Search

Summary Background Breast cancer has distinct causes, prognoses, and outcomes and effects in patients at premenopausal and postmenopausal ages. We sought to assess the global burden and trends in breast cancer by menopausal status. Methods We did a population-based analysis of global breast cancer incidence and mortality among premenopausal and postmenopausal women. Menopausal status was defined using age as a proxy, whereby breast cancer cases or deaths at age 50 years or older were regarded as postmenopausal. Age-standardised breast cancer incidence and mortality in 2018 were calculated using GLOBOCAN data. Incidence trends for 1998–2012 were assessed in 44 populations from 41 countries using the Cancer in Five Continents plus database, by calculating the annual average percent change. Findings Approximately 645 000 premenopausal and 1·4 million postmenopausal breast cancer cases were diagnosed worldwide in 2018, with more than 130 000 and 490 000 deaths occurring in each menopausal group, respectively. Proportionally, countries with a low UNDP human development index (HDI) faced a greater burden of premenopausal breast cancer for both new cases and deaths compared with higher income countries. Countries with a very high HDI had the highest premenopausal and postmenopausal breast cancer incidence (30·6 and 253·6 cases per 100 000, respectively), whereas countries with low and medium HDI had the highest premenopausal and postmenopausal mortality, respectively (8·5 and 53·3 deaths per 100 000, respectively). When examining breast cancer trends, we noted significantly increasing age-standardised incidence rates (ASIRs) for premenopausal breast cancer in 20 of 44 populations and significantly increasing ASIRs for postmenopausal breast cancer in 24 of 44 populations. The growth exclusively at premenopausal ages largely occurred in high-income countries, whereas the increasing postmenopausal breast cancer burden was most notable in countries under transition. Interpretation We provide evidence of a rising burden of both premenopausal and postmenopausal breast cancer worldwide. Although early diagnosis and access to treatment remain crucial in low-income and middle-income countries, primary prevention efforts seeking to decrease exposure to known breast cancer risk factors are warranted in all world regions to curb the future breast cancer burden. Funding None.

High mammographic density (MD) is a strong risk factor for breast cancer; however, data on the association between MD and breast cancer subtypes has been inconsistent and most studies have been conducted using data from Western women. Studies have shown that Asian women, who in general have denser breasts compared with Western women, were more likely to develop luminal B and HER2-enriched tumors. We previously reported that higher MD, assessed using Breast Imaging Reporting and Data System (BI-RADS) categories, was associated with HER2-enriched tumors among Chinese breast cancer patients, which may at least partially explain the higher incidence of HER2-enriched tumors observed in Asian women. Since BI-RADS MD measurement is categorical and known to be subjective, in this study, we aimed to re-evaluate the MD-subtype association using an automated quantitative density metric. The analysis included 1,549 women with invasive breast cancer who were diagnosed and treated in a tertiary hospital in Beijing, China. Subtypes were defined as Luminal A (n=606): ER+ and PR+, HER2-, and low Ki-67 ( Citation Format: Xiaohong R Yang, Yuan Tian, Jennifer Guida, Hela Koka, Ariane Chan, Changyuan Guo, Erni Li, Eric Tang, Hyuna Sung, Ning Lu, Nan Hu, Gretchen Gierach, Jing Li. Association between quantitative mammographic density and breast cancer subtypes among Chinese breast cancer patients [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 P5-08-20.

PURPOSE: Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS: MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS: The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m(2) (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08–3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m(2)) BMI (OR = 2.43, 95% CI 1.24–4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38–2.52, p = 0.96). CONCLUSIONS: Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+ tumors previously reported in Asian women.

TP53 is a well-known tumor suppressor gene and mutations in TP53 are the most frequent genomic event in most cancers including breast cancer. Recent studies have shown that the frequency, spectrum, timing, and clinical implications of TP53 mutations varied in different molecular subtypes of breast cancer. For example, the frequency of TP53 mutations is the highest in basal-like subtype and lowest in luminal A tumors. However, the evaluation of TP53 protein expression, as a surrogate for TP53 mutations, in large studies in the context of tumor subtypes is limited. In addition, the etiologic relevance of TP53 expression is yet to be investigated. The goal of this study is to evaluate the association of clinical and breast cancer risk factors with TP53 expression, measured using immunohistochemistry (IHC), in breast cancer molecular subtypes. The analysis included 7,226 women with invasive breast cancer who were diagnosed and treated in a tertiary hospital in Beijing, China. Subtypes were defined as Luminal A: ER+ and PR+, HER2–, and low grade (grades 1 or 2); luminal B/HER2–: ER+ and/or PR+, HER2–, and high grade (grade 3); luminal B/HER2+: ER+ and/or PR+, HER2+ (regardless of grade); HER2-enriched: ER–, PR–, and HER2+; Triple-negative (TN): ER–, PR–, and HER2–. As expected, positive TP53 staining showed the lowest frequency in the luminal A (46%) and highest in the TN (61%) and HER2-enriched (63%) subtypes (P-value Citation Format: Yang XR, Abubakar M, Guo C, Koka H, Sung H, Guida J, Deng J, Zhou B, Hu N, Lu N. TP53 expression in relation to clinical and etiologic factors in breast cancer subtypes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-12.

Background This study was aimed at examining the risks of subsequent primary cancers (SPCs) among breast cancer survivors by hormone receptor (HR) status and age at diagnosis. Methods Data from 12 Surveillance, Epidemiology, and End Results registries were used to identify 431,222 breast cancer survivors (at least 1 year) diagnosed between the ages of 20 and 84 years from 1992 to 2015. Risks of SPCs were measured as the standardized incidence ratio (SIR) and the excess absolute risk (EAR) per 10,000 person-years. Poisson regression was used to test the difference in SIRs by HR status. Results In comparison with the general population, the risk of new cancer diagnoses among survivors was 20% higher for those with HR-positive cancers (SIR, 1.20; 95% confidence interval [CI], 1.19-1.21; EAR, 23.3/10,000 person-years) and 44% higher for those with HR-negative cancers (SIR, 1.44; 95% CI, 1.41-1.47; EAR, 45.2/10,000 person-years), with the risk difference between HR statuses statistically significant. The higher risk after HR-negative cancer was driven by acute nonlymphocytic leukemia and breast, ovarian, peritoneal, and lung cancers. By age at diagnosis, the total EAR per 10,000 person-years ranged from 15.8 (95% CI, 14.1-17.5; SIR, 1.11) among late-onset (age, 50-84 years) HR-positive survivors to 69.4 (95% CI, 65.1-73.7; SIR, 2.24) among early-onset (age, 20-49 years) HR-negative survivors, with subsequent breast cancer representing 73% to 80% of the total EAR. After breast cancer, the greatest EARs were for ovarian cancer among early-onset HR-negative survivors, lung cancer among early- and late-onset HR-negative survivors, and uterine corpus cancer among late-onset HR-positive survivors. Conclusions Risks of SPCs after breast cancer differ substantially by subtype and age. This suggests that more targeted approaches for cancer prevention and early-detection strategies are needed in survivorship care planning.

BackgroundStudies investigating associations between mammographic density (MD) and breast cancer subtypes have generated mixed results. We previously showed that having extremely dense breasts was associated with the human epidermal growth factor receptor-2 (HER2)-enriched subtype in Chinese breast cancer patients.MethodsIn this study, we reevaluated the MD-subtype association in 1549 Chinese breast cancer patients, using VolparaDensity software to obtain quantitative MD measures. All statistical tests were 2-sided.ResultsCompared with women with luminal A tumors, women with luminal B/HER2- (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.04 to 1.38; P = .01), luminal B/HER2+ (OR = 1.22, 95% CI = 1.03 to 1.46; P = .03), and HER2-enriched tumors (OR = 1.30, 95% CI = 1.06 to 1.59; P = .01) had higher fibroglandular dense volume. These associations were stronger in patients with smaller tumors (ConclusionAlthough biological mechanisms remain to be investigated, the associations for the HER2-enriched and luminal B subtypes with increasing MD may partially explain the higher prevalence of luminal B and HER2+ breast cancers previously reported in Asian women.

