (20.9%) 706 (15.7%) 
 Unknown 102 (5.4%) 18 (0.4%) 104 (4.7%) 35 (0.8%) 
Age < 55Age ≥ 55
CasesControlsCasesControls
N 1,884 4,072 2,211 4,486 
Standardized % PMD, median (IQR) 40.7 (30.2) 32 (30.8) 25 (26.1) 19 (23.2) 
Standardized dense area, cm2, median (IQR) 51.9 (44.4) 42.2 (41.8) 41.1 (43.0) 31.6 (37.3) 
Standardized nondense area, cm2, median (IQR) 79.6 (92.4) 98 (100.7) 130.7 (123.7) 138.6 (119.9) 
Mean age at mammogram (SD) 47.2 (4.6) 47.3 (4.5) 64.9 (7.4) 65.1 (7.4) 
Mean age at diagnosis (SD) 51.6 (5.5) — 69 (7.6) — 
Mean BMI (SD) 24.2 (6.5) 25.2 (6) 25.6 (7.8) 25.9 (5.5) 
Body mass index categories, kg/m2 
 <25 1,072 (56.9%) 2,352 (57.8%) 909 (41.1%) 2,213 (49.3%) 
 25–29 507 (26.9%) 1,007 (24.7%) 701 (31.7%) 1,422 (31.7%) 
 30–34 157 (8.3%) 399 (9.8%) 319 (14.4%) 553 (12.3%) 
 35+ 85 (4.5%) 275 (6.8%) 177 (8.0%) 275 (6.1%) 
 Unknown 63 (3.3%) 39 (1.0%) 105 (4.7%) 23 (0.5%) 
Menopausal status 
 Premenopausal 1,159 (61.5%) 2,629 (64.6%) 16 (0.7%) 44 (1.0%) 
 Postmenopausal 556 (29.5%) 1,220 (30.0%) 2,191 (99.1%) 4,434 (98.8%) 
 Unknown 169 (9.0%) 223 (5.5%) 4 (0.2%) 8 (0.2%) 
Parity 
 Nulliparous 419 (22.2%) 901 (22.1%) 330 (14.9%) 624 (13.9%) 
 Parous 1,315 (69.8%) 3,046 (74.8%) 1,675 (75.8%) 3,526 (78.6%) 
 Unknown 150 (8.0%) 125 (3.1%) 206 (9.3%) 336 (7.5%) 
Postmenopausal hormone therapya 
 Not current user 193 (41.1%) 498 (45.8%) 923 (51.6%) 2,403 (61.9%) 
 Current, estrogen 90 (19.1%) 256 (23.5%) 272 (15.2%) 561 (14.5%) 
 Current, estrogen + progestin 155 (33.0%) 290 (26.7%) 373 (20.9%) 574 (14.8%) 
 Unknown 32 (6.8%) 44 (4.0%) 220 (12.3%) 343 (8.8%) 
Family history 
 No 1,467 (77.9%) 3,588 (88.1%) 1,644 (74.4%) 3,745 (83.5%) 
 Yes 315 (16.7%) 466 (11.4%) 463 (20.9%) 706 (15.7%) 
 Unknown 102 (5.4%) 18 (0.4%) 104 (4.7%) 35 (0.8%) 

aAmong postmenopausal women in MMHS, NHS, NHSII, and UCSF.

This study was approved by the Institutional Review Boards at Mayo Clinic (Rochester, MN), Brigham and Women's Hospital (Boston, MA), the University of California, San Francisco (UCSF, San Francisco, CA), and the Connecticut Department of Public Health Human Investigations Committee. Informed consent was obtained or implied by return of questionnaires (NHS, NHSII).

Assessment of mammographic density

As described previously (3), dense area (DA) and nondense area (NDA), were measured using two computer-assisted threshold techniques [Cumulus (19) and UCSF custom mammographic density software (20)] from digitized images of prediagnostic film screening mammograms of the craniocaudal view. PMD was calculated as the proportion of absolute DA over total breast area (DA + NDA). With the exception of NHS and NHSII, for which average DA and NDA of both breasts was used, DA and NDA were estimated from the contralateral breast for cases and corresponding side for matched controls.

We standardized PMD, DA, and NDA measurements made within each study to remove variability in measurements due to reader (1, 21), time of density assessment, and age distributions of different study populations for pooled analyses (Supplementary Fig. S1). We have previously described and applied this method to PMD using a logit transformation (3). For absolute dense and nondense areas, an appropriate transformation was selected via the Box–Cox procedure. For DA, the square root transformation was selected while the 4th root was selected for nondense area. Briefly, the following procedure was implemented on each measure after appropriate transformation. First, we focused on women without breast cancer and estimated study-specific linear age trends in the medians of transformed mammographic density (TMD) values using quantile regression. Study-specific age trends were removed by computing the difference between each individual's observed TMD and the age-predicted median TMD from the corresponding study set. Variability was standardized across studies by dividing the residuals within each study by the corresponding interquartile range (IQR), and then multiplying these rescaled residual values by the IQR of the original residuals from all studies. This ensured that the variability in standardized TMD was consistent across studies, and roughly equivalent to the observed variability in TMD. Finally, we estimated an overall age by TMD trend from the original data, and added the age-predicted median TMD to the rescaled residuals from each individual. This reincorporated the known age trend in MD into the standardized TMD measurements (Supplementary Fig. S2). These TMD values were back-transformed to the original scale for use in analyses. Of note, variability in the tails of the smoother and limited data under age 40 (n = 68 controls), resulted in an apparent difference in the distribution for DA for the NHS2 study (Supplementary Fig. S2).

Assessment of tumor characteristics among cases

Information on tumor type, histology, grade, nodal involvement, tumor size, and ER, PR, and HER2 status was obtained from state-wide Surveillance Epidemiology and End Results programs (SFMR), pathology reports (NHS, NHSII), state and clinic cancer registries (MMHS, MCMAM, MCBCS), and medical records (MMHS, MCMAM, MCBCS). For 313 cases in NHS, 52 cases in NHS II, and 194 cases in MCMAM with missing receptor data on pathology reports, receptor status was obtained from immunohistochemical staining performed on paraffin sections of the tumor TMA according to a standard protocol (22). A proportion of cases (18%; N = 624 cases ranging from 8% to 34% across studies) were still missing HER2 status after incorporating the TMA data and were excluded from HER2 analyses. Another 2% were cases with borderline HER2 results (2+ without available FISH) and not used in analyses.

Statistical analyses

We categorized the standardized DA and NDA measurements into quartiles based on the control distribution across studies. We fit polytomous (multinomial) logistic regression models to estimate OR and 95% confidence intervals (CI) for the associations of DA and NDA with risk of breast cancer overall as well as with breast cancer defined by tumor type (invasive or DCIS), histologic type (ductal or lobular), grade (well-differentiated, moderately differentiated, or poorly differentiated), tumor size (<1.1 cm, 1.1–2.0 cm, or 2.1+ cm), involvement of lymph nodes (positive or negative), and receptor status (ER+ or ER; PR+ or PR; HER2+ or HER2). We also updated our prior analyses of PMD (3) with this larger sample size for comparison purposes; PMD categories were 0%–10%, 11%–25% (reference), 26%–50%, and 51%+.

We pooled data across the six studies and adjusted for study site, age (continuous), and body mass index (BMI, continuous) in multivariable models. We further considered potential confounding by parity (nulliparous, parous, or unknown) and first-degree family history of breast cancer (yes, no, or unknown) by evaluating the magnitude of change in ORs observed after including each potential confounder individually in the model. Postmenopausal hormone therapy (current estrogen alone, current estrogen plus progesterone, never/former, or unknown) was also evaluated as a confounder among postmenopausal women in the subset of studies for which this information was available (MMHS, NHS, NHSII, and SFMR). Addition of these variables to the models did not substantially change risk estimates and were not included in final models. In secondary analyses, we considered models that mutually adjusted for continuous measures of square root DA and NDA.

Because our previous findings suggested differences of PMD and tumor characteristics primarily for younger women, we stratified by ages <55 years versus ≥55 years only. We evaluated whether the associations between DA or NDA and breast cancer differed by specific tumor characteristics, both overall and within age groups, using polytomous logistic regression models (Phet). For subtypes with a natural ordering, including tumor size and grade, tests of trend (Ptrend) across categories were used to assess significance. Formal tests of interaction (Page-interaction) assessed the significance of differential DA and NDA associations with each of the breast cancer characteristics and subtype by age groups.

Before pooling data across the six studies, study-specific estimates were obtained by fitting separate models for each study and assessing individual associations between MD and each tumor subtype. We assessed the statistical significance of differences in associations by study site by testing for interactions between study group and DA or NDA category in the pooled analysis and, in general, found no evidence of differences across study (P >0.09) other than as noted in results below.

Analyses were performed using SAS software (version 9.3, SAS Institute). All statistical tests were two-sided and P values <0.05 were considered statistically significant.

Overall, mean age at mammogram was 57 years among both cases and controls. Median time to diagnosis at mammogram was 4.1 years (IQR: 2.3–6.0) for cases. DA and NDA were not strongly correlated in the combined study population (r = 0.07 based on continuous measure) or across individual study populations [correlations ranged from 0.06 (NHS) to 0.29 (NHS2)]. Among both cases and controls, median PMD and DA was lower while NDA was higher in women ages ≥55 years than women <55 years. Furthermore, within each age group, median PMD and DA was higher among cases versus controls. Median NDA was lower among cases versus controls in both age groups (Table 1). DCIS was more common among women ages <55 years (15.8%) versus women ≥55 years (11.7%), while, among invasive cancers, more aggressive tumor characteristics were evident in women <55 years at mammography compared with women ≥55 years (Table 2).

Table 2.

Distribution (%) of breast cancer cases from six studies by age and tumor characteristics

Age < 55Age ≥ 55
N (%)N (%)
Controls 4,072 (68.4) 4,486 (67.0) 
Cases 1,884 (31.6) 2,211 (33.0) 
 Invasive 1,579 (83.8) 1,944 (87.9) 
In situ 297 (15.8) 259 (11.7) 
 Unknown 8 (0.4) 8 (0.4) 
Tumor characteristics 
Histology 
 Ductal 1,277 (80.9) 1,437 (73.9) 
 Lobular 156 (9.9) 265 (13.6) 
 Mixed 88 (5.6) 133 (6.8) 
 Unknown/other 58 (3.7) 109 (5.6) 
Histologic grade 
 Well differentiated 393 (24.9) 622 (32.0) 
 Moderately differentiated 605 (38.3) 739 (38.0) 
 Poorly differentiated 447 (28.3) 373 (19.2) 
 Unknown 134 (8.5) 210 (10.8) 
Tumor size 
 0.1–1.0 cm 488 (30.9) 701 (36.1) 
 1.1–2.0 cm 633 (40.1) 744 (38.3) 
 2.1+ cm 409 (25.9) 435 (22.4) 
 Unknown 49 (3.1) 64 (3.3) 
Involvement of lymph nodes 
 Negative 1,054 (66.8) 1,323 (68.1) 
 Positive 445 (28.2) 422 (21.7) 
 Unknown 80 (5.1) 199 (10.2) 
ER status 
 Negative 289 (18.3) 279 (14.4) 
 Positive 1,236 (78.3) 1,581 (81.3) 
 Borderline/unknown 54 (3.4) 84 (4.3) 
PR status 
 Negative 407 (25.8) 476 (24.5) 
 Positive 1,114 (70.6) 1,383 (71.1) 
 Borderline/unknown 58 (3.7) 85 (4.4) 
HER2 status 
 Negative 1,092 (69.2) 1,268 (65.2) 
 Positive 231 (14.6) 223 (11.5) 
 Borderline/unknown 256 (16.2) 453 (23.3) 
Age < 55Age ≥ 55
N (%)N (%)
Controls 4,072 (68.4) 4,486 (67.0) 
Cases 1,884 (31.6) 2,211 (33.0) 
 Invasive 1,579 (83.8) 1,944 (87.9) 
In situ 297 (15.8) 259 (11.7) 
 Unknown 8 (0.4) 8 (0.4) 
Tumor characteristics 
Histology 
 Ductal 1,277 (80.9) 1,437 (73.9) 
 Lobular 156 (9.9) 265 (13.6) 
 Mixed 88 (5.6) 133 (6.8) 
 Unknown/other 58 (3.7) 109 (5.6) 
Histologic grade 
 Well differentiated 393 (24.9) 622 (32.0) 
 Moderately differentiated 605 (38.3) 739 (38.0) 
 Poorly differentiated 447 (28.3) 373 (19.2) 
 Unknown 134 (8.5) 210 (10.8) 
Tumor size 
 0.1–1.0 cm 488 (30.9) 701 (36.1) 
 1.1–2.0 cm 633 (40.1) 744 (38.3) 
 2.1+ cm 409 (25.9) 435 (22.4) 
 Unknown 49 (3.1) 64 (3.3) 
Involvement of lymph nodes 
 Negative 1,054 (66.8) 1,323 (68.1) 
 Positive 445 (28.2) 422 (21.7) 
 Unknown 80 (5.1) 199 (10.2) 
ER status 
 Negative 289 (18.3) 279 (14.4) 
 Positive 1,236 (78.3) 1,581 (81.3) 
 Borderline/unknown 54 (3.4) 84 (4.3) 
PR status 
 Negative 407 (25.8) 476 (24.5) 
 Positive 1,114 (70.6) 1,383 (71.1) 
 Borderline/unknown 58 (3.7) 85 (4.4) 
HER2 status 
 Negative 1,092 (69.2) 1,268 (65.2) 
 Positive 231 (14.6) 223 (11.5) 
 Borderline/unknown 256 (16.2) 453 (23.3) 

