Associations Of Breast Cancer Risk Factors Research Articles

Abstract P3-01-26: Mammographic density in relation to breast cancer risk factors among Chinese women

Abstract Higher mammographic density (MD) is a known risk factor for breast cancer (BC), however, studies examining determinants of density in Chinese populations are limited. Asian women tend to have higher MD compared to European women, and yet they have a lower overall BC incidence rate. The goal of this study was to investigate the influence of established BC risk factors on quantitatively measured MD among Chinese women. The study population included 7,351 Chinese women, who had mammograms at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, between 2016 and 2017 for different indications, including but not limited to screening exam, breast pain, and suspected breast tumors. Only subjects with BI-RADS (Breast Imaging-Reporting and Data System) diagnostic classification of 1 (negative, n= 2,293), 2 (benign, n= 3,519), and 3 (probably benign, n= 1,539) were included in this analysis. VolparaDensity software was used to obtain quantitative MD measures including absolute dense breast volume and percent breast density. We conducted multivariable linear regression modeling on each density measurement to test for its associations with well-established breast cancer risk factors. The mean age of this study population was 50.1 years old (range= (25, 82)), the average body mass index (BMI) was 24.0 kg/m2 (range= (14.2, 48.9)), and about 46% of women were postmenopausal. The mean absolute dense and percent dense volumes were 58.4 (SD= 32.1) and 14.8 (SD= 7.1, equivalent to Volpara Density Grade= 3), respectively. Associations between quantitative MD measures and BC risk factors did not vary significantly across the three BI-RADS diagnostic classes and we therefore combined these patients in subsequent analyses. Most risk factors we examined showed similar associations with dense volume and percent density. For example, both dense volume and percent density were inversely associated with age, parity, longer duration (> 1 year) of breastfeeding, and postmenopausal status, while they were positively associated with age at menopause. In contrast, the associations with age at menarche and BMI showed opposite directions for dense volume and percent density. While increasing BMI was positively associated with dense volume, it was inversely associated with percent density. Age at menarche, however, was inversely correlated with dense volume, but positively associated with percent density. When stratifying by menopausal status, the associations for age, BMI, and parity were similar among pre- and post-menopausal women, while the associations for age at first birth and breastfeeding were stronger among postmenopausal women. In general, observed breast cancer risk factor associations with quantitative breast density metrics in this Chinese population are similar to those previously reported in Western women. We did not observe striking differences in associations of breast density with reproductive factors and BMI among Asian women in this large analysis based on quantitative density measurements. Other risk factors such as genetic susceptibility loci associated with MD should be examined in large Asian studies to further our understanding on how MD influences breast cancer risk in Asian populations. Citation Format: Hela Koka, Yuan Tian, Deng Lu, Kai Yu, Er-Ni Li, Changyuan Guo, Bin Zhu, Jennifer L Guida, Ariane Chan, Nan Hu, Ning Lu, Gretchen Gierach, Jing Li, Xiaohong R Yang. Mammographic density in relation to breast cancer risk factors among Chinese women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-26.

Differences in breast cancer-risk factors between screen-detected and non-screen-detected cases (MCC-Spain study)

PurposeThe variation in breast cancer (BC)-risk factor associations between screen-detected (SD) and non-screen-detected (NSD) tumors has been poorly studied, despite the interest of this aspect in risk assessment and prevention. This study analyzes the differences in breast cancer-risk factor associations according to detection method and tumor phenotype in Spanish women aged between 50 and 69.MethodsWe examined 900 BC cases and 896 controls aged between 50 and 69, recruited in the multicase–control MCC-Spain study. With regard to the cases, 460 were detected by screening mammography, whereas 144 were diagnosed by other means. By tumor phenotype, 591 were HR+, 153 were HER2+, and 58 were TN. Lifestyle, reproductive factors, family history of BC, and tumor characteristics were analyzed. Logistic regression models were used to compare cases vs. controls and SD vs. NSD cases. Multinomial regression models (controls used as a reference) were adjusted for case analysis according to phenotype and detection method.ResultsTN was associated with a lower risk of SD BC (OR 0.30 IC 0.10–0.89), as were intermediate (OR 0.18 IC 0.07–0.44) and advanced stages at diagnosis (OR 0.11 IC 0.03–0.34). Nulliparity in postmenopausal women and age at menopause were related to an increased risk of SD BC (OR 1.60 IC 1.08–2.36; OR 1.48 IC 1.09–2.00, respectively). Nulliparity in postmenopausal women was associated with a higher risk of HR+ (OR 1.66 IC 1.15–2.40). Age at menopause was related to a greater risk of HR+ (OR 1.60 IC 1.22–2.11) and HER2+ (OR 1.59 IC 1.03–2.45) tumors.ConclusionReproductive risk factors are associated with SD BC, as are HR+ tumors. Differences in BC-risk factor associations according to detection method may be related to prevailing phenotypes among categories.