Compared with white women, black women have higher incidence rates for triple-negative breast cancer but lower rates for hormone receptor (HR)–positive cancers in the United States. Whether similar racial difference occurs in male breast cancer is unclear. We examined racial differences in incidence rates of breast cancer subtypes defined by HR and human epidermal growth factor receptor 2 (HER2) by sex using nationwide data from 2010 to 2016. Among men, rates were higher in blacks than whites for all subtypes, with the black-to-white incidence rate ratios of 1.41 (95% confidence interval [CI ]= 1.32 to 1.50) for HR+/HER-, 1.65 (95% CI = 1.40 to 1.93) for HR+/HER2+, 2.62 (95% CI = 1.48 to 4.43) for HR-/HER2+, and 2.27 (95% CI = 1.67 to 3.03) for triple-negative subtype. Conversely, among women, rates in blacks were 21% lower for HR+/HER2- and comparable for HR+/HER2+ but 29% and 93% higher for HR-/HER2+ and triple-negative subtypes, respectively. Future studies are needed to identify contributing factors to the dissimilar racial patterns in breast cancer subtype incidence between men and women.

Recent studies from high-risk countries such as the US, Denmark and Ireland have shown rising incidence rates of hormone receptor (HR)-positive and falling rates of HR-negative breast cancers (BC). However, it remains unclear whether a similar pattern occurs in low-risk countries. Detailed clinical and risk factor data were collected from 2,977 female invasive BC patients (≥20 years) in Sarawak General Hospital, Malaysia, representing 93% of the population. The population-at-risk was obtained from the Department of Statistics Malaysia. Secular trends in age-standardized incidence rates were assessed using estimated average annual percent changes. Associations between established BC risk factors and tumor subtypes defined by HR or joint human epidermal growth factor receptor 2 (HR/HER2) status were examined by case-case comparisons using logistic regression. From 2006 to 2015, incidence rates increased for HR-positive cancers by 4.46%/year (95% CI = 2.19-6.78) and decreased for HR-negative cancers by 2.29%/year (95% CI = -4.31 to -0.24). When further stratified by HER2, the most contrasting difference in linear trends was observed between HR+/HER2- and HR-/HER2- subtypes. After controlling for potential confounders, cases with excess body weight (ORoverweight vs. normal = 0.82; 95% CI = 0.69-0.98; ORobese vs. normal = 0.62; 95% CI = 0.48-0.80), later age at first birth (OR≥26 years vs.

TP53 mutations are common in breast cancer and are typically associated with more aggressive tumor characteristics, but little is known about the clinicopathological and epidemiological relevance of p53 protein expression, a TP53 mutation surrogate, in breast cancer subtypes. In this study of 7226 Chinese women with invasive breast cancer, we defined breast cancer subtypes using immunohistochemical (IHC) measures of hormone receptors and HER2 in conjunction with histologic grade. p53 expression status was then used to further stratify subtypes into p53-positive and p53-negative. Odds ratios (ORs) and 95% confidence intervals (CIs) in case-only logistic regression analyses were used to examine heterogeneity across different subtypes. The frequency of p53 protein expression varied by breast cancer subtype, being lowest in the luminal A-like and highest in the triple-negative and HER2-enriched subtypes (P-value parous vs. nulliparous = 2.67 (1.60, 4.51); P-value ever vs. never = 1.38 (1.03, 1.85); P-value = 0.03]. p53 positivity was not associated with examined clinical and risk factors in other tumor subtypes. Overall, these findings suggest that p53 expression, which is readily available in many settings, can be used to identify phenotypes of luminal A-like breast cancer with distinct clinical and epidemiological implications.

Background: Breast cancer has distinct etiologies, prognoses, and patient impact at pre- and post-menopausal ages. We sought to assess the global burden and trends in breast cancer by menopausal status. Methods: Menopausal status was defined using age as a proxy, where breast cancer cases/deaths at >50 years were considered as post-menopausal. Age-standardized breast cancer incidence and mortality rates in 2018 were calculated using GLOBOCAN data. Incidence trends for 1998-2012 were assessed in 44 populations from 41 countries using CI5plus data by calculating the annual average percent change. Findings: Approximately 645,000 pre-menopausal and 1.4 million post-menopausal breast cancer cases were diagnosed in 2018, with approximately 130,000 and 490,000 deaths occurring in each menopausal group, respectively. Proportionally, Low Human Development Index (HDI) countries faced a greater burden of pre-menopausal breast cancer for both incidence and mortality compared to more developed countries. Very High HDI countries had the highest pre- and post-menopausal breast cancer incidence rates (30·6 and 253·6 per 100,000 respectively), while Low and Medium HDI countries had the highest pre-menopausal and post-menopausal mortality rates respectively (8·5 and 53·3 per 100,000 respectively). When examining incidence trends, we observed significantly increasing rates of pre-menopausal breast cancer in 20/44 populations, and significantly increasing rates of post-menopausal breast cancer in 24/44 populations. The increases exclusively at pre-menopausal ages largely occurred in the most developed countries, while the increasing post-menopausal breast cancer burden was most notable in countries under transition. Interpretation: We provide evidence of a rising burden of both pre- and post-menopausal breast cancer worldwide, and wide inequities in breast cancer care. Although early diagnosis and access to treatment remain crucial in developing countries, primary prevention efforts seeking to decrease obesity and alcohol consumption, and increase physical activity and breastfeeding, are warranted in all world regions to curb the future breast cancer burden. Funding Statement: This study was undertaken without any funding. Declaration of Interests: All authors declare no conflicts of interests. Ethics Approval Statement: Not required.

Extensive mammographic density (MD), a well-established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low-risk population but with high prevalence of dense breasts. Diagnostic pre-treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI-RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2 , span [μm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI-RADS, c-d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08-63.1; ptrend < 0.0001) compared to those with non-dense breasts (BI-RADS, a-b). Among women

Historically low breast cancer incidence rates among Asian women have risen worldwide; purportedly due to the adoption of a "Western" life style among younger generations (i.e., the more recent birth cohorts). However, no study has simultaneously compared birth cohort effects between both younger and older women in different Asian and Western populations. Using cancer registry data from rural and urban China, Singapore and the United States (1990-2008), we estimated age-standardized incidence rates (ASR), annual percentage change (EAPC) in the ASR, net drifts, birth cohort specific incidence rates and cohort rate ratios (CRR). Younger (30-49 years, 1943-1977 birth cohorts) and older women (50-79 years; 1913-1957 birth cohorts) were assessed separately. CRRs among Chinese populations were estimated using birth cohort specific rates with US non-Hispanic white women (NHW) serving as the reference population with an assigned CRR of 1.0. We observed higher EAPCs and net drifts among those Chinese populations with lower ASRs. Similarly, we observed the most rapidly increasing cohort-specific incidence rates among those Chinese populations with the lowest baseline CRRs. Both trends were more significant among older than younger women. Average CRRs were 0.06-0.44 among older and 0.18-0.81 among younger women. Rapidly rising cohort specific rates have narrowed the historic disparity between Chinese and US NHW breast cancer populations particularly in regions with the lowest baseline rates and among older women. Future analytic studies are needed to investigate risk factors accounting for the rapid increase of breast cancer among older and younger women separately in Asian populations.