In general, results of our updated analyses for PMD were consistent with our previous report which included a large subset of these data (3) and are presented in Tables 3 and 4. However, our earlier report stratified age into three categories, instead of two as shown here (Table 4). Consistent with our earlier analyses, we found significant positive associations between PMD and breast cancer risk. Briefly, with the addition of new cases (mostly invasive) and controls, we found similar or stronger associations than what we previously reported. In the updated analyses, we continue to observe stronger associations with increasing tumor size, positive nodal status, and lobular (vs. ductal) cancer; Phet < 0.02) across age groups (Table 3). Among women <55 years, there were stronger associations with node-positive versus node-negative tumors (Table 4). Of note, the associations of PMD with ER-negative versus ER-positive tumors are not statistically significantly different across the two age groups examined here, <55 vs. 55+ (Page-interaction = 0.12). However, when we analyzed by the original three age groups, the age-interaction remains (Page-interaction = 0.048) suggesting it is partially driven by differential associations across the older age groups (data not shown). Below, we focus on results for DA and NDA.

Table 3.

Associations of categoriesa of percent density, DA, and NDA with breast cancer overall and by morphologic subtypes

Percent densityDANDA
Cases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)b
Overall breast cancer 
  Category 1 517 1,784 0.63 (0.56–0.72) 618 2,139 0.65 (0.58–0.74) 1280 2,139 1.39 (1.25–1.55) 
  Category 2 (ref) 1,015 2,597 1.00 (ref) 910 2,140 1.00 (ref) 983 2,140 1.00 (ref) 
  Category 3 1,626 2,890 1.62 (1.47–1.79) 1134 2,139 1.22 (1.10–1.37) 943 2,139 0.88 (0.78–0.98) 
  Category 4 937 1,287 2.34 (2.07–2.65) 1433 2,140 1.55 (1.40–1.73) 889 2,140 0.72 (0.63–0.81) 
Invasiveness 
In situ 
  Category 1 51 1,784 0.51 (0.37–0.72) 73 2,139 0.56 (0.42–0.75) 184 2,139 1.19 (0.94–1.51) 
  Category 2 (ref) 140 2,597 1.00 (ref) 135 2,140 1.00 (ref) 143 2,140 1.00 (ref) 
  Category 3 242 2,890 1.58 (1.26–1.98) 167 2,139 1.18 (0.93–1.50) 124 2,139 0.85 (0.66–1.10) 
  Category 4 123 1,287 1.88 (1.42–2.49) 181 2,140 1.29 (1.02–1.63) 105 2,140 0.75 (0.56–1.00) 
 Invasive 
  Category 1 461 1,784 0.64 (0.56–0.73) 542 2,139 0.67 (0.59–0.76) 1089 2,139 1.42 (1.27–1.60) 
  Category 2 (ref) 875 2,597 1.00 (ref) 770 2,140 1.00 (ref) 836 2,140 1.00 (ref) 
  Category 3 1,377 2,890 1.62 (1.45–1.80) 961 2,139 1.23 (1.10–1.38) 818 2,139 0.89 (0.79–1.00) 
  Category 4 810 1,287 2.40 (2.11–2.74) 1250 2,140 1.61 (1.44–1.80) 780 2,140 0.71 (0.62–0.81) 
   Phet   0.18   0.25   0.40 
Histologyc 
 Ductal 
  Category 1 356 1,784 0.67 (0.57–0.77) 433 2,139 0.72 (0.63–0.83) 838 2,139 1.38 (1.22–1.56) 
  Category 2 (ref) 665 2,597 1.00 (ref) 581 2,140 1.00 (ref) 650 2,140 1.00 (ref) 
  Category 3 1073 2,890 1.62 (1.44–1.82) 749 2,139 1.27 (1.12–1.44) 635 2,139 0.90 (0.79–1.03) 
  Category 4 620 1,287 2.32 (2.01–2.67) 951 2,140 1.61 (1.42–1.82) 591 2,140 0.71 (0.61–0.82) 
 Lobular 
  Category 1 49 1,784 0.51 (0.36–0.72) 51 2,139 0.49 (0.35–0.70) 135 2,139 1.59 (1.21–2.10) 
  Category 2 (ref) 114 2,597 1.00 (ref) 96 2,140 1.00 (ref) 98 2,140 1.00 (ref) 
  Category 3 148 2,890 1.44 (1.11–1.87) 107 2,139 1.13 (0.85–1.50) 95 2,139 0.82 (0.61–1.11) 
  Category 4 110 1,287 3.00 (2.23–4.04) 167 2,140 1.83 (1.41–2.37) 93 2,140 0.65 (0.47–0.89) 
   Phet   0.02   0.03   0.50 
Histologic grade 
 Well differentiated 
  Category 1 139 1,784 0.62 (0.50–0.77) 157 2,139 0.70 (0.56–0.87) 284 2,139 1.25 (1.03–1.51) 
  Category 2 (ref) 274 2,597 1.00 (ref) 215 2,140 1.00 (ref) 247 2,140 1.00 (ref) 
  Category 3 379 2,890 1.44 (1.22–1.71) 283 2,139 1.35 (1.11–1.63) 246 2,139 0.91 (0.75–1.10) 
  Category 4 223 1,287 2.23 (1.81–2.74) 360 2,140 1.75 (1.45–2.10) 238 2,140 0.77 (0.62–0.95) 
 Moderately differentiated 
  Category 1 177 1,784 0.65 (0.53–0.79) 202 2,139 0.69 (0.57–0.84) 398 2,139 1.37 (1.16–1.62) 
  Category 2 (ref) 327 2,597 1.00 (ref) 280 2,140 1.00 (ref) 313 2,140 1.00 (ref) 
  Category 3 523 2,890 1.64 (1.40–1.91) 353 2,139 1.25 (1.05–1.48) 329 2,139 0.96 (0.81–1.14) 
  Category 4 317 1,287 2.53 (2.10–3.04) 509 2,140 1.81 (1.54–2.13) 304 2,140 0.74 (0.61–0.90) 
 Poorly differentiated 
  Category 1 99 1,784 0.65 (0.50–0.84) 120 2,139 0.62 (0.48–0.79) 279 2,139 1.55 (1.27–1.90) 
  Category 2 (ref) 184 2,597 1.00 (ref) 188 2,140 1.00 (ref) 195 2,140 1.00 (ref) 
  Category 3 335 2,890 1.79 (1.47–2.17) 221 2,139 1.12 (0.91–1.38) 170 2,139 0.80 (0.64–0.99) 
  Category 4 202 1,287 2.62 (2.08–3.30) 291 2,140 1.45 (1.19–1.77) 176 2,140 0.65 (0.51–0.83) 
   Phet   0.68   0.77   0.76 
Tumor size 
 <1.1 cm 
  Category 1 219 1,784 0.90 (0.75–1.09) 244 2,139 0.90 (0.74–1.08) 319 2,139 1.19 (0.99–1.42) 
  Category 2 (ref) 318 2,597 1.00 (ref) 262 2,140 1.00 (ref) 282 2,140 1.00 (ref) 
  Category 3 429 2,890 1.33 (1.13–1.56) 314 2,139 1.19 (1.00–1.42) 280 2,139 0.94 (0.78–1.12) 
  Category 4 223 1,287 1.70 (1.39–2.07) 369 2,140 1.42 (1.20–1.69) 308 2,140 0.93 (0.77–1.14) 
 1.1–2.0 cm 
  Category 1 149 1,784 0.52 (0.43–0.64) 188 2,139 0.57 (0.47–0.69) 463 2,139 1.62 (1.37–1.90) 
  Category 2 (ref) 349 2,597 1.00 (ref) 320 2,140 1.00 (ref) 311 2,140 1.00 (ref) 
  Category 3 547 2,890 1.60 (1.37–1.86) 388 2,139 1.20 (1.02–1.41) 328 2,139 0.96 (0.81–1.14) 
  Category 4 332 1,287 2.45 (2.05–2.93) 481 2,140 1.50 (1.29–1.76) 275 2,140 0.68 (0.56–0.82) 
 2.1+ cm 
  Category 1 74 1,784 0.42 (0.32–0.56) 91 2,139 0.51 (0.39–0.66) 273 2,139 1.47 (1.21–1.79) 
  Category 2 (ref) 189 2,597 1.00 (ref) 165 2,140 1.00 (ref) 214 2,140 1.00 (ref) 
  Category 3 349 2,890 2.02 (1.67–2.45) 224 2,139 1.32 (1.07–1.64) 186 2,139 0.74 (0.60–0.92) 
  Category 4 232 1,287 3.60 (2.88–4.51) 364 2,140 2.13 (1.75–2.60) 171 2,140 0.49 (0.39–0.63) 
   Phet   <0.001   <0.001   <0.001 
Involvement of lymph nodes 
 Negative 
  Category 1 314 1,784 0.64 (0.55–0.75) 370 2,139 0.68 (0.59–0.79) 722 2,139 1.37 (1.20–1.57) 
  Category 2 (ref) 609 2,597 1.00 (ref) 520 2,140 1.00 (ref) 565 2,140 1.00 (ref) 
  Category 3 908 2,890 1.50 (1.33–1.69) 658 2,139 1.24 (1.08–1.41) 568 2,139 0.93 (0.81–1.07) 
  Category 4 546 1,287 2.25 (1.95–2.61) 829 2,140 1.58 (1.39–1.79) 522 2,140 0.73 (0.63–0.85) 
 Positive 
  Category 1 89 1,784 0.56 (0.43–0.74) 117 2,139 0.61 (0.48–0.78) 300 2,139 1.61 (1.32–1.96) 
  Category 2 (ref) 189 2,597 1.00 (ref) 186 2,140 1.00 (ref) 202 2,140 1.00 (ref) 
  Category 3 369 2,890 1.96 (1.62–2.37) 230 2,139 1.18 (0.96–1.45) 191 2,139 0.86 (0.70–1.07) 
  Category 4 220 1,287 2.89 (2.31–3.61) 334 2,140 1.70 (1.40–2.07) 174 2,140 0.63 (0.49–0.80) 
   Phet   0.01   0.39   0.11 
ER status 
 Negative 
  Category 1 69 1,784 0.70 (0.51–0.95) 88 2,139 0.57 (0.43–0.75) 209 2,139 1.66 (1.31–2.10) 
  Category 2 (ref) 126 2,597 1.00 (ref) 151 2,140 1.00 (ref) 136 2,140 1.00 (ref) 
  Category 3 236 2,890 1.81 (1.43–2.27) 153 2,139 0.96 (0.76–1.21) 113 2,139 0.76 (0.59–0.99) 
  Category 4 137 1,287 2.49 (1.89–3.26) 176 2,140 1.11 (0.88–1.40) 110 2,140 0.61 (0.45–0.81) 
 Positive 
  Category 1 373 1,784 0.63 (0.54–0.72) 431 2,139 0.69 (0.60–0.79) 837 2,139 1.38 (1.22–1.56) 
  Category 2 (ref) 716 2,597 1.00 (ref) 589 2,140 1.00 (ref) 667 2,140 1.00 (ref) 
  Category 3 1082 2,890 1.57 (1.40–1.76) 764 2,139 1.28 (1.13–1.45) 664 2,139 0.90 (0.79–1.03) 
  Category 4 646 1,287 2.40 (2.09–2.76) 1033 2,140 1.74 (1.54–1.97) 649 2,140 0.73 (0.64–0.85) 
   Phet   0.64   0.003   0.05 
PR status 
 Negative 
  Category 1 119 1,784 0.67 (0.53–0.86) 137 2,139 0.59 (0.47–0.73) 277 2,139 1.41 (1.16–1.72) 
  Category 2 (ref) 220 2,597 1.00 (ref) 221 2,140 1.00 (ref) 215 2,140 1.00 (ref) 
  Category 3 349 2,890 1.61 (1.34–1.93) 245 2,139 1.08 (0.89–1.31) 191 2,139 0.81 (0.66–1.01) 
  Category 4 195 1,287 2.23 (1.79–2.78) 280 2,140 1.24 (1.03–1.50) 200 2,140 0.72 (0.57–0.90) 
 Positive 
  Category 1 324 1,784 0.63 (0.54–0.73) 381 2,139 0.70 (0.60–0.82) 762 2,139 1.42 (1.24–1.61) 
  Category 2 (ref) 619 2,597 1.00 (ref) 515 2,140 1.00 (ref) 588 2,140 1.00 (ref) 
  Category 3 971 2,890 1.61 (1.43–1.82) 670 2,139 1.28 (1.12–1.47) 590 2,139 0.91 (0.79–1.04) 
  Category 4 583 1,287 2.47 (2.14–2.86) 931 2,140 1.79 (1.58–2.04) 557 2,140 0.71 (0.61–0.83) 
   Phet   0.70   0.007   0.74 
HER2 status 
 Negative 