Abstract 3286: Breast cancer risk factors and survival by tumor subtypes: A pooled analysis from the breast cancer association consortium studies

Abstract Background: Breast cancer (BC) is a heterogeneous disease with differing risk factors, prognosis and response to treatment strategies. Lifestyle and personal factors have been shown to influence BC prognosis. It is unknown whether lifestyle factors are differentially associated with prognosis according to BC subtypes. Methods: Analyses were based on 102,823 BC patients from 58 studies participating in the Breast Cancer Association Consortium. Cox regression models were used to assess associations between prediagnosis lifestyle and reproductive BC risk factors—including age at menarche, age at first full-term pregnancy, parity, breastfeeding, time since last full-term birth, BMI, oral contraceptive (OC) use, use of estrogen and progesterone therapy (EPT) and cigarette smoking- and 10-year overall survival (OS) and BC survival in all patients and by tumor subtypes. We used two tumor classifications: by estrogen receptor (ER) status; and by invasive subtypes based on ER, progesterone receptor, the human epidermal growth factor receptor 2 (HER2), and grade. Multiple imputation of risk factors and clinico-pathological variables was performed simultaneously. All analyses were stratified by study and adjusted for age at diagnosis, tumor size, nodal status, tumor grade (except for the luminal B HER2- subgroup), and systemic treatment. Multiple testing was accounted for using Bonferroni correction. Results: There were a total of 13,953 total deaths and 6,893 BC deaths over 10 years. The most significant associations were observed between OS and the following risk factors: parous vs nulliparous (HR (95%CI): 0.84 (0.78,0.89), P=1.4E-07); OC use vs never use (0.82 (0.78,0.87), P=1.2E-11); EPT use vs never use (0.64 (0.58,0.70), P=1.5E-19); BMI > 30 kg/m2 vs 18.5-25.0 kg/m2 in postmenopausal women (1.25 (1.17,1.34), P=1.9E-10 and 1.34 (1.18, 1.53), P=4.6E-06 in premenopausal women); cigarette smoking vs nonsmokers (1.37 (1.28,1.47), P=2.1E-19); time since last full-term birth < 5 years vs ≥ 10 years (2.09 (1.78, 2.44), P=1.3E-19). Associations with BC survival were similar to those for OS but weaker. We observed no differential associations by tumor subtype. The strongest evidence of subtype differential effects was for time since last full-term birth < 5 years vs ≥ 10 years for luminal A (3.00 (2.25,3.98)) vs luminal B-HER2- (1.69 (1.27,2.24)), HER2+ enriched (1.40 (0.96,2.05)), and triple negative (1.49 (1.15,1.93)), respectively. Multivariable models are being constructed to account for the interplay between risk factors. Conclusion: Our results suggest that BC risk factors influence survival after diagnosis. The effect appears to be stronger when OS is considered as endpoint, which may be due to power or associations of BC risk factors with other diseases. The data did not support a strong differential effect of BC risk factors on prognosis by tumor subtype. Citation Format: Anna Morra, Audrey Y. Jung, Sabine Behrens, Rose Yang, Heather Eliassen, Michelle Holmes, Montserrat Garcia-Closas, Marjanka K. Schmidt, Jenny Chang-Claude, on behalf of the Breast Cancer Association Consortium. Breast cancer risk factors and survival by tumor subtypes: A pooled analysis from the breast cancer association consortium studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3286.