Epidemiological studies have shown that associations between breast cancer risk and risk factors vary by tumor pathology such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. Mammographic density (MD) is a strong risk factor for breast cancer, but data on the association between MD and breast cancer subtypes have been inconsistent and most studies have been conducted among Western women. The goal of this study was to evaluate the association between MD and breast cancer subtypes in an Asian population where the proportion of dense breast tissue is higher but the overall breast cancer incidence rate is much lower compared with Western countries. Breast cancer cases from a cancer hospital in Beijing, China with MD and ER, PR, and HER2 immunohistochemical (IHC) data were included in this analysis. To reduce subtype misclassification, we excluded cases that were HER2 2+ for IHC but had no FISH data. Tumor subtypes were defined as Luminal A (ER+ or PR+ and HER2-, N=376), Luminal B (ER+ or PR+ and HER2+, N=97), HER2-overexpressing (ER- and PR- and HER2+, N=71), and triple negative (TN, ER- and PR- and HER2-, N=66). MD was assessed on digital mammograms and categorized into four levels using the Breast Imaging Reporting and Data System (BI-RADS) scoring system (a=almost entirely fat, b=scattered fibroglandular densities, c=heterogeneously dense, and d=extremely dense). Because there were few cases with almost entirely fat breasts, we combined MD levels "a" and "b" as our reference group. Polychotomous logistic regression was used to assess the association between MD and breast cancer subtypes with the adjustment of age, menopausal status, parity, age at menarche, and body mass index (BMI) since all these variables showed significant inverse associations with MD (P=0.002 for age at menarche and P Citation Format: Yang XR, Li J, Li E-N, Guida JL, Li M, Sung H, Lu N, Hu N, Gierach GL. Association between mammographic density and breast cancer subtypes among Chinese women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-10.

Purpose Experimental studies implicate tea and tea polyphenols may be preventive against breast cancer, but evidence from epidemiological studies has been inconsistent. We conducted a hospital-based case–control study to evaluate the role of tea especially green tea in breast cancer etiology. Methods We consecutively recruited 756 incident breast cancer cases and 789 hospital controls who had completed information on tea consumption. We calculated odds ratios (ORs) for tea consumption using unconditional multivariable logistic regression. We further conducted stratified analyses to assess whether the effect of tea consumption varied by menopausal status and estrogen receptor (ER). Results Overall, 439 (58.1%) breast cancer cases and 434 (55.0%) controls reported habits of regular tea drinking, showing an adjusted OR of 1.01 (95%CI: 0.78–1.31) and 1.20 (95%CI: 0.80–1.78) for any tea and green tea drinking, respectively. Regular tea drinking was significantly associated with a lower risk for breast cancer in pre-menopausal women (OR=0.62, 95%CI: 0.40–0.97) but an increased risk in post-menopausal women (OR=1.40, 95%CI: 1.00–1.96). The positive association among postmenopausal women was strongest among ER-negative green tea drinkers (OR=2.99, 95% CI: 1.26–7.11). Conclusions Tea or green tea drinking was not associated with overall breast cancer risk, which may be masked by the differential effect in pre- and post-menopausal women.

Background: Luminal A breast cancer defined as hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative is known to be heterogeneous. Previous study showed that luminal A tumours with the expression of basal markers ((cytokeratin (CK) 5 or CK5/6) or epidermal growth factor receptor (EGFR)) were associated with poorer prognosis compared with those that stained negative for basal markers. Prompted by this study, we assessed whether tumour characteristics and risk factors differed by basal marker status within luminal A tumours.\ud \ud Methods: We pooled 5040 luminal A cases defined by immunohistochemistry (4490 basal-negative ((CK5 (or CK5/6))− and EGFR−) and 550 basal-positive ((CK5 (or CK5/6+)) or EGFR+)) from eight studies participating in the Breast Cancer Association Consortium. Case–case comparison was performed using unconditional logistic regression.\ud \ud Results: Tumour characteristics and risk factors did not vary significantly by the expression of basal markers, although results suggested that basal-positive luminal tumours tended to be smaller and node negative, and were more common in women with a positive family history and lower body mass index.\ud \ud Conclusions: Most established breast cancer risk factors were similar in basal-positive and basal-negative luminal A tumours. The non-significant but suggestive differences in tumour features and family history warrant further investigations.

Background Limited evidence, mostly from studies in Western populations, suggests that the prognostic effects of lifestyle-related risk factors may be molecular subtype-dependent. Here, we examined whether pre-diagnostic lifestyle-related risk factors for breast cancer are associated with clinical outcomes by molecular subtype among patients from an understudied Asian population. Methods In this population-based case series, we evaluated breast cancer risk factors in relation to 10-year all-cause mortality (ACM) and 5-year recurrence by molecular subtype among 3012 women with invasive breast cancer in Sarawak, Malaysia. A total of 579 deaths and 314 recurrence events occurred during a median follow-up period of ~ 24 months. Subtypes (luminal A-like, luminal B-like, HER2-enriched, triple-negative) were defined using immunohistochemical markers for hormone receptors and human epidermal growth factor receptor 2 (HER2) in conjunction with histologic grade. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between risk factors and ACM/recurrence were estimated in subtype-specific Cox regression models. Results We observed heterogeneity in the relationships between parity/breastfeeding, age at first full-term pregnancy (FFP), family history, body mass index (BMI), and tumor subtype (p value 30 vs

Elevated mammographic density (MD) is an established breast cancer risk factor. Studies examining relationships between MD and breast cancer risk factors are limited in China, where established breast cancer risk factors are less prevalent but dense breasts are more prevalent than Western countries. This study included 11,478 women (45-69 years; 36% premenopausal) participating in an ongoing national cancer screening program in 11 urban provinces in China and predicted as having high-risk for breast cancer. Polytomous logistic regression was performed to assess associations between MD and risk factors by comparing each higher Breast Imaging Reporting and Data System (BI-RADS) category (2, 3, or 4) to the lowest category (BI-RADS, 1). We found associations of increasing age, body mass index, weight, postmenopausal status, and parity with lower MD. Higher levels of education, increasing height, and later first birth were associated with higher MD. These associations did not vary by menopausal status. Additionally, the association between longer period of breastfeeding and lower MD was seen among postmenopausal women only (Pinteraction = 0.003). Having first-degree relatives with breast cancer diagnosed before 50 years was associated with lower MD only among premenopausal women (Pinteraction = 0.061). We found effects of established breast cancer risk factors on MD showed similar directions in Chinese and Western women, supporting the hypothesis that MD represents cumulative exposure to breast cancer risk factors over the life course. Our findings help to understand the biological basis of the association of MD with breast cancer risk and have implications for breast cancer prevention research in China., Epidemiology: Breast cancer risk factors similar in urban China and Western countries Demographic variables linked to dense breast tissue — a strong risk factor for cancer — are similar among women living in China and the West. Xiaohong Yang from the US National Cancer Institute in Bethesda, Maryland, USA, and colleagues looked for predictors of elevated breast density, as measured on a mammogram, among participants of an ongoing cancer screening program in 11 urban provinces in China. In their analysis of 11,478 women aged 45 to 69 deemed at high-risk for breast cancer, the researchers identified many variables — incliuding age, height, weight, menopausal status, educational level and history of pregnancies — that were all related to mammographic density in some way. Similar associations were previously found among women in Western countries, suggesting that many of these risk factors are consistent across populations.