  Category 1 325 1,784 0.66 (0.57–0.77) 355 2,139 0.65 (0.56–0.76) 686 2,139 1.36 (1.19–1.56) 
  Category 2 (ref) 591 2,597 1.00 (ref) 517 2,140 1.00 (ref) 543 2,140 1.00 (ref) 
  Category 3 898 2,890 1.56 (1.38–1.76) 613 2,139 1.17 (1.03–1.34) 566 2,139 0.96 (0.83–1.10) 
  Category 4 546 1,287 2.40 (2.07–2.78) 875 2,140 1.68 (1.48–1.91) 565 2,140 0.81 (0.70–0.95) 
 Positive 
  Category 1 52 1,784 0.70 (0.49–0.99) 63 2,139 0.67 (0.48–0.93) 154 2,139 1.37 (1.06–1.77) 
  Category 2 (ref) 92 2,597 1.00 (ref) 92 2,140 1.00 (ref) 121 2,140 1.00 (ref) 
  Category 3 204 2,890 2.16 (1.67–2.80) 141 2,139 1.46 (1.11–1.92) 93 2,139 0.72 (0.54–0.95) 
  Category 4 106 1,287 2.67 (1.96–3.64) 158 2,140 1.64 (1.25–2.14) 86 2,140 0.54 (0.39–0.75) 
   Phet   0.07   0.21   0.04 
Percent densityDANDA
Cases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)b
Overall breast cancer 
  Category 1 517 1,784 0.63 (0.56–0.72) 618 2,139 0.65 (0.58–0.74) 1280 2,139 1.39 (1.25–1.55) 
  Category 2 (ref) 1,015 2,597 1.00 (ref) 910 2,140 1.00 (ref) 983 2,140 1.00 (ref) 
  Category 3 1,626 2,890 1.62 (1.47–1.79) 1134 2,139 1.22 (1.10–1.37) 943 2,139 0.88 (0.78–0.98) 
  Category 4 937 1,287 2.34 (2.07–2.65) 1433 2,140 1.55 (1.40–1.73) 889 2,140 0.72 (0.63–0.81) 
Invasiveness 
In situ 
  Category 1 51 1,784 0.51 (0.37–0.72) 73 2,139 0.56 (0.42–0.75) 184 2,139 1.19 (0.94–1.51) 
  Category 2 (ref) 140 2,597 1.00 (ref) 135 2,140 1.00 (ref) 143 2,140 1.00 (ref) 
  Category 3 242 2,890 1.58 (1.26–1.98) 167 2,139 1.18 (0.93–1.50) 124 2,139 0.85 (0.66–1.10) 
  Category 4 123 1,287 1.88 (1.42–2.49) 181 2,140 1.29 (1.02–1.63) 105 2,140 0.75 (0.56–1.00) 
 Invasive 
  Category 1 461 1,784 0.64 (0.56–0.73) 542 2,139 0.67 (0.59–0.76) 1089 2,139 1.42 (1.27–1.60) 
  Category 2 (ref) 875 2,597 1.00 (ref) 770 2,140 1.00 (ref) 836 2,140 1.00 (ref) 
  Category 3 1,377 2,890 1.62 (1.45–1.80) 961 2,139 1.23 (1.10–1.38) 818 2,139 0.89 (0.79–1.00) 
  Category 4 810 1,287 2.40 (2.11–2.74) 1250 2,140 1.61 (1.44–1.80) 780 2,140 0.71 (0.62–0.81) 
   Phet   0.18   0.25   0.40 
Histologyc 
 Ductal 
  Category 1 356 1,784 0.67 (0.57–0.77) 433 2,139 0.72 (0.63–0.83) 838 2,139 1.38 (1.22–1.56) 
  Category 2 (ref) 665 2,597 1.00 (ref) 581 2,140 1.00 (ref) 650 2,140 1.00 (ref) 
  Category 3 1073 2,890 1.62 (1.44–1.82) 749 2,139 1.27 (1.12–1.44) 635 2,139 0.90 (0.79–1.03) 
  Category 4 620 1,287 2.32 (2.01–2.67) 951 2,140 1.61 (1.42–1.82) 591 2,140 0.71 (0.61–0.82) 
 Lobular 
  Category 1 49 1,784 0.51 (0.36–0.72) 51 2,139 0.49 (0.35–0.70) 135 2,139 1.59 (1.21–2.10) 
  Category 2 (ref) 114 2,597 1.00 (ref) 96 2,140 1.00 (ref) 98 2,140 1.00 (ref) 
  Category 3 148 2,890 1.44 (1.11–1.87) 107 2,139 1.13 (0.85–1.50) 95 2,139 0.82 (0.61–1.11) 
  Category 4 110 1,287 3.00 (2.23–4.04) 167 2,140 1.83 (1.41–2.37) 93 2,140 0.65 (0.47–0.89) 
   Phet   0.02   0.03   0.50 
Histologic grade 
 Well differentiated 
  Category 1 139 1,784 0.62 (0.50–0.77) 157 2,139 0.70 (0.56–0.87) 284 2,139 1.25 (1.03–1.51) 
  Category 2 (ref) 274 2,597 1.00 (ref) 215 2,140 1.00 (ref) 247 2,140 1.00 (ref) 
  Category 3 379 2,890 1.44 (1.22–1.71) 283 2,139 1.35 (1.11–1.63) 246 2,139 0.91 (0.75–1.10) 
  Category 4 223 1,287 2.23 (1.81–2.74) 360 2,140 1.75 (1.45–2.10) 238 2,140 0.77 (0.62–0.95) 
 Moderately differentiated 
  Category 1 177 1,784 0.65 (0.53–0.79) 202 2,139 0.69 (0.57–0.84) 398 2,139 1.37 (1.16–1.62) 
  Category 2 (ref) 327 2,597 1.00 (ref) 280 2,140 1.00 (ref) 313 2,140 1.00 (ref) 
  Category 3 523 2,890 1.64 (1.40–1.91) 353 2,139 1.25 (1.05–1.48) 329 2,139 0.96 (0.81–1.14) 
  Category 4 317 1,287 2.53 (2.10–3.04) 509 2,140 1.81 (1.54–2.13) 304 2,140 0.74 (0.61–0.90) 
 Poorly differentiated 
  Category 1 99 1,784 0.65 (0.50–0.84) 120 2,139 0.62 (0.48–0.79) 279 2,139 1.55 (1.27–1.90) 
  Category 2 (ref) 184 2,597 1.00 (ref) 188 2,140 1.00 (ref) 195 2,140 1.00 (ref) 
  Category 3 335 2,890 1.79 (1.47–2.17) 221 2,139 1.12 (0.91–1.38) 170 2,139 0.80 (0.64–0.99) 
  Category 4 202 1,287 2.62 (2.08–3.30) 291 2,140 1.45 (1.19–1.77) 176 2,140 0.65 (0.51–0.83) 
   Phet   0.68   0.77   0.76 
Tumor size 
 <1.1 cm 
  Category 1 219 1,784 0.90 (0.75–1.09) 244 2,139 0.90 (0.74–1.08) 319 2,139 1.19 (0.99–1.42) 
  Category 2 (ref) 318 2,597 1.00 (ref) 262 2,140 1.00 (ref) 282 2,140 1.00 (ref) 
  Category 3 429 2,890 1.33 (1.13–1.56) 314 2,139 1.19 (1.00–1.42) 280 2,139 0.94 (0.78–1.12) 
  Category 4 223 1,287 1.70 (1.39–2.07) 369 2,140 1.42 (1.20–1.69) 308 2,140 0.93 (0.77–1.14) 
 1.1–2.0 cm 
  Category 1 149 1,784 0.52 (0.43–0.64) 188 2,139 0.57 (0.47–0.69) 463 2,139 1.62 (1.37–1.90) 
  Category 2 (ref) 349 2,597 1.00 (ref) 320 2,140 1.00 (ref) 311 2,140 1.00 (ref) 
  Category 3 547 2,890 1.60 (1.37–1.86) 388 2,139 1.20 (1.02–1.41) 328 2,139 0.96 (0.81–1.14) 
  Category 4 332 1,287 2.45 (2.05–2.93) 481 2,140 1.50 (1.29–1.76) 275 2,140 0.68 (0.56–0.82) 
 2.1+ cm 
  Category 1 74 1,784 0.42 (0.32–0.56) 91 2,139 0.51 (0.39–0.66) 273 2,139 1.47 (1.21–1.79) 
  Category 2 (ref) 189 2,597 1.00 (ref) 165 2,140 1.00 (ref) 214 2,140 1.00 (ref) 
  Category 3 349 2,890 2.02 (1.67–2.45) 224 2,139 1.32 (1.07–1.64) 186 2,139 0.74 (0.60–0.92) 
  Category 4 232 1,287 3.60 (2.88–4.51) 364 2,140 2.13 (1.75–2.60) 171 2,140 0.49 (0.39–0.63) 
   Phet   <0.001   <0.001   <0.001 
Involvement of lymph nodes 
 Negative 
  Category 1 314 1,784 0.64 (0.55–0.75) 370 2,139 0.68 (0.59–0.79) 722 2,139 1.37 (1.20–1.57) 
  Category 2 (ref) 609 2,597 1.00 (ref) 520 2,140 1.00 (ref) 565 2,140 1.00 (ref) 
  Category 3 908 2,890 1.50 (1.33–1.69) 658 2,139 1.24 (1.08–1.41) 568 2,139 0.93 (0.81–1.07) 
  Category 4 546 1,287 2.25 (1.95–2.61) 829 2,140 1.58 (1.39–1.79) 522 2,140 0.73 (0.63–0.85) 
 Positive 
  Category 1 89 1,784 0.56 (0.43–0.74) 117 2,139 0.61 (0.48–0.78) 300 2,139 1.61 (1.32–1.96) 
  Category 2 (ref) 189 2,597 1.00 (ref) 186 2,140 1.00 (ref) 202 2,140 1.00 (ref) 
  Category 3 369 2,890 1.96 (1.62–2.37) 230 2,139 1.18 (0.96–1.45) 191 2,139 0.86 (0.70–1.07) 
  Category 4 220 1,287 2.89 (2.31–3.61) 334 2,140 1.70 (1.40–2.07) 174 2,140 0.63 (0.49–0.80) 
   Phet   0.01   0.39   0.11 
ER status 
 Negative 
  Category 1 69 1,784 0.70 (0.51–0.95) 88 2,139 0.57 (0.43–0.75) 209 2,139 1.66 (1.31–2.10) 
  Category 2 (ref) 126 2,597 1.00 (ref) 151 2,140 1.00 (ref) 136 2,140 1.00 (ref) 
  Category 3 236 2,890 1.81 (1.43–2.27) 153 2,139 0.96 (0.76–1.21) 113 2,139 0.76 (0.59–0.99) 
  Category 4 137 1,287 2.49 (1.89–3.26) 176 2,140 1.11 (0.88–1.40) 110 2,140 0.61 (0.45–0.81) 
 Positive 
  Category 1 373 1,784 0.63 (0.54–0.72) 431 2,139 0.69 (0.60–0.79) 837 2,139 1.38 (1.22–1.56) 
  Category 2 (ref) 716 2,597 1.00 (ref) 589 2,140 1.00 (ref) 667 2,140 1.00 (ref) 
  Category 3 1082 2,890 1.57 (1.40–1.76) 764 2,139 1.28 (1.13–1.45) 664 2,139 0.90 (0.79–1.03) 
  Category 4 646 1,287 2.40 (2.09–2.76) 1033 2,140 1.74 (1.54–1.97) 649 2,140 0.73 (0.64–0.85) 
   Phet   0.64   0.003   0.05 
PR status 
 Negative 
  Category 1 119 1,784 0.67 (0.53–0.86) 137 2,139 0.59 (0.47–0.73) 277 2,139 1.41 (1.16–1.72) 
  Category 2 (ref) 220 2,597 1.00 (ref) 221 2,140 1.00 (ref) 215 2,140 1.00 (ref) 
  Category 3 349 2,890 1.61 (1.34–1.93) 245 2,139 1.08 (0.89–1.31) 191 2,139 0.81 (0.66–1.01) 
  Category 4 195 1,287 2.23 (1.79–2.78) 280 2,140 1.24 (1.03–1.50) 200 2,140 0.72 (0.57–0.90) 
 Positive 
  Category 1 324 1,784 0.63 (0.54–0.73) 381 2,139 0.70 (0.60–0.82) 762 2,139 1.42 (1.24–1.61) 
  Category 2 (ref) 619 2,597 1.00 (ref) 515 2,140 1.00 (ref) 588 2,140 1.00 (ref) 
  Category 3 971 2,890 1.61 (1.43–1.82) 670 2,139 1.28 (1.12–1.47) 590 2,139 0.91 (0.79–1.04) 
  Category 4 583 1,287 2.47 (2.14–2.86) 931 2,140 1.79 (1.58–2.04) 557 2,140 0.71 (0.61–0.83) 
   Phet   0.70   0.007   0.74 
HER2 status 
 Negative 
  Category 1 325 1,784 0.66 (0.57–0.77) 355 2,139 0.65 (0.56–0.76) 686 2,139 1.36 (1.19–1.56) 
  Category 2 (ref) 591 2,597 1.00 (ref) 517 2,140 1.00 (ref) 543 2,140 1.00 (ref) 
  Category 3 898 2,890 1.56 (1.38–1.76) 613 2,139 1.17 (1.03–1.34) 566 2,139 0.96 (0.83–1.10) 
  Category 4 546 1,287 2.40 (2.07–2.78) 875 2,140 1.68 (1.48–1.91) 565 2,140 0.81 (0.70–0.95) 
 Positive 
  Category 1 52 1,784 0.70 (0.49–0.99) 63 2,139 0.67 (0.48–0.93) 154 2,139 1.37 (1.06–1.77) 
  Category 2 (ref) 92 2,597 1.00 (ref) 92 2,140 1.00 (ref) 121 2,140 1.00 (ref) 
  Category 3 204 2,890 2.16 (1.67–2.80) 141 2,139 1.46 (1.11–1.92) 93 2,139 0.72 (0.54–0.95) 
  Category 4 106 1,287 2.67 (1.96–3.64) 158 2,140 1.64 (1.25–2.14) 86 2,140 0.54 (0.39–0.75) 
   Phet   0.07   0.21   0.04 