Abstract 3451: Breast cancer risk factor associations by loss of E-cadherin tumor tissue expression: A pooled analysis of 5,896 cases in 12 studies from the Breast Cancer Association Consortium (BCAC)

Abstract Purpose: Expression of the tumor suppressor gene E-cadherin is diminished in lobular breast cancers and has been implicated in epithelial mesenchymal transition. We assessed risk factor associations for breast cancer stratified by low vs. high E-cadherin protein expression in a pooled analysis within the Breast Cancer Association Consortium (BCAC) studies. Methods: E-cadherin tumor tissue staining was performed centrally at the NCI on formalin-fixed paraffin-embedded tissue microarray (TMA) sections representing 6,010 breast cancer patients from 12 US and European BCAC studies. TMAs were digitally scanned and scored using the SlidePath Digital Image Hub (Leica Biosystems, Wetzlar, Germany). For 5,896 cancers with evaluable tumors, E-cadherin was visually scored as estimated percent of positive cells times stain intensity (0, 1+, 2+, 3+) (score range 0-300). E-cadherin low was defined as tumors with a score < 100. Risk factor associations for low vs. high E-cadherin expressing tumors were evaluated by logistic regression, adjusted for age and study site, and stratified by ER status and histologic subtype. To assess the consistency in results by study, meta-analyses were performed using the random-effects model. All statistical tests were two-sided. Results: E-cadherin low cancers comprised 20% of tumors and were associated with lobular histology, well/moderately differentiated cancers, > 2cm in size, and HER2-negative status (χ2, P < 0.003 for all factors). E-cadherin low status was associated with family history of breast cancer (FH) (OR = 1.32, 95% CI = 1.09-1.60, P-het = 0.005) and ever use of menopausal hormones (OR = 1.26, 95% CI = 1.02-1.56, P-het = 0.03). Study specific meta-plots showed consistent effects across studies for menopausal hormone therapy (I2 = 0.0%, p = 0.64); however, E-cadherin loss by FH did show evidence of heterogeneity by study (I2 = 54%, P = 0.03). Differences in E-cadherin expression remained significant for FH, and menopausal hormone use when further adjusted for ER (P < 0.05). We also found relationships with E-cadherin loss to vary by BMI, number of live births, age at first birth, and oral contraceptive use in stratified analysis by ER status and histologic subtype. Conclusion: This large pooled analysis shows that breast cancer risk factor associations may differ by E-cadherin expression independent of ER status, suggesting that it may represent a marker of etiologic heterogeneity. Citation Format: Hisani N. Horne, Hannah Oh, Mark E. Sherman, Maya Palakal, Stephen H. Hewitt, Marjanka Schmidt, Javier Benitez, Roger Milne, Hermann Brenner, Heli Nevanlinna, Arto Mannermaa, Georgia Chenevix-Trench, Fergus Couch, Peter Devilee, Diana Eccles, Maartje Hooning, Anthony J. Swerdlow, Nick Orr, Melissa A. Troester, Renata Cora, Paul D. Pharoah, Montserrat Garcia-Closas, Jonine D. Figueroa. Breast cancer risk factor associations by loss of E-cadherin tumor tissue expression: A pooled analysis of 5,896 cases in 12 studies from the Breast Cancer Association Consortium (BCAC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3451.

Breast cancer risk factor associations differ for pure versus invasive carcinoma with an in situ component in case-control and case-case analyses.

Invasive ductal carcinoma (IDC) is diagnosed with or without a ductal carcinoma in situ (DCIS) component. Previous analyses have found significant differences in tumor characteristics between pure IDC lacking DCIS and mixed IDC with DCIS. We will test our hypothesis that pure IDC represents a form of breast cancer with etiology and risk factors distinct from mixed IDC/DCIS. We compared reproductive risk factors for breast cancer risk, as well as family and smoking history between 831 women with mixed IDC/DCIS (n = 650) or pure IDC (n = 181), and 1,620 controls, in the context of the Women's Circle of Health Study (WCHS), a case-control study of breast cancer in African-American and European-American women. Data on reproductive and lifestyle factors were collected during interviews, and tumor characteristics were abstracted from pathology reports. Case-control and case-case analyses were conducted using unconditional logistic regression. Most risk factors were similarly associated with pure IDC and mixed IDC/DCIS. However, among postmenopausal women, risk of pure IDC was lower in women with body mass index (BMI) 25 to <30 [odds ratio (OR) 0.66; 95 % confidence interval (CI) 0.35-1.23] and BMI ≥ 30 (OR 0.33; 95 % CI 0.18-0.67) compared to women with BMI < 25, with no associations with mixed IDC/DCIS. In case-case analyses, women who breastfed up to 12 months (OR 0.55; 95 % CI 0.32-0.94) or longer (OR 0.47; 95 % CI 0.26-0.87) showed decreased odds of pure IDC than mixed IDC/DCIS compared to those who did not breastfeed. Associations with some breast cancer risk factors differed between mixed IDC/DCIS and pure IDC, potentially suggesting differential developmental pathways. These findings, if confirmed in a larger study, will provide a better understanding of the developmental patterns of breast cancer and the influence of modifiable risk factors, which in turn could lead to better preventive measures for pure IDC, which have worse disease prognosis compared to mixed IDC/DCIS.

Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue expression

E-cadherin is involved in cell-cell adhesion and epithelial-to-mesenchymal transitions. In cancers, loss or inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to determine, if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs) differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on 1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and 6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity was used to follow-up promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more strongly associated with risk of E-cadherin low tumors (OR=1.30, 95% CI = 1.08-1.56) than with E-cadherin high tumors [OR=1.06, 95% CI = 0.95-1.18; case-only p-heterogeneity (p-het)=0.05]. Findings in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only p-het=0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors that were ER-positive and of lobular histology. Our results in two independent data sets suggest that rs11249433, which is located between the NOTCH2 and FCGR1B genes within the 1p11.2 locus, is more strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor associations.

Abstract 4465: Breast cancer risk factor associations with breast tissue morphometry: results from the Komen for the Cure® Tissue Bank

Abstract Little is known about the effects of many recognized breast cancer risk factors on the normal breast. We hypothesize that risk factors affect the number and morphometry of terminal ductal lobular units (TDLUs), the microanatomical structure from which most breast cancers arise. To assess this hypothesis, we evaluated relationships between breast cancer risk factors and TDLU number, TDLU diameter, and acini per TDLU in breast tissue donated by healthy volunteers. Subjects included 786 healthy women ages 18-84 years without a personal history of any cancer, who provided a risk factor questionnaire and donated a 10-guage needle core from the upper outer breast quadrant. A pathologist, masked to subject data, assessed TDLU number per section, TDLU diameter and acini per TDLU using digitized images of hematoxylin and eosin stained sections of tissue. Seventy-two randomly selected images were examined by two additional pathologists. We generated ordered categorical variables for the number of TDLUs per section (0-1, 2-8, 9+), median TDLU diameter (53-262, 263-377, 378-1375 microns) and median number of acini per TDLU (2-10, 11-20, 21+). We computed Spearman correlations between measures, and intraobserver and interobserver agreement. Associations between breast cancer risk factors and TDLU measures were assessed by estimating odds ratios (OR) and 95% confidence intervals (CI) using ordinal logistic regression models, adjusted for age. TDLU diameter and acini count were highly correlated (rho =0.71); TDLU number per section was less strongly related to the diameter (rho= 0.18) and acini measures (rho=0.20). Inter and intraobserver agreement for TDLU measures were highly correlated (rho range 0.68-0.98). All TDLU measurements were significantly lower among women age 50 years and older compared with younger women. Compared with Caucasians, African American women had more TDLUs per section (ORadj=2.03, 95% CI= 1.06-3.89). Greater numbers of TDLUs were also related to having a family history of two or more relatives with breast cancer compared with none (ORadj=2.01, 95% CI=0.91-4.46); and for parous compared with nulliparous women (ORadj=1.61, 95% CI=1.16-2.25). In contrast, parity was associated with reduced median number of acini per TDLU (ORadj=0.60, 95% CI = 0.40-0.90) and median diameter (ORadj=0.64, 95% CI = 0.42-0.96) compared with nulliparity. Our data suggest that TDLUs are more frequent among women with a positive family history of breast cancer or African Americans. Parity, an established protective factor for breast cancer risk, was related to increased numbers of TDLUs, but fewer acini per TDLU, suggesting that TDLUs may increase with pregnancy and then involute. Our data, along with published results linking TDLU involution with a reduction in breast cancer risk, suggest TDLU morphometry may reflect early biologic changes marking breast cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4465. doi:1538-7445.AM2012-4465

P4-10-03: Association between BMI, Physical Activity and Breast Cancer Histologic Types.