PURPOSE: To characterize the spectrum of germline muta-tions in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. Methods Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site. RESULTS: We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86%for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also iden-tified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites. CONCLUSION: Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.

Background Terminal duct lobular unit (TDLU) involution is a physiological process of breast tissue aging characterized by a reduction in the epithelial component. In studies of women with benign breast disease, researchers have found that age-matched women with lower levels of TDLU involution are at increased risk of developing breast cancer. We previously showed that breast cancer cases with core basal phenotype (CBP; estrogen receptor negative [ER−], progesterone receptor-negative [PR−], human epidermal growth factor receptor 2-negative [HER2−], cytokeratins (CK 5 or CK5/6)-positive [CK5/6+] and/or epidermal growth factor receptor-positive [EGFR+]) tumors had significantly reduced TDLU involution compared with cases with luminal A (ER+ and/or PR+, HER2−, CK5/6−, EGFR−) tumors from a population-based case-control study in Poland. We evaluated the association of TDLU involution with tumor subtypes in an independent population of women in China, where the breast cancer incidence rate, prevalence of known risk factors, and mammographic breast density are thought to be markedly different from those of Polish women. Methods We performed morphometric assessment of TDLUs by using three reproducible semiquantitative measures that inversely correlate with TDLU involution (TDLU count/100 mm2, TDLU span in micrometer, and acini count/TDLU) by examining benign tissue blocks from 254 age-matched luminal A and 250 triple-negative (TN; ER−, PR−, HER2−, including 125 CBP) breast cancer cases treated in a tertiary hospital in Beijing, China. Results Overall, we found that TN and particularly CBP cases tended to have greater TDLU measures (less involution) than luminal A cases in logistic regression models accounting for age, body mass index, parity, and tumor grade. The strongest association was observed for tertiles of acini count among younger women (aged

Limited numbers of epidemiological studies have examined the relationship between adipokines and breast cancer survival. Preoperative serum levels of obesity-related adipokines (leptin and adiponectin) were here measured in 370 breast cancer patients, recruited from two hospitals in Korea. We examined the association between those adipokines and disease-free survival (DFS). The TNM stage, ER status and histological grade were aslo assessed in relation to breast cancer survival. Elevated adiponectin levels were associated with reduced DFS of breast cancer (P trend =0.03) among patients with normal body weight, predominantly in postmenopausal women. There was no association of leptin with breast cancer survival. In conclusion, our study suggests that high levels of adiponectin at diagnosis are associated with breast cancer survival among women with normal body weight.Keywords: Breast cancer - leptin and adiponectin level at diagnosis - prognosis - serum biomarker RESEARCH ARTICLE

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

Breast cancer is heterogeneous in clinical behavior by subtypes; however, it is unclear how this heterogeneity is related to epidemiological factors. To evaluate the differences in epidemiological factors by breast tumor subtypes, we investigated the associations of epidemiological factors between tumor subtypes in Korean women. From the Seoul Breast Cancer Study, a total of 3,058 patients with breast cancer were included in the analyses. Tumor subtypes were classified based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses. The epidemiological factors of each subtype were compared through case–case analyses using multivariate a polytomous logistic regression model adjusted for age and recruiting centers. The distribution of the subtypes was as follows: 1,714 HR+ HER2− (56.0%), 414 HR+ HER2+ (13.5%), 423 HR− HER2+ (13.9%) and 507 HR− HER2− (16.6%) patients with breast cancer. There were significant differences in age, menopausal status, age at menarche, number of children, age at first full-term pregnancy (FFTP), duration of breastfeeding and duration of endogenous estrogen exposure between tumor subtypes (p

Background: Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study (GWAS) conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations. Methods: We evaluated nine of those nonreplication loci in East Asians to identify new risk variants for breast cancer in these regions. First, we analyzed single-nucleotide polymorphisms (SNP) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (stage 1). In each region, we selected an SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (stage 2). Logistic regression models were used to calculate adjusted ORs and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants. Results: Two SNPs were replicated in stage 2 at P < 0.05: rs1419026 at 6q14 [per allele OR, 1.07; 95% confidence interval (CI), 1.03–1.12; P = 3.0 × 10−4] and rs941827 at 10q25 (OR, 0.92, 95% CI, 0.89–0.96; P = 5.3 × 10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR, 0.88; 95% CI, 0.82–0.97; P = 5.3 × 10−5). Conclusion: We identified a new breast cancer risk variant at 10q25 in East Asian women. Impact: Results from this study improve the understanding of the genetic basis for breast cancer. Cancer Epidemiol Biomarkers Prev; 22(7); 1297–303. ©2013 AACR.

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of, published_or_final_version

Background: Matrix metalloproteinase-2 (MMP-2) has been thought of as a predictor of recurrence or metastasis risk or prognostic markers in cancer. We evaluated whether preoperative serum levels of MMP-2 work as a prognostic biomarker in breast cancer prognosis. Methods: Preoperative serum levels of MMP-2 were measured with ELISA in 303 patients with histologically confirmed breast cancer. The median follow-up time for all patients was 4.24 years. The relationship of MMP-2 to survival was investigated using Cox proportional hazard regression model adjusted for the tumor–node–metastasis (TNM) stage and estrogen receptor (ER) status. Results: In the multivariate analysis, disease-free survival (DFS) was worse among patients with the third tertile of MMP-2 level than with the first tertile of MMP-2 level [hazard ratio, 1.80; 95% confidence interval (CI), 1.04–3.11; P = 0.04]. However, when the patients were stratified by age, ER status, histologic grade, and nuclear grade, inverse correlation was shown between serum MMP-2 levels and prognostic factors, and the associations between MMP-2 and DFS were only significant among patients with poor prognostic factors (HR, 2.75; 95% CI, 1.32–5.73 in ER-negative; HR, 2.90; 95% CI, 1.42–5.92 in histologic grade III; and HR, 2.61; 95% CI, 1.26–5.39 in nuclear grade III). Conclusions: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival in patients with breast cancer in ER-negative, higher histologic grade, or higher nuclear grade breast cancers. Impact: Our results indicate that serum levels of MMP-2 may play a role as prognostic biomarker in breast cancer survival. Cancer Epidemiol Biomarkers Prev; 21(8); 1371–80. ©2012 AACR.

Recent compelling evidence indicates that mutation, aberrant expression, and dysregulation of microRNA (miRNA) biogenesis are implicated in cancer development and progression. Based on the important role of miRNA biogenesis pathway in carcinogenesis, we hypothesized that genetic variations in this pathway genes may play a role as susceptibility factors for breast cancer. To test this hypothesis, we investigated the associations between 41 single nucleotide polymorphisms (SNPs) in 14 genes involved in miRNA biogenesis pathway and breast cancer risk in a case–control study of 559 Korean breast cancer cases and 567 controls frequency-matched by age. In all women, 3 SNPs (AGO1 rs595055, AGO2 rs3864659, and p68 rs1991401) were significantly associated with breast cancer risk. In stratified analysis by menopausal status, altered risk associations were observed for 7 SNPs in postmenopausal breast cancer. When subjects were grouped by the number of high-risk genotypes, we found a progressive increase in gene-dosage effect (P trend = 9.46E−7). The protective effects of AGO2 rs3864659 and HIWI rs11060845 were more pronounced in progesterone receptor-positive (PR+) cancer than in progesterone receptor-negative (PR−) cancer (odds ratio (OR), 0.50; 95% confidence interval (CI), 0.30–0.84 vs. OR, 0.94; 95% CI, 0.60–1.84; P heterogeneity = 0.04 and OR, 0.57; 95% CI, 0.37–0.88 vs. OR, 0.97; 95% CI, 0.65–1.44; P heterogeneity = 0.02, respectively), and the DROSHA rs644236 had stronger association with estrogen receptor-negative (ER−) cancer than for estrogen receptor-positive (ER+) cancer (OR, 1.39; 95% CI, 1.08–1.78 vs. OR, 1.05; 95% CI, 0.85–1.29; P heterogeneity = 0.04). Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer risk, and the modifiable effects might be different according to the menopausal status and hormone receptor status.