Abbreviation: Phet, test for heterogeneity in association by subtype.

aCategories are 1, 0%–10%; 2, 11%–25%; 3, 26%–50%; and 4, 51%+ for PMD and quartiles for DA and NDA.

bAdjusted for study site, age, and BMI.

cMixed and other histology categories are excluded.

Table 4.

Pooled associations of categoriesa of percent density, DA, and NDA for morphologic subtypes of invasive breast cancer by age

Percent densityDANDA
Age < 55Age ≥ 55Age < 55Age ≥ 55Age < 55Age ≥ 55
Cases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)b
Overall breast cancer 
  Category 1 109 530 0.60 (0.47–0.77) 408 1,254 0.61 (0.53–0.71) 191 759 0.65 (0.53–0.80) 427 1,380 0.64 (0.55–0.75) 822 1,357 1.44 (1.24–1.66) 458 782 1.33 (1.13–1.56) 
  Category 2 (ref) 316 1,016 1.00 (ref) 699 1,581 1.00 (ref) 376 948 1.00 (ref) 534 1,192 1.00 (ref) 456 1,087 1.00 (ref) 527 1,053 1.00 (ref) 
  Category 3 809 1,604 1.68 (1.44–1.97) 817 1,286 1.60 (1.41–1.83) 553 1,135 1.22 (1.04–1.43) 581 1,004 1.26 (1.09–1.46) 362 878 0.96 (0.81–1.14) 581 1,261 0.82 (0.71–0.96) 
  Category 4 650 922 2.40 (2.02–2.86) 287 365 2.16 (1.79–2.61) 764 1,230 1.56 (1.34–1.81) 669 910 1.58 (1.37–1.83) 244 750 0.70 (0.57–0.86) 645 1,390 0.67 (0.57–0.79) 
Invasiveness 
 In situ 
  Category 1 15 530 0.64 (0.35–1.18) 36 1,254 0.43 (0.29–0.64) 33 759 0.79 (0.50–1.24) 40 1,380 0.42 (0.28–0.62) 129 1,357 1.14 (0.84–1.54) 55 782 1.21 (0.82–1.78) 
  Category 2 (ref) 44 1,016 1.00 (ref) 96 1,581 1.00 (ref) 56 948 1.00 (ref) 79 1,192 1.00 (ref) 81 1,087 1.00 (ref) 62 1,053 1.00 (ref) 
  Category 3 138 1,604 1.96 (1.37–2.81) 104 1,286 1.40 (1.04–1.89) 91 1,135 1.33 (0.94–1.88) 76 1,004 1.10 (0.79–1.54) 58 878 0.86 (0.60–1.23) 66 1,261 0.86 (0.60–1.24) 
  Category 4 100 922 2.38 (1.60–3.54) 23 365 1.31 (0.80–2.13) 117 1,230 1.60 (1.15–2.24) 64 910 1.06 (0.75–1.49) 29 750 0.57 (0.35–0.91) 76 1,390 0.81 (0.55–1.19) 
 Invasive 
  Category 1 92 530 0.58 (0.45–0.76) 369 1,254 0.63 (0.54–0.74) 158 759 0.63 (0.51–0.79) 384 1,380 0.68 (0.58–0.80) 688 1,357 1.49 (1.28–1.74) 401 782 1.35 (1.14–1.59) 
  Category 2 (ref) 272 1,016 1.00 (ref) 603 1,581 1.00 (ref) 317 948 1.00 (ref) 453 1,192 1.00 (ref) 374 1,087 1.00 (ref) 462 1,053 1.00 (ref) 
  Category 3 667 1,604 1.62 (1.37–1.92) 710 1,286 1.63 (1.42–1.87) 458 1,135 1.19 (1.01–1.42) 503 1,004 1.29 (1.10–1.51) 304 878 0.99 (0.82–1.19) 514 1,261 0.82 (0.70–0.96) 
  Category 4 548 922 2.39 (1.99–2.88) 262 365 2.27 (1.87–2.76) 646 1,230 1.56 (1.33–1.83) 604 910 1.68 (1.44–1.95) 213 750 0.72 (0.58–0.90) 567 1,390 0.65 (0.55–0.77) 
   Phet   0.55   0.08   0.78   0.03   0.40   0.58 
Histologyc 
 Ductal 
  Category 1 82 530 0.65 (0.49–0.86) 274 1,254 0.65 (0.54–0.77) 135 759 0.66 (0.52–0.83) 298 1,380 0.75 (0.63–0.90) 546 1,357 1.47 (1.24–1.73) 292 782 1.29 (1.07–1.55) 
  Category 2 (ref) 216 1,016 1.00 (ref) 449 1,581 1.00 (ref) 260 948 1.00 (ref) 321 1,192 1.00 (ref) 302 1,087 1.00 (ref) 348 1,053 1.00 (ref) 
  Category 3 544 1,604 1.67 (1.39–2.00) 529 1,286 1.61 (1.38–1.88) 374 1,135 1.19 (0.99–1.42) 375 1,004 1.35 (1.14–1.61) 253 878 1.02 (0.84–1.24) 382 1,261 0.83 (0.69–0.98) 
  Category 4 435 922 2.41 (1.97–2.95) 185 365 2.12 (1.71–2.63) 508 1,230 1.50 (1.26–1.78) 443 910 1.75 (1.47–2.07) 176 750 0.74 (0.58–0.93) 415 1,390 0.65 (0.53–0.78) 
 Lobular 
  Category 1 530 0.29 (0.11–0.78) 44 1,254 0.53 (0.36–0.78) 12 759 0.59 (0.29–1.18) 39 1,380 0.45 (0.30–0.68) 75 1,357 1.55 (1.03–2.33) 60 782 1.55 (1.06–2.26) 
  Category 2 (ref) 27 1,016 1.00 (ref) 87 1,581 1.00 (ref) 26 948 1.00 (ref) 70 1,192 1.00 (ref) 39 1,087 1.00 (ref) 59 1,053 1.00 (ref) 
  Category 3 57 1,604 1.43 (0.89–2.30) 91 1,286 1.47 (1.08–2.01) 42 1,135 1.31 (0.80–2.17) 65 1,004 1.08 (0.76–1.54) 22 878 0.65 (0.38–1.12) 73 1,261 0.90 (0.62–1.29) 
  Category 4 67 922 3.14 (1.91–5.17) 43 365 2.73 (1.83–4.08) 76 1,230 2.22 (1.41–3.51) 91 910 1.68 (1.21–2.32) 20 750 0.58 (0.32–1.08) 73 1,390 0.64 (0.43–0.95) 
   Phet   0.07   0.27   0.18   0.08   0.31   0.79 
Histologic grade 
 Well differentiated 
  Category 1 19 530 0.48 (0.29–0.82) 120 1,254 0.62 (0.49–0.80) 39 759 0.72 (0.48–1.07) 118 1,380 0.67 (0.52–0.87) 170 1,357 1.31 (1.00–1.71) 114 782 1.16 (0.89–1.52) 
  Category 2 (ref) 72 1,016 1.00 (ref) 202 1,581 1.00 (ref) 72 948 1.00 (ref) 143 1,192 1.00 (ref) 103 1,087 1.00 (ref) 144 1,053 1.00 (ref.) 
  Category 3 159 1,604 1.41 (1.05–1.90) 220 1,286 1.48 (1.20–1.83) 111 1,135 1.29 (0.95–1.76) 172 1,004 1.41 (1.11–1.80) 75 878 0.91 (0.66–1.25) 171 1,261 0.90 (0.71–1.15) 
  Category 4 143 922 2.31 (1.67–3.18) 80 365 2.02 (1.51–2.72) 171 1,230 1.86 (1.39–2.48) 189 910 1.70 (1.34–2.16) 45 750 0.62 (0.41–0.92) 193 1,390 0.78 (0.60–1.01) 
 Moderately differentiated 
  Category 1 44 530 0.77 (0.53–1.13) 133 1,254 0.59 (0.47–0.75) 65 759 0.74 (0.54–1.03) 137 1,380 0.65 (0.51–0.83) 254 1,357 1.50 (1.19–1.89) 144 782 1.26 (0.98–1.61) 
  Category 2 (ref) 97 1,016 1.00 (ref) 230 1,581 1.00 (ref) 111 948 1.00 (ref) 169 1,192 1.00 (ref) 137 1,087 1.00 (ref) 176 1,053 1.00 (ref) 
  Category 3 254 1,604 1.74 (1.35–2.25) 269 1286 1.61 (1.32–1.97) 167 1,135 1.25 (0.97–1.62) 186 1,004 1.27 (1.01–1.60) 126 878 1.13 (0.87–1.47) 203 1,261 0.86 (0.68–1.07) 
  Category 4 210 922 2.64 (2.00–3.48) 107 365 2.43 (1.85–3.18) 262 1,230 1.81 (1.43–2.30) 247 910 1.85 (1.49–2.30) 88 750 0.82 (0.60–1.12) 216 1,390 0.65 (0.51–0.83) 
 Poorly differentiated 
  Category 1 23 530 0.53 (0.32–0.86) 76 1,254 0.65 (0.48–0.89) 39 759 0.52 (0.35–0.77) 81 1,380 0.67 (0.49–0.91) 197 1,357 1.47 (1.14–1.90) 82 782 1.63 (1.18–2.25) 
  Category 2 (ref) 71 1,016 1.00 (ref) 113 1,581 1.00 (ref) 95 948 1.00 (ref) 93 1,192 1.00 (ref) 109 1,087 1.00 (ref) 86 1,053 1.00 (ref) 
  Category 3 202 1,604 1.87 (1.40–2.50) 133 1,286 1.69 (1.29–2.22) 142 1,135 1.24 (0.94–1.64) 79 1,004 0.97 (0.71–1.33) 76 878 0.85 (0.62–1.16) 94 1,261 0.77 (0.56–1.05) 
  Category 4 151 922 2.53 (1.84–3.49) 51 365 2.49 (1.73–3.59) 171 1,230 1.36 (1.04–1.78) 120 910 1.59 (1.19–2.12) 65 750 0.73 (0.51–1.05) 111 1,390 0.56 (0.40–0.79) 
   Phet   0.48   0.91   0.36   0.40   0.70   0.15 
Tumor size 
 <1.1 cm 
  Category 1 46 530 0.94 (0.65–1.37) 173 1,254 0.85 (0.68–1.06) 70 759 0.94 (0.68–1.30) 174 1,380 0.86 (0.68–1.08) 195 1,357 1.28 (1.00–1.65) 124 782 1.09 (0.85–1.41) 
  Category 2 (ref) 96 1,016 1.00 (ref) 222 1,581 1.00 (ref) 98 948 1.00 (ref) 164 1,192 1.00 (ref) 114 1,087 1.00 (ref) 168 1,053 1.00 (ref) 
  Category 3 196 1,604 1.25 (0.96–1.63) 233 1,286 1.40 (1.14–1.72) 134 1,135 1.13 (0.86–1.49) 180 1,004 1.27 (1.01–1.60) 97 878 1.12 (0.84–1.50) 183 1,261 0.84 (0.67–1.06) 
  Category 4 150 922 1.63 (1.21–2.17) 73 365 1.62 (1.20–2.18) 186 1,230 1.47 (1.14–1.91) 183 910 1.41 (1.12–1.78) 82 750 1.14 (0.82–1.59) 226 1,390 0.79 (0.62–1.01) 
 1.1–2.0 cm 
  Category 1 32 530 0.50 (0.33–0.76) 117 1,254 0.51 (0.40–0.65) 57 759 0.53 (0.39–0.74) 131 1,380 0.58 (0.45–0.74) 288 1,357 1.68 (1.34–2.10) 175 782 1.56 (1.23–1.98) 
  Category 2 (ref) 110 1,016 1.00 (ref) 239 1,581 1.00 (ref) 136 948 1.00 (ref) 184 1,192 1.00 (ref) 139 1,087 1.00 (ref) 172 1,053 1.00 (ref) 
  Category 3 271 1,604 1.63 (1.28–2.07) 276 1,286 1.59 (1.31–1.93) 189 1,135 1.15 (0.91–1.46) 199 1,004 1.26 (1.01–1.57) 128 878 1.12 (0.86–1.45) 200 1,261 0.86 (0.69–1.08) 
  Category 4 220 922 2.39 (1.83–3.11) 112 365 2.43 (1.87–3.17) 251 1,230 1.42 (1.13–1.78) 230 910 1.59 (1.28–1.97) 78 750 0.71 (0.52–0.99) 197 1,390 0.61 (0.47–0.78) 
 2.1+ cm 
  Category 1 12 530 0.28 (0.15–0.54) 62 1,254 0.44 (0.32–0.61) 28 759 0.49 (0.31–0.77) 63 1,380 0.51 (0.36–0.71) 183 1,357 1.47 (1.13–1.91) 90 782 1.42 (1.05–1.92) 
  Category 2 (ref) 60 1,016 1.00 (ref) 129 1,581 1.00 (ref) 71 948 1.00 (ref) 94 1,192 1.00 (ref) 107 1,087 1.00 (ref) 107 1,053 1.00 (ref) 
  Category 3 176 1,604 2.10 (1.53–2.88) 173 1,286 2.00 (1.56–2.56) 120 1,135 1.40 (1.03–1.91) 104 1,004 1.28 (0.95–1.71) 70 878 0.74 (0.54–1.03) 116 1261 0.75 (0.56–1.00) 
  Category 4 161 922 3.77 (2.69–5.28) 71 365 3.24 (2.33–4.51) 190 1,230 2.02 (1.51–2.70) 174 910 2.30 (1.76–3.01) 49 750 0.45 (0.30–0.67) 122 1390 0.48 (0.35–0.66) 
   Phet   <0.001   <0.001   0.002   <0.001   0.001   0.006 
Involvement of lymph nodes 
 Negative 
  Category 1 64 530 0.57 (0.42–0.77) 250 1,254 0.65 (0.54–0.78) 110 759 0.66 (0.52–0.86) 260 1,380 0.68 (0.56–0.82) 458 1,357 1.53 (1.28–1.83) 264 782 1.24 (1.02–1.50) 
  Category 2 (ref) 198 1,016 1.00 (ref) 411 1,581 1.00 (ref) 211 948 1.00 (ref) 309 1,192 1.00 (ref) 240 1,087 1.00 (ref) 325 1,053 1.00 (ref) 
  Category 3 427 1,604 1.41 (1.17–1.71) 481 1,286 1.58 (1.35–1.85) 309 1,135 1.21 (0.99–1.47) 349 1,004 1.29 (1.08–1.54) 210 878 1.08 (0.87–1.33) 358 1,261 0.84 (0.70–1.00) 
  Category 4 365 922 2.16 (1.75–2.66) 181 365 2.23 (1.79–2.78) 424 1,230 1.54 (1.28–1.86) 405 910 1.64 (1.38–1.95) 146 750 0.81 (0.63–1.04) 376 1,390 0.64 (0.53–0.78) 
 Positive 
  Category 1 23 530 0.62 (0.37–1.02) 66 1,254 0.51 (0.38–0.70) 38 759 0.53 (0.35–0.78) 79 1,380 0.66 (0.48–0.91) 195 1,357 1.47 (1.13–1.90) 105 782 1.81 (1.34–2.45) 
