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Supplementary Table 1. Relationship of square-root transformed percent density to age at menarche and late adolescent BMI; Supplementary Table 2. Relationship of cube-root transformed dense area to age at menarche and late adolescent BMI ;Supplementary Table 3. Effect modification by menopause of the associations of late adolescent BMI with percent density and dense area.

Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density.Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders.Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend P value for trend 16 years was associated with an increase in PD of 1.47% (95% CI, 0.69–2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48–2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models.Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images.Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. Cancer Epidemiol Biomarkers Prev; 26(9); 1450–8. ©2017 AACR.

Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Results: Alcohol use was positively associated with PD (Ptrend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

Background: High percent density (PD) is common and is among the strongest risk factors for breast cancer. The prevalence of heterogeneously dense or extremely dense breasts is between 40% to 60% of screening age women, and is estimated to account for up to one third of all breast cancer (BC) diagnoses. PD decreases with age, body mass index (BMI), number of children, and menopause; and increases with age at menarche, age at first birth, and family history of breast cancer. Of particular interest are modifiable exposures believed to alter PD, such as the use of menopausal hormone therapy (MHT), tamoxifen and alcohol that could provide opportunities for women to reduce their BC risk. The dense area (DA) of the breast appears radiopaque on a mammogram and contains greater proportions of collagen, epithelial and stromal cells compared to the nondense area (NDA), which largely consists of fatty tissue. Recent studies have shown that NDA is inversely associated with BC risk, independently of DA, suggesting that normal breast fat may play a protective role. The underlying mechanisms through which mammographic density (MD) phenotypes are associated with BC risk are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric (GE). MD measurements were obtained using Cumulus an average of 2.9 years after the survey date. Machine-specific effects were estimated using linear regression, adjusted for known biologically plausible correlates of MD, and combined using random effects meta-analysis methods. Results: Alcohol use was positively associated with PD (ptrend=0.01), unassociated with DA (ptrend=0.23), and inversely associated with NDA (ptrend=0.02) in models adjusted for age, BMI, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (ptrend=0.0008), unassociated with DA (ptrend=0.93), and positively associated with NDA (ptrend Conclusions: This study provides the strongest evidence to date that association of alcohol and tobacco use with PD result from their associations with NDA rather than DA. Impact: Alcohol consumption, and less consistently tobacco use, have been shown to increase risk of breast cancer. These findings indicate that PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health. Citation Format: Russell B McBride, Kezhen Fei, Joseph H Rothstein, Stacey E Alexeeff, Xiaoyu Song, Lori C Sakoda, Valerie McGuire, Ninah Achacoso, Luana Acton, Rhea Y Liang, Jafi A Lipson, Martin J Yaffe, Daniel L Rubin, Alice S Whittemore, Laurel A Habel, Weiva Sieh. Alcohol and tobacco use in relation to mammographic density in 23,456 women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-01.

Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density.Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders.Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend 16 years was associated with an increase in PD of 1.47% (95% CI, 0.69–2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48–2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models.Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images.Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. Cancer Epidemiol Biomarkers Prev; 26(9); 1450–8. ©2017 AACR.

Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40-74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc., Marlborough, Massachusetts) or General Electric (General Electric Company, Boston, Massachusetts) FFDM machines between 2003 and 2013. We estimated the associations of parity, age at first birth, age at menarche, and menopausal status with percent density and dense area as measured by a single radiological technologist using Cumulus software (Canto Software, Inc., San Francisco, California). We found that associations between reproductive factors and mammographic density measured using processed FFDM images were generally similar in magnitude and direction to those from prior studies using film mammography. Estimated associations for both types of FFDM machines were in the same direction. There was some evidence of heterogeneity in the magnitude of the effect sizes by machine type, which we accounted for using random-effects meta-analysis when combining results. Our findings demonstrate the robustness of quantitative mammographic density measurements across FFDM and film mammography platforms.