Previous reports suggested that female breast cancer is associated with earlier ages at onset among Asian than Western populations. However, most studies utilized cross-sectional analyses that may be confounded by calendar-period and/or birth cohort effects. We, therefore, considered a longitudinal (forward-looking) approach adjusted for calendar-period changes and conditioned upon birth cohort.Invasive female breast cancer data (1988-2009) were obtained from cancer registries in China, Hong Kong, South Korea, Taiwan, Singapore, and the United States. Age-period-cohort models were used to extrapolate longitudinal age-specific incidence rates for the 1920, 1944, and 1970 birth cohorts.Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. In contrast, longitudinal age-specific rates were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The extrapolated estimates for the most recent cohorts in some Asian countries actually showed later ages at onset than in the United States. Additionally, over successive birth cohorts, the incidence rate ratios (IRRs) for the longitudinal curves converged (narrowed) between Asian and US white women.Similar longitudinal age-specific incidence rates along with converging IRRs indicate that the age effects for invasive breast cancer are more similar among Asian and Western populations than might be expected from a solely cross-sectional analysis. Indeed, the Asian breast cancer rates in recent generations are even surpassing the historically high rates in the United States, highlighting an urgent need for efficient prevention and treatment strategies among Asian populations.

Hormone receptor (HR) negative breast cancers are relatively more common in low-risk than high-risk countries and/or populations. However, the absolute variations between these different populations are not well established given the limited number of cancer registries with incidence rate data by breast cancer subtype. We, therefore, used two unique population-based resources with molecular data to compare incidence rates for the ‘intrinsic’ breast cancer subtypes between a low-risk Asian population in Malaysia and high-risk non-Hispanic white population in the National Cancer Institute’s surveillance, epidemiology, and end results 18 registries database (SEER 18). The intrinsic breast cancer subtypes were recapitulated with the joint expression of the HRs (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor-2 (HER2). Invasive breast cancer incidence rates overall were fivefold greater in SEER 18 than in Malaysia. The majority of breast cancers were HR-positive in SEER 18 and HR-negative in Malaysia. Notwithstanding the greater relative distribution for HR-negative cancers in Malaysia, there was a greater absolute risk for all subtypes in SEER 18; incidence rates were nearly 7-fold higher for HR-positive and 2-fold higher for HR-negative cancers in SEER 18. Despite the well-established relative breast cancer differences between low-risk and high-risk countries and/or populations, there was a greater absolute risk for HR-positive and HR-negative subtypes in the US than Malaysia. Additional analytical studies are sorely needed to determine the factors responsible for the elevated risk of all subtypes of breast cancer in high-risk countries like the United States.

Background: Although the role of miRNA in cancer development and progression has been well established, the association between genetic variants in miRNA biogenesis pathway genes and breast cancer risk has been yet unclear. Methods: We analyzed data from two genome-wide association studies conducted in East Asian women including 5,066 cases and 4,337 controls. Among the single-nucleotide polymorphisms (SNP), which were directly genotyped or imputed, we selected 237 SNPs in 32 genes involved in miRNA biogenesis pathway and its regulation. Results: Although eight SNPs were nominally associated with breast cancer risk in combined samples (P < 0.05), none of them were significant after adjustment for multiple comparisons. Conclusions: The common genetic variants in miRNA biogenesis pathway genes may not be associated with breast cancer risk. Impact: This study suggests no association between the polymorphisms in miRNA biogenesis pathway genes and breast cancer risk. Studies with large sample size and more genetic variants should be warranted to adequately evaluate the potential association. Cancer Epidemiol Biomarkers Prev; 21(8); 1385–7. ©2012 AACR.

Germline mutations in the BRCA1 and BRCA2 genes result in predisposition to breast and ovarian cancer. Detection of BRCA mutation carriers can lead to improved prevention and therapeutic interventions such as the targeted therapy using poly ADP ribose polymerase (PARP) inhibitors, which are particularly effective in BRCA mutation carriers. The spectrum of BRCA mutations varies depending on geographic origin, population, and ethnic group; however, the prevalence of BRCA mutations in non-Caucasian populations has been poorly characterized, particularly in a population-based setting. The goal of this study was to characterize the spectrum of germline mutations in BRCA1/2 and PALB2 in unselected breast cancer cases who were seen in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated. We performed targeted sequencing using a validated AmpliSeq panel on 467 cases with available risk factor questionnaire and clinical follow-up data. Breast cancer subtypes were defined by the joint expression of ER, PR, and HER2. Common variants with frequency >1% in any public database (1000 Genome, Exome Sequencing Project, The Exome Aggregation Consortium) were excluded. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants (frameshift and stop-gain), and variants that alter the first or second base of the splice site. Variants of unknown significance (VUS) were also defined using the ClinVar classification. We found 10 BRCA1 pathogenic variants in 12 patients, 10 BRCA2 pathogenic variants in 15 patients, and 4 PALB2 pathogenic variants in 4 patients, which gave a BRCA mutation prevalence of 5.78% among the unselected breast cancer cases in this population. All these variants were extremely rare in the general population ( Citation Format: Xiaohong (Rose) Yang, Beena Devi, Hyuna Sung, Jennifer Guida, Yanzi Xiao, Lisa Garland, Nan Hu, Maria Rodriguez-Herrera, Chaoyu Wang, Kristine Jones, Wen Luo, Belynda Hicks, Tieng Swee Tang, Karobi Moitra, Mike Dean. Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1294. doi:10.1158/1538-7445.AM2017-1294

Purpose The high mobility group box 1 (HMGB1) protein has roles in apoptosis and immune responses by acting as a ligand for receptor for advanced glycation end products (RAGE), Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 1. In particular, HMGB1/RAGE is involved in tumor metastasis by inducing matrix metalloproteinase 2 (MMP2) and MMP9 expression. We investigated the associations between genetic variations in HMGB1-related genes and disease-free survival (DFS) and overall survival (OS) in Korean female breast cancer patients. Methods A total of 2,027 patients in the Seoul Breast Cancer Study were included in the analysis. One hundred sixteen single nucleotide polymorphisms (SNPs) were extracted from eight genes. A multivariate Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) of each SNP. The effects of the SNPs on breast cancer prognosis were assessed at cumulative levels with polygenic risk scores. Results The SNPs significantly associated with DFS were rs243867 (hazard ratio, 1.26; 95% CI, 1.05–1.50) and rs243842 (hazard ratio, 1.24; 95% CI, 1.03–1.50); both SNPs were in MMP2. The SNPs significantly associated with OS were rs243842 in MMP2 (hazard ratio, 1.33; 95% CI 1.03–1.71), rs4145277 in HMGB1 (hazard ratio, 1.29; 95% CI, 1.00–1.66), rs7656411 in TLR2 (hazard ratio, 0.76; 95% CI, 0.60–0.98), and rs7045953 in TLR4 (hazard ratio, 0.50; 95% CI, 0.29–0.84). The polygenic risk score results for the DFS and OS patients showed third tertile hazard ratios of 1.72 (95% CI, 1.27–2.34) and 2.75 (95% CI, 1.79–4.23), respectively, over their first tertile references. Conclusion The results of the present study indicate that genetic polymorphisms in HMGB1-related genes are related to breast cancer prognosis in Korean women.