Abstract Background: Previous research indicates that certain breast cancer risk factor associations vary by histologic tumor type. However, most studies have been too small to examine risk factors for uncommon histologic types. We examined the association between body mass index (BMI), physical activity, and the relative risk of breast cancer histologic types in a large prospective cohort study to determine whether associations for these risk factors varied by histology. Methods: This analysis included women in the NIH-AARP Diet and Health Cohort Study who were 50 to 71 years old, postmenopausal at baseline, and not previously diagnosed with cancer (N=190,348). The study cohort was established in 1995–1996 when participants completed a baseline questionnaire regarding health and nutritional information. BMI (kg/m2) was calculated from self-reported height and weight. Daily routine physical activity at work or home was derived from a question asking women what best described their daily routine at work, or throughout the day if they did not work at a job. Choices were mostly sitting with little walking, sitting with a fair amount of walking, mostly standing or walking, light lifting or climbing stairs/hills, or heavy work/carrying heavy loads. Cancer diagnosis and histology were obtained from state cancer registries. This analysis includes participant follow-up through December 31, 2006. After a median 11.2 years of follow-up, 7,631 invasive breast cancers were diagnosed: 5,278 ductal, 831 lobular, 640 mixed ductal-lobular, 214 mucinous, 132 tubular, and 536 other types. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Results: Compared to women with a BMI of 18.5 to 24.9, obese women had increased risks of ductal (HR and 95% CI for BMI 30 to 34.9: 1.24, 1.14 — 1.36; BMI ≥ 35: 1.45, 1.30 — 1.62) and mucinous (HR and 95% CI for BMI 30 to 34.9: 1.58, 1.04 — 2.39; BMI ≥ 35: 1.93, 1.16 — 3.20) cancers. For both histologic types, the relative risk increased with increasing BMI (P-trend: ductal P&amp;lt;0.01; mucinous P&amp;lt;0.01). Women whose daily activity at work or home consisted of mostly standing or walking were at reduced risk of ductal and mixed ductal-lobular cancers compared with women who reported mostly sitting (HR and 95% CI for ductal: 0.86, 77 — 0.96; mixed-ductal lobular: 0.64, 0.48 — 0.86). Women who performed heavy work or carried heavy loads were also at a decreased risk of ductal and mixed ductal-lobular cancers compared with women reporting mostly sitting (HR and 95% CI for ductal: 0.68, 0.52−0.91; mixed ductal-lobular: 0.18, 0.04−0.72), though there were few mixed ductal-lobular cases who reported heavy activity. Conclusions: High BMI was associated with increased risk of ductal and mucinous breast cancers. Women who spent their daily routine activity mostly standing or walking or doing heavy work had a reduced risk of ductal and mixed ductal-lobular cancers. These differences suggest that associations of BMI and physical activity vary by breast cancer histologic type in postmenopausal women and may have different roles in the etiology of these cancers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-03.

Common Genetic Variants in the Vitamin D Pathway Including Genome-Wide Associated Variants Are Not Associated with Breast Cancer Risk among Chinese Women

Previous studies evaluating the association of vitamin D-related genetic variants with breast cancer risk have produced inconsistent results. We evaluated the association between breast cancer risk and 559 single-nucleotide polymorphisms (SNP) in 12 vitamin D-related genes, including 6 genes associated with circulating 25-hydroxyvitamin D [25(OH)D] level identified by recent genome-wide association studies (GWAS), using directly observed and imputed GWAS genotyping data from 2,919 breast cancer cases and 2,323 controls recruited in the Shanghai Breast Cancer Study. Of the SNPs studied, only rs12570116 in the ACADSB gene, rs4760658 in the VDR gene and rs6091822, rs8124792, and rs6097809 in the CYP24A1 gene, and rs10902845 in C10orf88 had a nominal association with breast cancer risk (P < 0.05 for all). None of these associations persisted after adjustment for multiple comparisons. The most extensively studied SNPs including rs10735810, also known as rs2228570 (Fok1, VDR), rs1544410 (Bsm1, VDR), and rs2296241 (CYP24A1), were not associated with breast cancer risk. GWAS-identified genetic variants that were associated with 25(OH)D were also not related to breast cancer risk. Our data suggest that genetic polymorphisms in vitamin D-related genes do not play a major role in breast cancer risk in Chinese women. Although our study confirms previously documented breast cancer risk factor associations, our null results suggest that common genetic variants in vitamin D genes and loci associated with control of vitamin D levels are not risk factors for breast cancer in Chinese women. Our data contribute to filling the gap in this field of research.

Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based case–control study from Poland

Background:Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case–control study conducted in two cities in Poland (2000–2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.Methods:We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.Results:Prolactin levels were associated with nulliparity in premenopausal (P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.Conclusions:Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations.