  Category 2 (ref) 59 1,016 1.00 (ref) 130 1,581 1.00 (ref) 91 948 1.00 (ref) 95 1,192 1.00 (ref) 109 1,087 1.00 (ref) 93 1,053 1.00 (ref) 
  Category 3 205 1,604 2.36 (1.73–3.22) 164 1,286 1.75 (1.36–2.24) 123 1,135 1.11 (0.83–1.48) 107 1,004 1.28 (0.96–1.72) 84 878 0.91 (0.67–1.24) 107 1,261 0.85 (0.63–1.14) 
  Category 4 158 922 3.40 (2.43–4.76) 62 365 2.48 (1.77–3.48) 193 1,230 1.60 (1.22–2.09) 141 910 1.83 (1.39–2.42) 57 750 0.60 (0.41–0.87) 117 1,390 0.61 (0.44–0.84) 
   Phet   0.02   0.28   0.56   0.78   0.54   0.06 
ER status 
 Negative 
  Category 1 14 530 0.53 (0.29–1.00) 55 1,254 0.73 (0.51–1.04) 28 759 0.47 (0.30–0.74) 60 1,380 0.65 (0.45–0.92) 139 1,357 1.72 (1.26–2.34) 70 782 1.64 (1.15–2.35) 
  Category 2 (ref) 42 1,016 1.00 (ref) 84 1,581 1.00 (ref) 74 948 1.00 (ref) 77 1,192 1.00 (ref) 70 1,087 1.00 (ref) 66 1,053 1.00 (ref) 
  Category 3 130 1,604 2.14 (1.48–3.09) 106 1,286 1.63 (1.21–2.21) 88 1,135 0.97 (0.70–1.35) 65 1,004 0.95 (0.67–1.34) 47 878 0.76 (0.51–1.12) 66 1,261 0.79 (0.55–1.13) 
  Category 4 103 922 3.16 (2.13–4.70) 34 365 1.86 (1.21–2.86) 99 1,230 1.01 (0.74–1.39) 77 910 1.24 (0.89–1.73) 33 750 0.48 (0.30–0.77) 77 1,390 0.67 (0.46–0.99) 
 Positive 
  Category 1 76 530 0.60 (0.45–0.80) 297 1,254 0.61 (0.51–0.72) 125 759 0.68 (0.54–0.87) 306 1,380 0.68 (0.57–0.82) 527 1,357 1.46 (1.23–1.74) 310 782 1.27 (1.06–1.53) 
  Category 2 (ref) 221 1,016 1.00 (ref) 495 1,581 1.00 (ref) 234 948 1.00 (ref) 355 1,192 1.00 (ref) 287 1,087 1.00 (ref) 380 1,053 1.00 (ref) 
  Category 3 509 1,604 1.51 (1.26–1.82) 573 1,286 1.62 (1.40–1.88) 348 1,135 1.23 (1.02–1.48) 416 1,004 1.36 (1.15–1.61) 247 878 1.06 (0.87–1.30) 417 1,261 0.81 (0.68–0.96) 
  Category 4 430 922 2.30 (1.88–2.81) 216 365 2.32 (1.89–2.86) 529 1,230 1.73 (1.45–2.07) 504 910 1.79 (1.52–2.11) 175 750 0.80 (0.63–1.01) 474 1,390 0.65 (0.54–0.77) 
   Phet   0.22   0.47   0.02   0.09   0.03   0.48 
PR status 
 Negative 
  Category 1 23 530 0.55 (0.33–0.89) 96 1,254 0.69 (0.53–0.92) 39 759 0.51 (0.34–0.75) 98 1,380 0.63 (0.47–0.83) 181 1,357 1.57 (1.20–2.06) 96 782 1.25 (0.94–1.68) 
  Category 2 (ref) 72 1,016 1.00 (ref) 148 1,581 1.00 (ref) 96 948 1.00 (ref) 125 1,192 1.00 (ref) 96 1,087 1.00 (ref) 119 1,053 1.00 (ref) 
  Category 3 180 1,604 1.70 (1.27–2.28) 169 1,286 1.54 (1.21–1.96) 131 1,135 1.13 (0.86–1.50) 114 1,004 1.03 (0.79–1.36) 74 878 0.91 (0.66–1.26) 117 1,261 0.76 (0.58–1.00) 
  Category 4 132 922 2.29 (1.66–3.17) 63 365 2.13 (1.53–2.96) 141 1,230 1.13 (0.86–1.49) 139 910 1.38 (1.06–1.79) 56 750 0.69 (0.47–1.01) 144 1,390 0.69 (0.51–0.92) 
 Positive 
  Category 1 67 530 0.61 (0.45–0.83) 257 1,254 0.61 (0.51–0.73) 112 759 0.69 (0.53–0.88) 269 1,380 0.70 (0.58–0.85) 479 1,357 1.46 (1.23–1.75) 283 782 1.35 (1.11–1.63) 
  Category 2 (ref) 188 1,016 1.00 (ref) 431 1,581 1.00 (ref) 209 948 1.00 (ref) 306 1,192 1.00 (ref) 261 1,087 1.00 (ref) 327 1,053 1.00 (ref) 
  Category 3 462 1,604 1.61 (1.33–1.96) 509 1,286 1.64 (1.41–1.92) 303 1,135 1.19 (0.98–1.46) 367 1,004 1.39 (1.17–1.66) 222 878 1.05 (0.85–1.29) 368 1,261 0.82 (0.69–0.98) 
  Category 4 397 922 2.49 (2.02–3.08) 186 365 2.28 (1.83–2.83) 490 1,230 1.79 (1.49–2.15) 441 910 1.82 (1.53–2.16) 152 750 0.75 (0.59–0.96) 405 1,390 0.63 (0.52–0.77) 
   Phet   0.73   0.64   0.007   0.15   0.68   0.73 
HER2 status 
 Negative 
  Category 1 69 530 0.63 (0.46–0.85) 256 1,254 0.64 (0.53–0.77) 106 759 0.61 (0.47–0.79) 249 1,380 0.66 (0.55–0.80) 451 1,357 1.39 (1.17–1.67) 235 782 1.27 (1.03–1.55) 
  Category 2 (ref) 186 1,016 1.00 (ref) 405 1,581 1.00 (ref) 221 948 1.00 (ref) 296 1,192 1.00 (ref) 262 1,087 1.00 (ref) 281 1,053 1.00 (ref) 
  Category 3 455 1,604 1.64 (1.35–1.99) 443 1,286 1.53 (1.30–1.80) 294 1,135 1.10 (0.91–1.34) 319 1,004 1.26 (1.05–1.51) 219 878 1.03 (0.84–1.26) 347 1,261 0.91 (0.75–1.09) 
  Category 4 382 922 2.52 (2.04–3.13) 164 365 2.12 (1.69–2.65) 471 1,230 1.63 (1.35–1.95) 404 910 1.75 (1.47–2.09) 160 750 0.79 (0.62–1.01) 405 1,390 0.77 (0.63–0.93) 
 Positive 
  Category 1 10 530 0.54 (0.26–1.12) 42 1,254 0.71 (0.47–1.07) 20 759 0.68 (0.39–1.19) 43 1,380 0.63 (0.42–0.96) 106 1,357 1.48 (1.06–2.08) 48 782 1.24 (0.83–1.84) 
  Category 2 (ref) 31 1,016 1.00 (ref) 61 1,581 1.00 (ref) 38 948 1.00 (ref) 54 1,192 1.00 (ref) 59 1,087 1.00 (ref) 62 1,053 1.00 (ref) 
  Category 3 115 1,604 2.43 (1.60–3.67) 89 1,286 2.00 (1.42–2.82) 82 1,135 1.79 (1.21–2.66) 59 1,004 1.24 (0.84–1.81) 40 878 0.83 (0.54–1.26) 53 1,261 0.64 (0.44–0.94) 
  Category 4 75 922 2.82 (1.78–4.45) 31 365 2.51 (1.58–3.99) 91 1,230 1.82 (1.23–2.69) 67 910 1.55 (1.07–2.24) 26 750 0.54 (0.32–0.91) 60 1,390 0.50 (0.33–0.75) 
   Phet   0.11   0.54   0.07   0.92   0.38   0.16 
Percent densityDANDA
Age < 55Age ≥ 55Age < 55Age ≥ 55Age < 55Age ≥ 55
Cases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)bCases, nControls, nOR (95% CI)b
Overall breast cancer 
  Category 1 109 530 0.60 (0.47–0.77) 408 1,254 0.61 (0.53–0.71) 191 759 0.65 (0.53–0.80) 427 1,380 0.64 (0.55–0.75) 822 1,357 1.44 (1.24–1.66) 458 782 1.33 (1.13–1.56) 
  Category 2 (ref) 316 1,016 1.00 (ref) 699 1,581 1.00 (ref) 376 948 1.00 (ref) 534 1,192 1.00 (ref) 456 1,087 1.00 (ref) 527 1,053 1.00 (ref) 
  Category 3 809 1,604 1.68 (1.44–1.97) 817 1,286 1.60 (1.41–1.83) 553 1,135 1.22 (1.04–1.43) 581 1,004 1.26 (1.09–1.46) 362 878 0.96 (0.81–1.14) 581 1,261 0.82 (0.71–0.96) 
  Category 4 650 922 2.40 (2.02–2.86) 287 365 2.16 (1.79–2.61) 764 1,230 1.56 (1.34–1.81) 669 910 1.58 (1.37–1.83) 244 750 0.70 (0.57–0.86) 645 1,390 0.67 (0.57–0.79) 
Invasiveness 
 In situ 
  Category 1 15 530 0.64 (0.35–1.18) 36 1,254 0.43 (0.29–0.64) 33 759 0.79 (0.50–1.24) 40 1,380 0.42 (0.28–0.62) 129 1,357 1.14 (0.84–1.54) 55 782 1.21 (0.82–1.78) 
  Category 2 (ref) 44 1,016 1.00 (ref) 96 1,581 1.00 (ref) 56 948 1.00 (ref) 79 1,192 1.00 (ref) 81 1,087 1.00 (ref) 62 1,053 1.00 (ref) 
  Category 3 138 1,604 1.96 (1.37–2.81) 104 1,286 1.40 (1.04–1.89) 91 1,135 1.33 (0.94–1.88) 76 1,004 1.10 (0.79–1.54) 58 878 0.86 (0.60–1.23) 66 1,261 0.86 (0.60–1.24) 
  Category 4 100 922 2.38 (1.60–3.54) 23 365 1.31 (0.80–2.13) 117 1,230 1.60 (1.15–2.24) 64 910 1.06 (0.75–1.49) 29 750 0.57 (0.35–0.91) 76 1,390 0.81 (0.55–1.19) 
 Invasive 
  Category 1 92 530 0.58 (0.45–0.76) 369 1,254 0.63 (0.54–0.74) 158 759 0.63 (0.51–0.79) 384 1,380 0.68 (0.58–0.80) 688 1,357 1.49 (1.28–1.74) 401 782 1.35 (1.14–1.59) 
  Category 2 (ref) 272 1,016 1.00 (ref) 603 1,581 1.00 (ref) 317 948 1.00 (ref) 453 1,192 1.00 (ref) 374 1,087 1.00 (ref) 462 1,053 1.00 (ref) 
  Category 3 667 1,604 1.62 (1.37–1.92) 710 1,286 1.63 (1.42–1.87) 458 1,135 1.19 (1.01–1.42) 503 1,004 1.29 (1.10–1.51) 304 878 0.99 (0.82–1.19) 514 1,261 0.82 (0.70–0.96) 
  Category 4 548 922 2.39 (1.99–2.88) 262 365 2.27 (1.87–2.76) 646 1,230 1.56 (1.33–1.83) 604 910 1.68 (1.44–1.95) 213 750 0.72 (0.58–0.90) 567 1,390 0.65 (0.55–0.77) 
   Phet   0.55   0.08   0.78   0.03   0.40   0.58 
Histologyc 
 Ductal 
  Category 1 82 530 0.65 (0.49–0.86) 274 1,254 0.65 (0.54–0.77) 135 759 0.66 (0.52–0.83) 298 1,380 0.75 (0.63–0.90) 546 1,357 1.47 (1.24–1.73) 292 782 1.29 (1.07–1.55) 
  Category 2 (ref) 216 1,016 1.00 (ref) 449 1,581 1.00 (ref) 260 948 1.00 (ref) 321 1,192 1.00 (ref) 302 1,087 1.00 (ref) 348 1,053 1.00 (ref) 
  Category 3 544 1,604 1.67 (1.39–2.00) 529 1,286 1.61 (1.38–1.88) 374 1,135 1.19 (0.99–1.42) 375 1,004 1.35 (1.14–1.61) 253 878 1.02 (0.84–1.24) 382 1,261 0.83 (0.69–0.98) 
  Category 4 435 922 2.41 (1.97–2.95) 185 365 2.12 (1.71–2.63) 508 1,230 1.50 (1.26–1.78) 443 910 1.75 (1.47–2.07) 176 750 0.74 (0.58–0.93) 415 1,390 0.65 (0.53–0.78) 
 Lobular 
  Category 1 530 0.29 (0.11–0.78) 44 1,254 0.53 (0.36–0.78) 12 759 0.59 (0.29–1.18) 39 1,380 0.45 (0.30–0.68) 75 1,357 1.55 (1.03–2.33) 60 782 1.55 (1.06–2.26) 
  Category 2 (ref) 27 1,016 1.00 (ref) 87 1,581 1.00 (ref) 26 948 1.00 (ref) 70 1,192 1.00 (ref) 39 1,087 1.00 (ref) 59 1,053 1.00 (ref) 
  Category 3 57 1,604 1.43 (0.89–2.30) 91 1,286 1.47 (1.08–2.01) 42 1,135 1.31 (0.80–2.17) 65 1,004 1.08 (0.76–1.54) 22 878 0.65 (0.38–1.12) 73 1,261 0.90 (0.62–1.29) 
  Category 4 67 922 3.14 (1.91–5.17) 43 365 2.73 (1.83–4.08) 76 1,230 2.22 (1.41–3.51) 91 910 1.68 (1.21–2.32) 20 750 0.58 (0.32–1.08) 73 1,390 0.64 (0.43–0.95) 
   Phet   0.07   0.27   0.18   0.08   0.31   0.79 
Histologic grade 
 Well differentiated 
  Category 1 19 530 0.48 (0.29–0.82) 120 1,254 0.62 (0.49–0.80) 39 759 0.72 (0.48–1.07) 118 1,380 0.67 (0.52–0.87) 170 1,357 1.31 (1.00–1.71) 114 782 1.16 (0.89–1.52) 
  Category 2 (ref) 72 1,016 1.00 (ref) 202 1,581 1.00 (ref) 72 948 1.00 (ref) 143 1,192 1.00 (ref) 103 1,087 1.00 (ref) 144 1,053 1.00 (ref.) 
  Category 3 159 1,604 1.41 (1.05–1.90) 220 1,286 1.48 (1.20–1.83) 111 1,135 1.29 (0.95–1.76) 172 1,004 1.41 (1.11–1.80) 75 878 0.91 (0.66–1.25) 171 1,261 0.90 (0.71–1.15) 
  Category 4 143 922 2.31 (1.67–3.18) 80 365 2.02 (1.51–2.72) 171 1,230 1.86 (1.39–2.48) 189 910 1.70 (1.34–2.16) 45 750 0.62 (0.41–0.92) 193 1,390 0.78 (0.60–1.01) 
 Moderately differentiated 