We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell's C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62-39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10-8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18-9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48-31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell's C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P

Lifestyle factors have been chronologically changed into western style ones, which could result in the rapid increase of breast cancer incidence in Korea. It is plausible that reproductive factors through hormonal mechanisms are differentially related to the risk of breast cancer subtypes. We investigated the association of reproductive risk factors on breast cancer by birth year groups and also evaluated the differential associations on the hormone receptor-defined subtypes. Using the data from the Seoul Breast Cancer Study (SeBCS), a multicenter case–control study, 3,332 breast cancer patients and 3,620 control subjects were analyzed. The distribution of subtypes among cases was as follows: 61.0 % estrogen receptor (ER)-positive, 51.9 % progesterone receptor (PR)-positive, and 43.4 % both ER/PR-positive status, respectively. Polytomous logistic regression and Wald tests for heterogeneity have been used across the subtypes. The frequencies of reproductive-related risk factors including early age at menarche, nulligravid, age at first full-term pregnancy (FFTP), duration of estrogen exposure before FFTP (EEBF), less number of children, never breastfeeding, and short duration of breastfeeding has increased as women were born later in both cases and controls, respectively (p trend

Introduction: There are three distinct South-East Asian ethnic groups in Sarawak, Malaysia (Chinese, Malay, and natives) whose breast cancer incidence rates and the distribution of tumor subtypes were reported to be significantly different. It remains unclear whether survival varies among breast cancer cases in these ethnic groups. We aimed to evaluate the relationship between survival and ethnicity when taking into account tumor characteristics. Methods: We analyzed incident breast cancer cases who were enrolled and treated in Sarawak General Hospital, Malaysia, between 1992 and 2014. The association of ethnicity with survival (relapse-free survival and overall survival) was evaluated using multivariate Cox-proportional hazard model. Subgroup analysis was conducted for each tumor subtype defined by hormone receptor (HR+, ER+ or PR+; HR-, ER- and PR-) and HER2 status (HR+/HER2-, HR+/HER2+, HR-/HER2-, and HR-/HER2+). Results: Among 2,758 eligible cases (median follow-up years, 2.90 years), there were 636 deceased and 423 relapsed cases. While there was no significant difference in disease recurrence, overall survival varied significantly by ethnicity. Compared with Chinese women, Malay women had a higher proportion of mortality (HR = 1.50; 95% CI = 1.14-1.96; P = 0.0037). This disparity remained significant only among cases with HR+ tumors (HR = 1.91; 95% CI = 1.17-3.11; P = 0.0091 among HR+/HER2-; HR = 2.74; 95% CI = 1.30-5.77; P = 0.0079 among HR+/HER2+). There was no difference in survival between Chinese and native women overall or stratified by subtype. Conclusions: Our results showed that Malay women experienced worse survival compared to Chinese women particularly among cases with HR+ tumors. Future studies are needed to clarify the underlying factors for this association in order to develop intervention strategies to reduce disparity. Citation Format: Hyuna Sung, C.R. Beena Devi, Jennifer Guida, Tieng Swee Tang, William F. Anderson, Xiaohong R. Yang. Ethnic disparities in breast cancer survival in Sarawak, Malaysia. [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 3414.

Background The 5-year survival rate for breast cancer among Korean women has increased steadily; however, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires an adequate supply of methyl group donors and B vitamins, may affect the prognosis of breast cancer. This aim of this study was to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis on the prognosis of breast cancer. Methods We assessed the dietary intake using a food frequency questionnaire with 980 women who were newly diagnosed and histopathologically confirmed to have primary breast cancer from hospitals in Korea, and 141 disease progression events occurred. Cox’s proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (95% CI) adjusting for age, education, recruitment sites, TNM stage, hormone status, nuclear grade and total calorie. Results There was no significant association between any one-carbon metabolism related nutrients (vitamin B2, B6 and folate) and the progression of breast cancer overall. However, one-carbon metabolism related nutrients were associated with disease progression in breast cancer patients stratified by subtypes. In ER + and/or PR + breast cancers, no association was observed; however, in ER–/PR– breast cancers, a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression (HR = 2.28; 95% CI, 1.20-4.35, HR = 1.84; 95% CI, 1.02-3.32, respectively) compared to a low intake. This positive association between the ER/PR status and progression of the disease was profound when the nutrient intakes were categorized in a combined score (Pinteraction = 0.018). In ER–/PR– breast cancers, high combined scores were associated with a significantly poor DFS compared to those belonging to the low score group (HR = 3.84; 95% CI, 1.70-8.71). Conclusions In conclusion, our results suggest that one-carbon related nutrients have a role in the prognosis of breast cancer depending on the ER/PR status.

Background Although a number of experimental studies have suggested the role of lipocalin-2 (LCN2) and matrix metalloproteinase-9 (MMP-9) in breast cancer progression, limited numbers of epidemiological studies have examined the relationship between the levels of lipocalin-2 and MMP-9 and breast cancer survival. Methods Preoperative serum levels of lipocalin-2 and MMP-9 were measured in 303 breast cancer patients and 74 healthy controls recruited between 2004 and 2007. We examined the association between lipocalin-2 and MMP-9 levels and disease-free survival (DFS) using Cox proportional hazard regression model. Results The serum levels of lipocalin-2 and MMP-9 were not significantly different between patients and controls (P > 0.05). Elevated lipocalin-2 and MMP-9 levels were associated with reduced DFS of breast cancer ( P trend = 0.029 and P trend = 0.063, respectively). When lipocalin-2 and MMP-9 levels were categorized based on the combined risk score, patients with higher levels of both lipocalin-2 and MMP-9 exhibited poor DFS compared to patients with lower levels (P trend = 0.004). Furthermore, these effects were profound in patients with BMI less than 25 kg/m2 (adjusted hazard ratio (aHR), 3.17; 95% confidence intervals (CI), 1.66-6.06, P trend P trend Conclusions Our study suggests that the elevated levels of lipocalin-2 and MMP-9 are associated with reduced breast cancer survival, particularly in patients with lower BMI and lymph-node negative breast cancers.

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.

PURPOSE:To identify the genetic variants associated with breast cancer survival, a genome-wide association study (GWAS) was conducted of Korean breast cancer patients. METHODS:From the Seoul Breast Cancer Study (SEBCS), 3,226 patients with breast cancer (1,732 in the discovery and 1,494 in the replication set) were included in a two-stage GWAS on disease-free survival (DFS) by tumor subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). The associations of the re-classified combined prognostic markers through recursive partitioning analysis (RPA) of DFS for breast cancer were assessed with the Cox proportional hazard model. The prognostic predictive values of the clinical and genetic models were evaluated by Harrell's C. RESULTS:In the two-stage GWAS stratified by tumor subtypes, rs166870 and rs10825036 were consistently associated with DFS in the HR+ HER2- and HR- HER2- breast cancer subtypes, respectively (Prs166870 = 2.88 × 10(-7) and Prs10825036 = 3.54 × 10(-7) in the combined set). When patients were classified by the RPA in each subtype, genetic factors contributed significantly to differentiating the high risk group associated with DFS inbreast cancer, specifically the HR+ HER2- (P discovery=1.18 × 10(-8) and P replication = 2.08 × 10(-5)) and HR- HRE2- subtypes (P discovery = 2.35 × 10(-4) and P replication = 2.60 × 10(-2)). The inclusion of the SNPs tended to improve the performance of the prognostic models consisting of age, TNM stage and tumor subtypes based on ER, PR, and HER2 status. CONCLUSION:Combined prognostic markers that include clinical and genetic factors by tumor subtypes could improve the prediction of survival in breast cancer.