Abstract 870: Analysis of breast cancer risk factors by expression of tumor markers: results of 34 studies in the Breast Cancer Association Consortium (BCAC)

Abstract Epidemiologic studies suggest that breast cancer risk factor associations vary by tumor marker expression; however, individual studies have had limited power to address this question. We pooled data from up to 35,568 invasive breast cancer cases from 34 studies participating in the Breast Cancer Association Consortium (BCAC) to evaluate associations between established risk factors (age at menarche, nulliparity, age at first full time birth [AFFTB], body mass index [BMI] and family history) and breast cancer subtypes, defined by immunohistochemical expression of ER, PR, HER2, and basal markers (CK5/6 or CK5, EGFR). We used polychotomous logistic regression to evaluate relationships between risk factors and tumor subtypes in case-only analyses and to estimate case-control odds ratios and 95% confidence intervals for the associations between risk factors and specific tumor subtypes in 11 population-based studies including up to 12,841 cases and 17,032 controls. In case-only analyses, we found that reproductive risk factors were more common in hormone receptor positive tumors: early age at menarche was most strongly related to PR status (34.6% vs. 32.4% of women with age at menarche ≤12 years among PR+ and PR- cases, respectively, P= 0.001); whereas nulliparity, and late AFFTB in parous women were most strongly related to ER status (15.3% vs. 13.6% nulliparous women, 17.1% vs. 15.2% women with late AFFTB [≥30 years], among ER+ and ER- cases, respectively, P=2.6×10−6 for nulliparity and P=2.0×10−7 for late AFFTB). Nulliparity and late AFFTB were less common among triple negative (TN) tumors overall and among TN tumors expressing basal markers. Elevated BMI in women aged 50 years or younger was more common in ER-&amp;PR- than ER+&amp;PR+ tumors (17.0% vs 13.6% women with BMI ≥30, respectively, P=1.3×10−7), whereas above age 50 years, elevated BMI was more common in ER+&amp;PR+ than ER+&amp;PR- tumors (20.9% vs 16.7% women with BMI ≥30, respectively, P=2.8×10−8 comparing BMI ≥30 to BMI &amp;lt;25). In case-control analyses, early age at menarche was associated with increased risk of PR+ tumors; nulliparity and late AFFTB were most strongly associated with increased risk of (ER+ or PR+)&amp;HER2- tumors, and did not increase the risk of TN tumors. Having a family history of breast cancer increased the risk of all tumor subtypes, although the association was strongest for TN tumors expressing basal markers. Our data provide convincing evidence for etiological heterogeneity with respect to breast cancer risk factors stratified by ER and PR status. Stratification by additional markers provides additional insights about etiologic differences in breast cancer risk. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 870.

Abstract 3762: Automated analysis of breast cancer tissue microarrays to investigate etiologic heterogeneity in the Breast Cancer Association Consortium

Abstract Background: Data suggest that breast cancer risk factor associations vary by tumor marker expression. However, individual studies often lack the power required to assess these relationships and pooled analyses are limited by non-standardized scoring of tumor markers. To address these limitations, the Breast Cancer Association Consortium is assessing whether automated image analysis of immunohistochemically stained tissue microarrays (TMAs) can permit standardized scoring of tumor markers. Methods: TMA sections prepared in 10 case-control studies containing up to 9,298 breast cancers stained for estrogen receptor (ER); progesterone receptor (PR); human epidermal growth factor receptor 2 (HER 2); epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) were scanned as digital images. Automated algorithms were used to score markers in tumor cells using the Ariol system. We are analyzing consistency of automated scores within individual studies; between studies; and against visual reads. Results: Preliminarily, distributions of automated scores were generally similar across different TMA blocks within a study; however isolated blocks yielded disparate results related to low or high intensity staining for a marker or the counterstain across the entire slide. Distributions of scores varied between studies, suggesting the need for study-specific cutpoints for negative vs. positive. Analysis of receiver operator characteristic curves comparing automated analysis to independently recorded visual reads in two studies demonstrated areas under the curves of 0.90 and 0.93 for tumors classified visually as ER+/PR+ and 0.91 and 0.88 for tumors scored visually as ER-/PR-. Cores scored as negative for EGFR or CK 5/6 by automated methods agreed well with visual scores, but many tumors scored as positive by automated analysis were negative by visual review, irrespective of ER / PR status. Thus, restricting analyses to ER-/PR- tumors (a subset of interest) reduced the number of discrepancies. Ongoing analyses are comparing automated and visual scores for all markers / studies and are assessing risk factor associations for breast cancer by tumor marker expression (negative vs. positive and strength of expression) based on automated scores. Conclusions: Automated analysis of immunohistochemically stained TMAs of breast cancers may be useful in standardizing high throughout characterization of cancer markers in multicenter studies and in consortia, although additional methodologic work is needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3762.