  Category 1 44 530 0.77 (0.53–1.13) 133 1,254 0.59 (0.47–0.75) 65 759 0.74 (0.54–1.03) 137 1,380 0.65 (0.51–0.83) 254 1,357 1.50 (1.19–1.89) 144 782 1.26 (0.98–1.61) 
  Category 2 (ref) 97 1,016 1.00 (ref) 230 1,581 1.00 (ref) 111 948 1.00 (ref) 169 1,192 1.00 (ref) 137 1,087 1.00 (ref) 176 1,053 1.00 (ref) 
  Category 3 254 1,604 1.74 (1.35–2.25) 269 1286 1.61 (1.32–1.97) 167 1,135 1.25 (0.97–1.62) 186 1,004 1.27 (1.01–1.60) 126 878 1.13 (0.87–1.47) 203 1,261 0.86 (0.68–1.07) 
  Category 4 210 922 2.64 (2.00–3.48) 107 365 2.43 (1.85–3.18) 262 1,230 1.81 (1.43–2.30) 247 910 1.85 (1.49–2.30) 88 750 0.82 (0.60–1.12) 216 1,390 0.65 (0.51–0.83) 
 Poorly differentiated 
  Category 1 23 530 0.53 (0.32–0.86) 76 1,254 0.65 (0.48–0.89) 39 759 0.52 (0.35–0.77) 81 1,380 0.67 (0.49–0.91) 197 1,357 1.47 (1.14–1.90) 82 782 1.63 (1.18–2.25) 
  Category 2 (ref) 71 1,016 1.00 (ref) 113 1,581 1.00 (ref) 95 948 1.00 (ref) 93 1,192 1.00 (ref) 109 1,087 1.00 (ref) 86 1,053 1.00 (ref) 
  Category 3 202 1,604 1.87 (1.40–2.50) 133 1,286 1.69 (1.29–2.22) 142 1,135 1.24 (0.94–1.64) 79 1,004 0.97 (0.71–1.33) 76 878 0.85 (0.62–1.16) 94 1,261 0.77 (0.56–1.05) 
  Category 4 151 922 2.53 (1.84–3.49) 51 365 2.49 (1.73–3.59) 171 1,230 1.36 (1.04–1.78) 120 910 1.59 (1.19–2.12) 65 750 0.73 (0.51–1.05) 111 1,390 0.56 (0.40–0.79) 
   Phet   0.48   0.91   0.36   0.40   0.70   0.15 
Tumor size 
 <1.1 cm 
  Category 1 46 530 0.94 (0.65–1.37) 173 1,254 0.85 (0.68–1.06) 70 759 0.94 (0.68–1.30) 174 1,380 0.86 (0.68–1.08) 195 1,357 1.28 (1.00–1.65) 124 782 1.09 (0.85–1.41) 
  Category 2 (ref) 96 1,016 1.00 (ref) 222 1,581 1.00 (ref) 98 948 1.00 (ref) 164 1,192 1.00 (ref) 114 1,087 1.00 (ref) 168 1,053 1.00 (ref) 
  Category 3 196 1,604 1.25 (0.96–1.63) 233 1,286 1.40 (1.14–1.72) 134 1,135 1.13 (0.86–1.49) 180 1,004 1.27 (1.01–1.60) 97 878 1.12 (0.84–1.50) 183 1,261 0.84 (0.67–1.06) 
  Category 4 150 922 1.63 (1.21–2.17) 73 365 1.62 (1.20–2.18) 186 1,230 1.47 (1.14–1.91) 183 910 1.41 (1.12–1.78) 82 750 1.14 (0.82–1.59) 226 1,390 0.79 (0.62–1.01) 
 1.1–2.0 cm 
  Category 1 32 530 0.50 (0.33–0.76) 117 1,254 0.51 (0.40–0.65) 57 759 0.53 (0.39–0.74) 131 1,380 0.58 (0.45–0.74) 288 1,357 1.68 (1.34–2.10) 175 782 1.56 (1.23–1.98) 
  Category 2 (ref) 110 1,016 1.00 (ref) 239 1,581 1.00 (ref) 136 948 1.00 (ref) 184 1,192 1.00 (ref) 139 1,087 1.00 (ref) 172 1,053 1.00 (ref) 
  Category 3 271 1,604 1.63 (1.28–2.07) 276 1,286 1.59 (1.31–1.93) 189 1,135 1.15 (0.91–1.46) 199 1,004 1.26 (1.01–1.57) 128 878 1.12 (0.86–1.45) 200 1,261 0.86 (0.69–1.08) 
  Category 4 220 922 2.39 (1.83–3.11) 112 365 2.43 (1.87–3.17) 251 1,230 1.42 (1.13–1.78) 230 910 1.59 (1.28–1.97) 78 750 0.71 (0.52–0.99) 197 1,390 0.61 (0.47–0.78) 
 2.1+ cm 
  Category 1 12 530 0.28 (0.15–0.54) 62 1,254 0.44 (0.32–0.61) 28 759 0.49 (0.31–0.77) 63 1,380 0.51 (0.36–0.71) 183 1,357 1.47 (1.13–1.91) 90 782 1.42 (1.05–1.92) 
  Category 2 (ref) 60 1,016 1.00 (ref) 129 1,581 1.00 (ref) 71 948 1.00 (ref) 94 1,192 1.00 (ref) 107 1,087 1.00 (ref) 107 1,053 1.00 (ref) 
  Category 3 176 1,604 2.10 (1.53–2.88) 173 1,286 2.00 (1.56–2.56) 120 1,135 1.40 (1.03–1.91) 104 1,004 1.28 (0.95–1.71) 70 878 0.74 (0.54–1.03) 116 1261 0.75 (0.56–1.00) 
  Category 4 161 922 3.77 (2.69–5.28) 71 365 3.24 (2.33–4.51) 190 1,230 2.02 (1.51–2.70) 174 910 2.30 (1.76–3.01) 49 750 0.45 (0.30–0.67) 122 1390 0.48 (0.35–0.66) 
   Phet   <0.001   <0.001   0.002   <0.001   0.001   0.006 
Involvement of lymph nodes 
 Negative 
  Category 1 64 530 0.57 (0.42–0.77) 250 1,254 0.65 (0.54–0.78) 110 759 0.66 (0.52–0.86) 260 1,380 0.68 (0.56–0.82) 458 1,357 1.53 (1.28–1.83) 264 782 1.24 (1.02–1.50) 
  Category 2 (ref) 198 1,016 1.00 (ref) 411 1,581 1.00 (ref) 211 948 1.00 (ref) 309 1,192 1.00 (ref) 240 1,087 1.00 (ref) 325 1,053 1.00 (ref) 
  Category 3 427 1,604 1.41 (1.17–1.71) 481 1,286 1.58 (1.35–1.85) 309 1,135 1.21 (0.99–1.47) 349 1,004 1.29 (1.08–1.54) 210 878 1.08 (0.87–1.33) 358 1,261 0.84 (0.70–1.00) 
  Category 4 365 922 2.16 (1.75–2.66) 181 365 2.23 (1.79–2.78) 424 1,230 1.54 (1.28–1.86) 405 910 1.64 (1.38–1.95) 146 750 0.81 (0.63–1.04) 376 1,390 0.64 (0.53–0.78) 
 Positive 
  Category 1 23 530 0.62 (0.37–1.02) 66 1,254 0.51 (0.38–0.70) 38 759 0.53 (0.35–0.78) 79 1,380 0.66 (0.48–0.91) 195 1,357 1.47 (1.13–1.90) 105 782 1.81 (1.34–2.45) 
  Category 2 (ref) 59 1,016 1.00 (ref) 130 1,581 1.00 (ref) 91 948 1.00 (ref) 95 1,192 1.00 (ref) 109 1,087 1.00 (ref) 93 1,053 1.00 (ref) 
  Category 3 205 1,604 2.36 (1.73–3.22) 164 1,286 1.75 (1.36–2.24) 123 1,135 1.11 (0.83–1.48) 107 1,004 1.28 (0.96–1.72) 84 878 0.91 (0.67–1.24) 107 1,261 0.85 (0.63–1.14) 
  Category 4 158 922 3.40 (2.43–4.76) 62 365 2.48 (1.77–3.48) 193 1,230 1.60 (1.22–2.09) 141 910 1.83 (1.39–2.42) 57 750 0.60 (0.41–0.87) 117 1,390 0.61 (0.44–0.84) 
   Phet   0.02   0.28   0.56   0.78   0.54   0.06 
ER status 
 Negative 
  Category 1 14 530 0.53 (0.29–1.00) 55 1,254 0.73 (0.51–1.04) 28 759 0.47 (0.30–0.74) 60 1,380 0.65 (0.45–0.92) 139 1,357 1.72 (1.26–2.34) 70 782 1.64 (1.15–2.35) 
  Category 2 (ref) 42 1,016 1.00 (ref) 84 1,581 1.00 (ref) 74 948 1.00 (ref) 77 1,192 1.00 (ref) 70 1,087 1.00 (ref) 66 1,053 1.00 (ref) 
  Category 3 130 1,604 2.14 (1.48–3.09) 106 1,286 1.63 (1.21–2.21) 88 1,135 0.97 (0.70–1.35) 65 1,004 0.95 (0.67–1.34) 47 878 0.76 (0.51–1.12) 66 1,261 0.79 (0.55–1.13) 
  Category 4 103 922 3.16 (2.13–4.70) 34 365 1.86 (1.21–2.86) 99 1,230 1.01 (0.74–1.39) 77 910 1.24 (0.89–1.73) 33 750 0.48 (0.30–0.77) 77 1,390 0.67 (0.46–0.99) 
 Positive 
  Category 1 76 530 0.60 (0.45–0.80) 297 1,254 0.61 (0.51–0.72) 125 759 0.68 (0.54–0.87) 306 1,380 0.68 (0.57–0.82) 527 1,357 1.46 (1.23–1.74) 310 782 1.27 (1.06–1.53) 
  Category 2 (ref) 221 1,016 1.00 (ref) 495 1,581 1.00 (ref) 234 948 1.00 (ref) 355 1,192 1.00 (ref) 287 1,087 1.00 (ref) 380 1,053 1.00 (ref) 
  Category 3 509 1,604 1.51 (1.26–1.82) 573 1,286 1.62 (1.40–1.88) 348 1,135 1.23 (1.02–1.48) 416 1,004 1.36 (1.15–1.61) 247 878 1.06 (0.87–1.30) 417 1,261 0.81 (0.68–0.96) 
  Category 4 430 922 2.30 (1.88–2.81) 216 365 2.32 (1.89–2.86) 529 1,230 1.73 (1.45–2.07) 504 910 1.79 (1.52–2.11) 175 750 0.80 (0.63–1.01) 474 1,390 0.65 (0.54–0.77) 
   Phet   0.22   0.47   0.02   0.09   0.03   0.48 
PR status 
 Negative 
  Category 1 23 530 0.55 (0.33–0.89) 96 1,254 0.69 (0.53–0.92) 39 759 0.51 (0.34–0.75) 98 1,380 0.63 (0.47–0.83) 181 1,357 1.57 (1.20–2.06) 96 782 1.25 (0.94–1.68) 
  Category 2 (ref) 72 1,016 1.00 (ref) 148 1,581 1.00 (ref) 96 948 1.00 (ref) 125 1,192 1.00 (ref) 96 1,087 1.00 (ref) 119 1,053 1.00 (ref) 
  Category 3 180 1,604 1.70 (1.27–2.28) 169 1,286 1.54 (1.21–1.96) 131 1,135 1.13 (0.86–1.50) 114 1,004 1.03 (0.79–1.36) 74 878 0.91 (0.66–1.26) 117 1,261 0.76 (0.58–1.00) 
  Category 4 132 922 2.29 (1.66–3.17) 63 365 2.13 (1.53–2.96) 141 1,230 1.13 (0.86–1.49) 139 910 1.38 (1.06–1.79) 56 750 0.69 (0.47–1.01) 144 1,390 0.69 (0.51–0.92) 
 Positive 
  Category 1 67 530 0.61 (0.45–0.83) 257 1,254 0.61 (0.51–0.73) 112 759 0.69 (0.53–0.88) 269 1,380 0.70 (0.58–0.85) 479 1,357 1.46 (1.23–1.75) 283 782 1.35 (1.11–1.63) 
  Category 2 (ref) 188 1,016 1.00 (ref) 431 1,581 1.00 (ref) 209 948 1.00 (ref) 306 1,192 1.00 (ref) 261 1,087 1.00 (ref) 327 1,053 1.00 (ref) 
  Category 3 462 1,604 1.61 (1.33–1.96) 509 1,286 1.64 (1.41–1.92) 303 1,135 1.19 (0.98–1.46) 367 1,004 1.39 (1.17–1.66) 222 878 1.05 (0.85–1.29) 368 1,261 0.82 (0.69–0.98) 
  Category 4 397 922 2.49 (2.02–3.08) 186 365 2.28 (1.83–2.83) 490 1,230 1.79 (1.49–2.15) 441 910 1.82 (1.53–2.16) 152 750 0.75 (0.59–0.96) 405 1,390 0.63 (0.52–0.77) 
   Phet   0.73   0.64   0.007   0.15   0.68   0.73 
HER2 status 
 Negative 
  Category 1 69 530 0.63 (0.46–0.85) 256 1,254 0.64 (0.53–0.77) 106 759 0.61 (0.47–0.79) 249 1,380 0.66 (0.55–0.80) 451 1,357 1.39 (1.17–1.67) 235 782 1.27 (1.03–1.55) 
  Category 2 (ref) 186 1,016 1.00 (ref) 405 1,581 1.00 (ref) 221 948 1.00 (ref) 296 1,192 1.00 (ref) 262 1,087 1.00 (ref) 281 1,053 1.00 (ref) 
  Category 3 455 1,604 1.64 (1.35–1.99) 443 1,286 1.53 (1.30–1.80) 294 1,135 1.10 (0.91–1.34) 319 1,004 1.26 (1.05–1.51) 219 878 1.03 (0.84–1.26) 347 1,261 0.91 (0.75–1.09) 
  Category 4 382 922 2.52 (2.04–3.13) 164 365 2.12 (1.69–2.65) 471 1,230 1.63 (1.35–1.95) 404 910 1.75 (1.47–2.09) 160 750 0.79 (0.62–1.01) 405 1,390 0.77 (0.63–0.93) 
 Positive 
  Category 1 10 530 0.54 (0.26–1.12) 42 1,254 0.71 (0.47–1.07) 20 759 0.68 (0.39–1.19) 43 1,380 0.63 (0.42–0.96) 106 1,357 1.48 (1.06–2.08) 48 782 1.24 (0.83–1.84) 
  Category 2 (ref) 31 1,016 1.00 (ref) 61 1,581 1.00 (ref) 38 948 1.00 (ref) 54 1,192 1.00 (ref) 59 1,087 1.00 (ref) 62 1,053 1.00 (ref) 
  Category 3 115 1,604 2.43 (1.60–3.67) 89 1,286 2.00 (1.42–2.82) 82 1,135 1.79 (1.21–2.66) 59 1,004 1.24 (0.84–1.81) 40 878 0.83 (0.54–1.26) 53 1,261 0.64 (0.44–0.94) 
  Category 4 75 922 2.82 (1.78–4.45) 31 365 2.51 (1.58–3.99) 91 1,230 1.82 (1.23–2.69) 67 910 1.55 (1.07–2.24) 26 750 0.54 (0.32–0.91) 60 1,390 0.50 (0.33–0.75) 
   Phet   0.11   0.54   0.07   0.92   0.38   0.16 