Many previous association studies have been addressed genetic variations in obesity related genes on breast cancer risk, however, limited consideration of genes and gene-environmental interaction was involved. We investigated the associations of known obesity-related genes on breast cancer risk by comprehensive assessment based on individual SNP analysis and gene-based pathway-analysis. This study was conducted in 1,786 cases and 1,789 controls from Seoul Breast Cancer Study (SEBCS), a multicenter case-control study. The selection of 1,561 candidate obesity-related gene for this study was involved based on GWAS catalog and previous published data associated with obesity. Associations of single-nucleotide polymorphism (SNP) with BMI were assessed by linear regression models under an additive genetic model adjusting for age and disease status to identify genetic loci for obesity. 2,366 BMI-related significant SNPs including additional significant 449 SNPs which independently associated with BMI in our data (p Citation Format: Seokang Chung, Nan Song, Hyuna Sung, Sue K. Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Keun-Young Yoo, Daehee Kang, Ji-Yeob Choi. Genetic variation in obesity-related genes and breast cancer risk in the Seoul Breast Cancer Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2014-3273

Introduction: Breast cancer incidence rates are much lower in Asian women than in Western women. However, the incidence rates in Asian countries are rapidly increasing in the recent decades and this dramatic rise has been largely attributed to a strong birth-cohort effect. For example, some of the well-established breast cancer risk factors may interact with age which may in turn lead to differential cohort effect among early- and late-onset breast cancers. Methods: We analyzed the incidence and population data (1988 through 2009) among Chinese women obtained from population-based cancer registries in different countries or geographical areas (urban China, rural China, Singapore, and the United States). The cohort relative risks adjusted for age and period effects were estimated separately for women younger than 50 years (30-49) and women age 50 or older (50-79) using the respective mid-year birth cohort as referent (1934 for older and 1960 for younger women, respectively). Results: Breast cancer incidence has increased in all Chinese populations examined, particularly in women aged 50-79 years with estimated annual percentage change (EAPC) ranging from 2.00%/year (95% CI, 0.95-3.07) for Chinese American to 6.24%/year (95% CI, 4.95-7.55) for rural China. In contrast, rates for younger women aged 30-49 were stable or increased at a slower rate with EAPC from -0.33%/year (95% CI, -1.39-1.08) for Chinese American to 4.72%/year (95% CI, 3.92-5.52) for rural China. The cohort relative risks of breast cancer in older women rose significantly in successive birth cohorts in all Chinese populations with the most dramatic 4.0-fold (95% CI, 3.07-5.24) increase seen in rural China and a more modest 1.7-fold (95% CI, 1.24-2.23) increase among Chinese American women born from 1934 to 1958. In contrast, the increases in cohort relative risk among younger women were markedly lower or non-significant in all Chinese populations except for rural Chinese women (2.1-fold; 95% CI, 1.36-3.17) born from 1960 to 1978. Consistently, the projection of future incidence also showed a greater increase in late-onset breast cancer than in early-onset breast cancer. Conclusions: Our findings suggest that cohort effect-driven risk of breast cancer attributed to rapid socioeconomic development and concurrent westernization in Asian countries has and will continue to result in an upsurge in breast cancer incidence, especially in older women. Our data further supports the previous hypothesis that early- and late-onset breast cancers might derive from distinct etiologic pathways. Citation Format: Hyuna Sung, Philip S. Rosenberg, Wan-Qing Chen, Mikael Hartman, Wei-yen Lim, Kee Seng Chia, Oscar Wai-kong Mang, Shelly Lap-ah Tse, William F. Anderson, Xiaohong R. Yang. Differential cohort effect on early- and late-onset breast cancer incidence among Chinese women in different populations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-288. doi:10.1158/1538-7445.AM2014-LB-288

Background: Breast cancer is heterogeneous disease according to ethnicity and molecular subtype. In this study, we conducted a genome-wide association study (GWAS) to evaluate the association between susceptibility loci and breast cancer survival by the molecular subtypes which were classified into four subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in Korean women. Methods: Analyses included 2,023 invasive breast cancer patients, comprised of ER/PR+ and HER2- (N=1,006), ER/PR+ and HER2+ (N=245), ER/PR- and HER2+ (N=226), ER/PR- and HER2- (N=279), and unknown subtype (N=267), from Seoul Breast Cancer Study (SeBCS). For analyses, 555,117 SNPs were genotyped using Affymetrix SNP Array 6.0 and 2,416,663 SNPs were imputated based on HapMap Phase II (release 22). Cox proportional hazard models adjusted for age, recruited centers, and TNM stage were used to test the association of these SNPs with disease-free survival (DFS) and overall survival (OS) by molecular subtype. Results: With median follow-up periods of 3.8 years in DFS and 4.0 years in OS, there was significant difference in survival between molecular subtypes tested by log-rank (P Conclusion: This study suggests that associations between SNPs and survival were heterogeneous according to the molecular subtype of breast cancer. Furthermore, Additional larger studies are needed to replicate these findings. Citation Format: Nan Song, Ji-Yeob Choi, Hyuna Sung, Keun-Young Yoo, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Daehee Kang. A genome-wide association study of breast cancer survival according to molecular subtype in Korean women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2550. doi:10.1158/1538-7445.AM2013-2550

Lifestyle factors have been chronologically changed into western-style in Korea, which may result in the rapid increase of breast cancer incidence. It is plausible reproductive factors through hormonal mechanisms are differentially related to risk of breast cancer subtypes defined estrogen receptor (ER) and progesterone receptor (PR) status. We investigated the differential association of reproductive risk factors on such subtypes and also evaluated the temporal trends between those factors and the subtypes. Using data of Seoul Breast Cancer Study (SeBCS), a multicenter based case-control study, 3,689 breast cancer patients and 3,870 control subjects were analyzed in this study. The distribution of subtypes among cases was 62.7% of ER+, 37.3% ER-, 53.2% of PR+ and 46.8% PR-, respectively. Reproductive factors including age at menarche, pregnancy history, age at first full term pregnancy, number of children, duration of estrogen exposure before first full term pregnancy (EEBF), duration of lifetime estrogen exposure (LEED), breast feeding history and duration of breast feeding were evaluated on breast cancer risk by hormone receptor status. Multinomial logistic regression and Wald tests for heterogeneity across the subtypes were conducted. The frequency of PR-positive breast cancer significantly was higher among the women born in 1960s (56.4%) compared to women born in 1940s (41.9%) (p for trend Our results suggest that association between the reproductive risk factors and breast cancer risk differs appreciably for breast cancer defined by hormone receptor status. Increasing distribution of PR-positive breast cancer might be attributed to changes of EEBF and LEED. Citation Format: Seokang Chung, Nan Song, Hyuna Sung, Sue K. Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Keun-Young Yoo, Daehee Kang, Ji-Yeob Choi. Chronological changes of hormone receptor status in breast cancer by reproductive factors: results from Seoul Breast Cancer Study (SeBCS). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 128. doi:10.1158/1538-7445.AM2013-128

microRNA (miRNA) are small noncoding molecules that function as regulators of the genome. Genetic variants in miRNA binding sites and miRNA genes have begun to be evaluated in relation to disease risk; however, no studies have yet comprehensively evaluated miRNA variants in relation to breast cancer risk. Using a two stage study design, and genome-wide association study (GWAS) data, we evaluated genetic variants within 1,425 miRNA genes (±5kb). In Stage 1, a total of 2,213 common genetic variants were evaluated among 2,876 breast cancer cases and 2,285 controls using data from the Shanghai Breast Cancer Genetics Study. Nominally significant associations (P value ≤0.05) were found for 108 variants in 96 genetic loci (r²≥0.6). In Stage 2, 94 variants in 84 loci were evaluated among 2,225 cases and 2,052 controls from the Seoul Breast Cancer Study; nine variants in eight loci had nominally significant associations. In analyses of the two study stages combined, 14 loci had highly significant associations (P value ≤0.01) and 19 additional loci had significant associations (P value ≤0.05) with breast cancer risk, all with consistent directions of association between the two study stages. These 36 variants in 33 loci have been mapped to 16 miRNA genes, many in the promoter regions. Based on our findings, genetic variants in miRNA genes are likely to contribute to breast cancer susceptibility. Citation Format: Alicia C. Beeghly-Fadiel, Hyuna Sung, Ben Zhang, Ji-Yeob Choi, Ryan J. Delahanty, Jirong Long, Yu-Tang Gao, Wei Lu, Qiuyin Cai, Xiao Ou Shu, Daehee King, Wei Zheng. Genetic variants in microRNA genes and breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2557. doi:10.1158/1538-7445.AM2013-2557