We examined the clinical/pathologic features of ipsilateral second breast cancers (IP-SBCs) following breast-conserving surgery (BCS) for DCIS among community-treated patients and ascertained the degree of correlation between the features of index DCIS and IP-SBC events. From a Cancer Research Network cohort of DCIS patients diagnosed 1990-2001 and treated with BCS, we identified women who subsequently developed an ipsilateral DCIS or invasive breast cancer. All index DCIS tumors underwent expert pathology review. Pathologic characteristics of IP-SBCs were abstracted from available medical records. Logistic regression was used to examine associations between pathologic characteristics and identify factors associated with invasive versus non-invasive IP-SBC. Of 1969 DCIS patients, 182 developed an IP-SBC within a median of 38 months (range 6-160). IP-SBCs were slightly more commonly non-invasive (53 %) versus invasive (47 %). Of invasive IP-SBCs, 31 % were high grade, 67 % were

PURPOSE: To assess the feasibility of quantifying long-term trends in breast tumor DNA copy number variation (CNV) profiles. METHODS: We evaluated CNV profiles in formalin-fixed paraffin-embedded (FFPE) tumor specimens from 30 randomly selected Kaiser Permanente Northern California health plan women members diagnosed with breast cancer from 1950–2010. Assays were conducted for five cases per decade who had available tumor blocks and pathology reports. RESULTS: As compared to the tumors from the 1970s to 2000s, the older tumors dating back to the 1950s and 1960s were much more likely to: (1) fail quality control, and (2) have fewer CNV events (average: 23 and 31 vs. 58 to 69), fewer CNV genes (average: 5.1k and 3.7k vs 8.1k to 10.3k), shorter CNV length (average: 2,440k and 3,300k vs. 5,740k to 9,280k), fewer high frequency Del genes (37% and 25% vs. 54% to 76%) and fewer high frequency high_Amp genes (20% vs. 56% to 73%). On average, assay interpretation took an extra 60 minutes/specimen for cases from the 1960s vs. 20 minutes/specimen for the most recent tumors. CONCLUSIONS: Assays conducted in the mid-2010s for CNVs may be feasible for FFPE tumor specimens dating back to the 1980s, but less feasible for older specimens.

Background Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care. Methods We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use. Results Median intra-reader reproducibility was high with a Pearson’s r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm2 (18.22 cm2) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41–2.04) for PD, and 1.54 (1.34–1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91–2.45), 2.57 (1.54–4.30), 3.22 (1.91–5.43), 4.88 (2.78–8.55) for PD, and 1.00 (ref.), 1.43 (0.85–2.40), 2.53 (1.53–4.19), 2.85 (1.73–4.69), 3.48 (2.14–5.65) for DA. Conclusions PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research.

Background: We examined whether mammographic density predicts risk of second breast cancers among patients with ductal carcinoma in situ (DCIS). Methods: The study included DCIS patients diagnosed during 1990 to 1997 and treated with breast-conserving surgery at Kaiser Permanente Northern California. Medical records were reviewed for clinical factors and subsequent breast cancers (DCIS and invasive). Ipsilateral mammograms from the index DCIS were assessed for density without knowledge of subsequent cancer status. Cox regression modeling was used to examine the association between mammographic density and risk of breast cancer events. Results: Of the 935 eligible DCIS patients, 164 (18%) had a subsequent ipsilateral breast cancer, and 59 (6%) had a new primary cancer in the contralateral breast during follow-up (median, 103 mo). Those with the greatest total area of density (upper 20% of values) were at increased risk for invasive disease in either breast [hazard ratio (HR), 2.1; 95% confidence interval (95% CI), 1.2-3.8] or any cancer (DCIS or invasive) in the ipsilateral (HR, 1.7; 95% CI, 1.0-2.9) or contralateral (HR, 3.0; 95% CI, 1.3-6.9) breast compared with those with the smallest area of density (bottom 20%). HRs for these same end points comparing those in the highest with those in the lowest American College of Radiology Breast Imaging Reporting and Data System category were 1.6 (95% CI, 0.7-3.6), 1.3 (95% CI, 0.7-2.6), and 5.0 (95% CI, 1.4-17.9), respectively. There was a suggestion of increasing risk of contralateral, but not ipsilateral, cancer with increasing percent density. Conclusions: Women with mammographically dense breasts may be at higher risk of subsequent breast cancer, especially in the contralateral breast. Impact: Information about mammographic density may help with DCIS treatment decisions. Cancer Epidemiol Biomarkers Prev; 19(10); 2488–95. ©2010 AACR.