Abbreviation: Phet, test for heterogeneity in association by subtype.

aCategories are 1, 0%–10%; 2, 11%–25%; 3, 26%–50%; and 4, 51%+ for PMD and quartiles for DA and NDA.

bAdjusted for study site, age, and BMI.

cMixed and other histology categories are excluded.

Overall and invasive breast cancer and DCIS

Overall, DA was significantly positively associated with breast cancer risk while NDA was significantly inversely associated with breast cancer risk (Table 3) and across age groups (Table 4). Specifically, the ORs for overall breast cancer associated with DA were: Q1 versus Q2, 0.65; Q3 versus Q2, 1.22; Q4 versus Q2, 1.55 (Ptrend < 0.001) and the ORs for overall breast cancer associated with NDA were: Q1 versus Q2, 1.39; Q3 versus Q2, 0.88; Q4 versus Q2, 0.72 (Ptrend < 0.001). For DA, associations were similar by age; for NDA, however, the interaction with age was statistically significant (Page-interaction < 0.01) although the differences in associations by age were not clinically meaningful: <55 years (OR for Q1 vs. Q2, 1.44; 95% CI, 1.24–1.66) compared with those ≥55 years (corresponding OR, 1.33; 95% CI: 1.13–1.56; Table 4).

DA was significantly positively associated with both invasive breast cancer and DCIS across all age groups (Tables 3 and 4; Fig. 1). Among women ≥55 years, this association was stronger for invasive tumors than DCIS (Phet = 0.03; Table 4; Fig. 1); however, there was no evidence of a significant interaction between age and DA for associations with tumor type (Page-interaction = 0.41). Again, even though a statistically significant association was seen by age (Page-interaction = 0.02), NDA was significantly inversely associated with risk of both invasive breast cancer and DCIS among both younger and older women (Tables 3 and 4; Fig. 2).

Figure 1.

Associations of categorical DA for breast cancer tumor type and selected tumor characteristics of invasive breast cancer, by age. ORs and 95% CIs, adjusted for age, body mass index, and study, are shown for quartiles of DA. Tumor type (A), tumor size (B), ER status (C), and PR status (D).

Figure 1.