Background: Although several low-penetrance loci associated with breast cancer risk were identified and confirmed, knowledge of the effect of multiple risk alleles is limited especially in Asian women. Therefore we evaluated the association between the polygenic risk scores and breast cancer risk in Korean women using the most recent list of breast cancer susceptibility loci. Methods: We analyzed 51 single-nucleotide polymorphisms (SNPs) located in 34 loci in 1,774 cases and age-frequency matched 1,774 control subjects participating in Seoul Breast Case-Control Study. The fourteen independent SNPs associated with breast cancer risk were selected based on the results of single SNP analysis. The genetic risk score (GRS) were calculated using simple count method and weighted method. Tests of association were conducted using the logistic regression for quintiles of each GRS with or without adjustment. The c-statistic was estimated to evaluate the contribution of GRS to risk prediction model including non-genetic factors (age, family history of breast cancer, education, BMI, menopausal status, age at menarche, age at first full-term pregnancy, and number of children). Results: Fourteen SNPs (rs13393577, rs4973768, rs7716600, rs1092913, rs889312, rs9485372, rs2046210, rs1562430, rs704010, rs10736303, rs7107217, rs10771399, rs3803662, and rs4784227), each of which reflected a genetically independent locus, were found to be associated with breast cancer risk. A highly significant trend was observed between the GRS and the risk of breast cancer. The adjusted odds ratios for women in the highest quintile of count GRS or weighted GRS vs. those in the lowest were 2.64 (95% confidence interval (95% CI), 2.09- 3.35; Ptrend=9.3E-19) and 2.76 (95% CI, 2.18- 3.50; Ptrend=5.9E-21), respectively. The c-statistic for model including the GRS in additional to the conventional risk factors was 0.6389 (95% CI, 0.620-0.658) vs. 0.6041 (95% CI, 0.585-0.623) with the conventional risk factors only. Conclusions: Supporting the polygenic inheritance model of breast cancer, our study showed that GRS based on low-penetrance SNPs adds very modest improvement to risk prediction models. Citation Format: Hyuna Sung, Ji-Yeob Choi, Sue K. Park, Wonshik Han, Keun-Young Yoo, Sei-Hyun Ahn, Dong-Young Noh, Daehee Kang. Combined effects of low-penetrance variants on breast cancer risk: Results from the Seoul Breast Cancer Study. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 60.

Background Although the role of microRNA’s (miRNA’s) biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown. Methods We used genotype data available from a previously conducted case–control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs) and both disease free survival (DFS) and overall survival (OS) among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died. Results Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779) and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845) and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI), 1.41-4.88) and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69). We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4–6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93) and 4.47 (95% CI, 2.45- 8.14), respectively (P for trend, 6.11E-07). Conclusions Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.

The 5-year survival rate for breast cancer has increased from 78% during 1993 to 1995 to 90% during 2004 to 2008 among Korean women. Despite such improvement, breast cancer remains the leading cause of cancer mortality among women. One-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may affect breast cancer prognosis. This study aimed to investigate the associations of dietary intake of vitamin B2, vitamin B6 and folate before diagnosis and breast cancer prognosis. We assessed dietary intake from Food Frequency Questionnaire in 980 women who were newly diagnosed and histopathologically confirmed first primary breast cancer from hospitals located in Seoul, Korea in 2004 to2007 and followed for an average of 5.3 years. Univariate and multivariate analyses were used to investigate association between dietary intake of B-vitamins and disease free survival. There was no association between dietary intake of B vitamins and breast cancer prognosis. However, we found higher dietary intake of vitamin B6 was associated with improved survival in patients with BMI more than 25kg/m2 (harzard ratio (HR), 0.32; 95% confidence intervals (CI), 0.11-0.94) or positive hormone status in estrogen receptor(ER)/progesterone receptor(PR) (HR, 0.39; 95%CI, 0.16-0.97). Our study suggests that the high intake of vitamin B6 is associated with improved breast cancer survival in patients with higher BMI and positive hormone status in ER/PR. 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 641. doi:1538-7445.AM2012-641

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: While the incidence of breast cancer is relatively low in Korean women, the proportion of breast cancer that develops in younger age is much higher than in western countries. Family-based linkage study has focused on the identification of a region which is associated with the age at onset in familial breast cancer. However, genetic factors for onset age of breast cancer are still largely unknown. While genome-wide association studies (GWAS) have identified over 20 susceptibility loci for breast cancer, no previous study has examined the relationship between the common genetic variations and the age at onset in breast cancer. Methods: To identify genetic factors underlying onset age of breast cancer, we investigated the association between genetic variants and age at diagnosis in 2,155 breast cancer cases. Over 1.9 million SNPs either directly genotyped using Affymetrix 6.0 or imputed with HapMap 2.0 as a reference panel were evaluated after quality control. Tests of association were conducted with Plink v1.01 using the additive genetic model and Mach2qtl with allelic dosages in a linear regression model in which onset age was included as a dependent variable (continuous). The differences of mean age across genotype-groups were also compared using one-way analysis of variance. Results: The mean age at onset in breast cancer was 48.1 ± 9.31. The SNPs with p-value less than 1×10-5 obtained from linear regression were clustered into two regions: two SNPs (rs6684400 and rs6659875) are at 1q25.3 in intergenic region between ZNF648 and GLUL gene; the other two ([rs669576][1] and [rs667007][2]) are at 11q25 in intronic region of NTM gene. Per-allele effect size was 1.4 ± 0.30 (p = 4.84E-06) for rs6684400 C allele and 3.1 ± 0.68 for [rs669576][1] T allele (p = 7.11E-06). The mean age at onset for the rs6684400 G/G, C/G and C/C groups were found to be 47.2 ± 9.00, 48.1 ± 9.32 and 49.7 ± 9.59, respectively (p = 0.0001). As for the [rs669576][1], the mean age at onset for G/G, G/T and T/T groups were 47.8 ± 9.15, 50.9 ± 10.38 and 54.3 ± 7.80, respectively (p < 0.0001) Conclusions: Our study suggests that the common genetic variants may be closely linked to age at onset in breast cancer. Further validation with a larger sample size is required to validate our result. 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 1655. doi:1538-7445.AM2012-1655 [1]: /lookup/external-ref?link_type=GEN&access_num=rs669576&atom=%2Fcanres%2F72%2F8_Supplement%2F1655.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs667007&atom=%2Fcanres%2F72%2F8_Supplement%2F1655.atom

Introduction Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. Methods To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. Results In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14). Conclusions This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.