The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences.We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182).Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09).We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered.

Determining long-term trends in tumor biomarker expression is essential for understanding aspects of tumor biology amenable to change. Limiting the availability of such data, currently used assays for biomarkers are relatively new. For example, assays for the estrogen receptor (ER), which are the oldest, extend back only to the 1970s. To extend scant knowledge about the feasibility of obtaining long-term data on tumor biomarkers, we randomly selected 60 breast cancer cases (10 per decade) diagnosed between 1947–2009 among women members of the Kaiser Permanente Northern California health plan to obtain and analyze their formalin-fixed paraffin-embedded (FFPE) tumor specimens. For each tumor specimen, we created duplicate tissue microarrays for analysis. We located tumor blocks and pathology reports for 50 of the 60 cases (83%), from which we randomly sampled 5 cases per decade for biomarker analysis (n=30). All 30 cases displayed excellent morphology and exhibited biomarkers compatible with histologic type and grade. Test–retest reliability was also excellent: 100% for ER; 97% for human epidermal growth factor receptor 2 and epidermal growth factor receptor; 93% for progesterone receptor and cytokeratin 5/6; and 90% for Ki67 and molecular phenotype; the kappa statistic was excellent (>0.9) for 4 of the 7 biomarkers, strong (0.6–0.8) for 2, and fair for only 1 (owing to low prevalence). These results indicate immunostaining for biomarkers commonly used to evaluate breast cancer biology and assign surrogate molecular phenotypes can reliably be employed on archival FFPE specimens up to 60 years old. Current biomarker-based methods for assessing breast cancer tumors can be used reliably on decades-old specimens to analyze long-term trends. Tumor biology is susceptible to changes from both external and internal sources over time. For example, the recent global rise and fall of breast cancer cases has been linked specifically to postmenopausal hormone therapy. Nancy Krieger at the Harvard T. H. Chan School of Public Health in Boston, United States, and co-workers tested whether modern biomarkers could be used to accurately assess tumor tissues that had been kept in storage for decades. The team randomly sampled five cases per decade from 1947 to 2009. Contemporary immunostaining techniques gave the researchers clear and definitive morphologic and molecular information for the majority of samples. The team therefore encourage investigations into long-term trends using stored tumor specimens.

Introduction Randomized trials indicate that adjuvant radiotherapy plus tamoxifen decrease the five-year risk of recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery from about 20% to 8%. The aims of this study were to examine the use and impact of these therapies on risk of recurrence among ductal carcinoma in situ patients diagnosed and treated in the community setting. Methods We identified 2,995 patients diagnosed with ductal carcinoma in situ between 1990 and 2001 and treated with breast-conserving surgery at three large health plans. Medical charts were reviewed to confirm diagnosis and treatment and to obtain information on subsequent breast cancers. On a subset of patients, slides from the index ductal carcinoma in situ were reviewed for histopathologic features. Cumulative incidence curves were generated and Cox regression was used to examine changes in five-year risk of recurrence across diagnosis years, with and without adjusting for trends in use of adjuvant therapies. Results Use of radiotherapy increased from 25.8% in 1990-1991 to 61.3% in 2000-2001; tamoxifen increased from 2.3% to 34.4%. A total of 245 patients had a local recurrence within five years of their index ductal carcinoma in situ. The five-year risk of any local recurrence decreased from 14.3% (95% confidence interval 9.8 to 18.7) for patients diagnosed in 1990-1991 to 7.7% (95% confidence interval 5.5 to 9.9) for patients diagnosed in 1998-1999; invasive recurrence decreased from 7.0% (95% confidence interval 3.8 to 10.3) to 3.1% (95% confidence interval 1.7 to 4.6). In Cox models, the association between diagnosis year and risk of recurrence was modestly attenuated after accounting for use of adjuvant therapy. Between 1990-1991 and 2000-2001, the proportion of patients with tumors with high nuclear grade decreased from 46% to 32% (P = 0.03) and those with involved surgical margins dropped from 15% to 0% (P = 0.03). Conclusions The marked increase in the 1990s in the use of adjuvant therapy for ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting only partially explains the 50% decline in risk of recurrence. Changes in pathology factors have likely also contributed to this decline.