Associations of categorical DA for breast cancer tumor type and selected tumor characteristics of invasive breast cancer, by age. ORs and 95% CIs, adjusted for age, body mass index, and study, are shown for quartiles of DA. Tumor type (A), tumor size (B), ER status (C), and PR status (D).

Close modal
Figure 2.

Associations of categorical NDA for breast cancer tumor type and selected tumor characteristics of invasive breast cancer, by age. ORs and 95% CIs, adjusted for age, body mass index, and study, are shown for quartiles of NDA. Tumor type (A), tumor size (B), ER status (C), and PR status (D).

Figure 2.

Associations of categorical NDA for breast cancer tumor type and selected tumor characteristics of invasive breast cancer, by age. ORs and 95% CIs, adjusted for age, body mass index, and study, are shown for quartiles of NDA. Tumor type (A), tumor size (B), ER status (C), and PR status (D).

Close modal

Grade, invasive histology, size, and nodal status

DA was significantly positively associated with all invasive tumor characteristics evaluated while NDA was significantly inversely associated with these characteristics (Tables 3 and 4). While there were no differences in the magnitude of associations of DA or NDA with tumor histology, grade, or nodal involvement, we did observe heterogeneity of associations with tumor size. Specifically, DA was positively associated with invasive tumors of all sizes; however, stronger positive associations of DA and breast cancer were noted for larger tumors ≥2.1 cm compared with smaller tumors across all ages (Ptrend < 0.01; Fig. 1). For example, the overall ORs comparing women in Q4 of DA versus Q2 were 1.42, 1.50, and 2.13 for tumors <1.1 cm, 1.1–2.0 cm, ≥2.1 cm, respectively (Table 3) and findings were similar among ages <55 and ≥55 years (Table 4; Fig. 1; Page-interaction = 0.91). The opposite trend was observed for associations of NDA with tumor size, with a stronger inverse association noted for larger tumors compared with smaller tumors across age groups (Ptrend < 0.01), with the strongest associations most apparent for tumors 1.1–2.0 cm and 2.1+ cm in women ages <55 and ≥55 years (Table 4; Fig. 2). This trend was also similar across age (Page-interaction = 0.30).

ER, PR, and HER2 receptor status

Among women of all ages, stronger associations of DA were noted for ER+ and PR+ tumors compared with hormone receptor negative tumors (Phet < 0.01). Although there was no significant evidence of differences by age (Page-interaction > 0.38), among women <55 years, stronger associations were observed for ER+ (OR for Q4 versus Q2, 1.73; 95% CI, 1.45–2.07) vs. ER (corresponding OR, 1.01; 95% CI, 0.74–1.39; Phet = 0.02; Table 4; Fig. 1) and PR+ (OR for Q4 vs. Q2, 1.79; 95% CI, 1.49–2.15) vs. PR (corresponding OR, 1.13; 95% CI, 0.86–1.49; Phet = 0.01; Table 4; Fig. 1). Similarly, although not significantly different by age group (Page-interaction = 0.08), among women <55 years, NDA was more strongly inversely associated with ER tumors (OR for Q4 vs. Q2, 0.48; 95% CI, 0.30–0.77) than with ER+ tumors (corresponding OR, 0.8; 95% CI, 0.63–1.01; Phet = 0.03; Table 4; Fig. 2). In contrast, among women ages ≥55, DA and NDA were similarly associated with tumors defined by ER or PR status (Phet > 0.08; Table 4; Fig. 2). Finally, DA and NDA were similarly associated with tumors defined by HER2 status (Tables 3 and 4).

Results were not materially changed in models that included mutual adjustment for DA and NDA (data not shown). Finally, there was little evidence of differences across study (majority of P >0.09). Between-study heterogeneity was noted, however, for associations of DA with overall breast cancer (P = 0.02) and tumor histology (P = 0.04), suggesting caution when interpreting these results.

In this large study, the positive associations between PMD and breast cancer overall and by tumor characteristics were similar or stronger than in our first paper based on a subset of these data (3). In analyses of DA and NDA, we found that DA was significantly associated with increased breast cancer risk and NDA was significantly associated with decreased risk and that these were independent risk factors for breast cancer. Furthermore, statistically significant associations of the absolute DA and NDA measures with breast cancer were apparent for all tumor characteristics evaluated. Our findings suggest greater magnitude of association for DA with ER+ versus ER disease and PR+ versus PR disease and stronger associations of NDA with ER versus ER+ disease in women <55 years. We also observed significant positive and inverse trends for associations of DA and NDA, respectively, with tumor size across all ages.

Our findings of opposing associations of DA and NDA with breast cancer risk generally agree with most of the existing literature in this area, including a recent large meta-analysis that included several of the studies here (7). However, while the meta-analysis found that associations for NDA were attenuated in many studies upon adjustment for absolute DA (7), we did not observe attenuation in mutually adjusted models, possibly because correlations between DA and NDA were low (0.06–0.29) and similar across studies or because we adjusted for BMI, which is a surrogate for NDA. We conclude DA and absolute NDA are independent risk factors associated with breast cancer risk.

Few previous studies reported associations of absolute DA or NDA with breast cancer according to specific tumor characteristics. Consistent with our findings, in 601 cases and 667 controls from the Multiethnic Cohort, absolute DA was associated with both invasive breast cancer and DCIS (23); although in the current analysis, there was suggestion of a stronger association for invasive cancers versus DCIS among women ≥55 years. Also in the Multiethnic Cohort, stronger associations of DA with ER+/PR+ versus ER/PR tumors were observed (24). Like us, Eriksson and colleagues (25) reported stronger associations of absolute DA with ER+ versus ER tumors (P = 0.065) and with PR+ versus PR (P = 0.099) in a case-only study of 110 breast cancer patients. Positive associations of absolute DA with ER+ versus ER tumors and larger versus smaller tumors were also observed in recent UK case–control study (26). Similar to our findings, a case-only study among postmenopausal women (n = 286) reported a nonsignificant positive trend of DA with tumor size and a nonsignificant trend of NDA with tumor size as well as significant positive associations between DA and ER and PR positivity (27). Our study is among the first to comprehensively explore associations of absolute NDA with breast tumor characteristics and, to our knowledge, is the largest to date. Current hypotheses to explain associations between increased MD and breast cancer risk have been reviewed recently (28) and include the higher amount of fibroglandular tissue “at risk” of transformation into cancer (29) and the increased epithelial and fibroblast cellular activity and interaction between stroma and epithelium in dense tissue (30, 31) as well as hormonal mechanisms, including the influence of sex steroid hormones and growth factors on density and breast cancer risk (32). Evaluating associations by tumor characteristics can provide insight into these hypothesized mechanisms. If the mechanism of action were purely through hormonal influences, then we might expect to observe associations of DA with ER+ tumors only; however, we observed significant positive associations of DA with both ER+ and ER tumors, although the magnitude of association was greater for ER+ tumors among women <55 years. Moreover, we observed strong inverse associations of NDA with ER tumors in this age group, independent of DA. Our findings of independent associations of DA and NDA with breast cancer risk across tumor characteristics suggest that several causal pathways may play a role in associations with risk. Petterson and Tamimi (33) propose several mechanisms by which breast fat (NDA) may lead to reduced risk of breast cancer, including the possible direct effect of adipose tissue on normal breast development, indirect effects of adipose tissue in regard to the endocrine environment of the breast, or via lobular involution, which is positively correlated with NDA and inversely associated with breast cancer risk (34). On the other hand, some studies have suggested breast fat as a risk factor for breast cancer (6, 35).

As in our previously published analysis based on a subset of these data (3), we found that PMD was more strongly associated with risk of ER breast cancer than with ER+ breast cancer among women <55 years of age. Our current findings of the MD area phenotypes further suggest that the positive association observed between PMD and ER disease among women <55 years is driven by the inverse association of NDA with ER disease in this group, rather than by a positive association with absolute dense breast area. On the basis of the results of our analyses and considering the current body of published literature on this topic, it appears that breast density (including percent and area measures) plays an important role in tumor aggressiveness, especially in younger women, giving differential associations observed with respect to tumor size, nodal status as well as ER status. In light of the lack of significant age-interaction, however, we cannot discount an association of MD phenotypes with tumor aggressiveness among older women.

Limitations of the study have been described (3) and include variation in study design and populations, use of clinical pathology as opposed to central pathology review; changes in diagnostic criteria over time that may influence tumor characteristics and receptor status, in particular, and generalizability of results primarily to Caucasian women. Even with > 4,000 cases, power to detect age-interactions remained limited. Detection bias is also a potential limitation, given that extent of breast density may make earlier tumors more difficult to detect on screening mammogram (36). While we were not able to evaluate the influence of detection bias directly in this analysis due to the lack of high-quality data regarding interval versus screen-detected cancers for most included studies, in the Breast Cancer Surveillance Consortium, Kerlikowske and colleagues reported that higher breast density in premenopausal women was more strongly related to aggressive tumors and that this finding persisted in analyses restricted to screen-detected cases only (37). We did find evidence of study heterogeneity for the analyses of DA with overall breast cancer and by invasive versus in situ status, so these results should be cautiously interpreted. However, our associations of these absolute measures with overall breast cancer were consistent with the literature. Finally, this study relied on digitized film mammograms versus more contemporary full-field digital mammograms.

Strengths of this pooled analysis include the large sample size with mammograms available years before the cancer (for cases), standardized estimates of NDA and DA, detailed information on covariates and tumor characteristics from pathology reports, supplemented with information from TMAs, and screening mammograms assessed in a generally systematic fashion.

In summary, we found that PMD and absolute dense breast area were associated with increased breast cancer risk while NDA was associated with decreased risk across all ages and invasive tumor characteristics. Among women <55 years, DA was more strongly associated with an increased risk for ER+ versus ER tumors (Phet = 0.02) while NDA was more strongly associated with a decreased risk for ER versus ER+ tumors (Phet = 0.03). DA was similarly associated with increased risk (and NDA decreased risk) of both node-positive and node-negative tumors, while significant trends in the magnitude of these associations were observed with increasing tumor size.

Our results suggest DA is positively associated (and NDA, inversely associated) with breast cancer across tumor characteristics. Furthermore, these results suggest differential associations for these phenotypes with ER+ versus ER tumors, particularly in younger women. As such, DA and NDA may be important to consider when developing age- and subtype-specific risk models for breast cancer. Further research is warranted to clarify the possible differential associations of DA and NDA on breast cancer risk according to tumor characteristics.

No potential conflicts of interest were disclosed.

Conception and design: K.A. Bertrand, C.G. Scott, R.M. Tamimi, F.J. Couch, S.R. Cummings, K. Kerlikowske, C.M. Vachon

Development of methodology: K.A. Bertrand, C.G. Scott, K. Kerlikowske

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): K.A. Bertrand, C.G. Scott, R.M. Tamimi, D.W. Visscher, F.J. Couch, J.A. Shepherd, Y.-Y. Chen, L. Ma, A.H. Beck, K. Kerlikowske, C.M. Vachon

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K.A. Bertrand, C.G. Scott, M.R. Jensen, V.S. Pankratz, D.W. Visscher, J.A. Shepherd, Y.-Y. Chen, B. Fan, A.H. Beck, K. Kerlikowske, C.M. Vachon

Writing, review, and/or revision of the manuscript: K.A. Bertrand, C.G. Scott, R.M. Tamimi, V.S. Pankratz, A.D. Norman, D.W. Visscher, F.J. Couch, J.A. Shepherd, Y.-Y. Chen, B. Fan, A.H. Beck, S.R. Cummings, K. Kerlikowske, C.M. Vachon

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.D. Norman, F.J. Couch, C.M. Vachon

Study supervision: K.A. Bertrand, R.M. Tamimi, L. Ma, K. Kerlikowske, C.M. Vachon

Other (IT support): F.-F. Wu, K. Kerlikowske

The authors thank the participants and staff of all the studies for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, MN, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WI, WY. The authors assume full responsibility for analyses and interpretation of these data.

This work was supported in part by the following NIH, NCI grants: R01 CA140286, R01 CA128931, and R01 CA97396 (to C.M. Vachon); R01 CA124865 and R01 CA131332 (to R.M. Tamimi); P50 CA116201 to Dr. Ingle (F.J. Couch has Project on SPORE); P50 CA58207, U01 CA63740, and P01 CA154292 (to K. Kerlikowske); R01 CA116167 (to F.J. Couch); P01CA087969 and UM1 CA186107 to Dr. Stampfer (supporting NHS); and R01 CA050385, UM1 CA176726, and Breast Cancer Research Foundation to Dr. Willett (supporting NHS2). Additional support was provided by the Simeon J. Fortin Charitable Foundation, Bank of America, N.A., Co-Trustee to Dr. Bertrand; Department of Defense (DAMD 17-00-1-033; to Dr. C.M. Vachon).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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