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PURPOSE With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. METHODS In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. RESULTS Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy. CONCLUSION Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.

Mammographic density is a measurable and modifiable biomarker that is strongly and independently associated with breast cancer risk. Paradoxically, although Asian women have lower risk of breast cancer, studies of minority Asian women in predominantly Caucasian populations have found that Asian women have higher percent density. In this cross-sectional study, we compared the distribution of mammographic density for a matched cohort of Asian women from Malaysia and Caucasian women from Sweden, and determined if variations in mammographic density could be attributed to population differences in breast cancer risk factors.Volumetric mammographic density was compared for 1501 Malaysian and 4501 Swedish healthy women, matched on age and body mass index. We used multivariable log-linear regression to determine the risk factors associated with mammographic density and mediation analysis to identify factors that account for differences in mammographic density between the two cohorts.Compared to Caucasian women, percent density was 2.0% higher among Asian women (p 0.001), and dense volume was 5.7 cmOur analysis suggests that among post-menopausal women, population differences in mammographic density and risk to breast cancer may be accounted for by height, weight, and parity. Given that pre-menopausal Asian and Caucasian women have similar population risk to breast cancer but different dense volume, development of more appropriate biomarkers of risk in pre-menopausal women is required.

Background APOBEC3B is a cytosine deaminase implicated in immune response to viral infection, cancer predisposition and carcinogenesis. Germline APOBEC3B deletion is more common in East Asian women and confers a modest risk to breast cancer in both East Asian and Caucasian women. Analysis of tumour samples from women of European descent has shown that germline APOBEC3B deletion is associated with an increased propensity to develop somatic mutations and with an enrichment for immune response-related gene sets. However, this has not been examined in Asian tumour samples, where population differences in genetic and dietary factors may have an impact on the immune system. Methods In this study, we determined the prevalence of germline APOBEC3B deletion and its association with breast cancer risk in a cross-sectional hospital-based Asian multi-ethnic cohort of 1451 cases and 1442 controls from Malaysia. We compared gene expression profiles of breast cancers arising from APOBEC3B deletion carriers and non-carriers using microarray analyses. Finally, we characterised the overall abundance of tumour-infiltrating immune cells in breast cancers from TCGA and METABRIC using ESTIMATE and relative frequency of 22 immune cell subsets in breast cancers from METABRIC using CIBERSORT. Results The minor allelic frequency of APOBEC3B deletion was estimated to be 0.35, 0.42 and 0.16 in female populations of Chinese, Malay and Indian descent, respectively, and that germline APOBEC3B deletion was associated with breast cancer risk with odds ratios of 1.23 (95 % CI: [1.05, 1.44]) for one-copy deletion and 1.38 (95 % CI: [1.10, 1.74]) for two-copy deletion compared to women with no deletion. Germline APOBEC3B deletion was not associated with any clinicopathologic features or the expression of any APOBEC family members but was associated with immune response-related gene sets (FDR q values

Mammographic density is an independent risk factor for breast cancer and has been shown to differ among populations with varying risk to breast cancer. We sought to compare the distribution of known breast cancer risk factors between an Asian and a Caucasian population, and to determine if the variations in mammographic density between Asian and Caucasian populations can be attributed to the differences in the distribution of these risk factors. 2948 women with no personal history of breast cancer attending an opportunistic screening program in Malaysia (MyMammo) were included in the analysis. Participants were age and BMI matched to 8837 women of the Karolinska Mammography Project for Risk Reduction of Breast Cancer (KARMA) study in Sweden. For analyses involving mammographic density, a subset of Malaysian women with available raw FFDM images (n = 1501) and matched Swedish women (n = 4501) were included for analysis. Volume-based mammographic density measurements for both cohorts were measured using an automated method (Volpara). Descriptive statistics were used to describe the distribution of breast cancer risk factors and mammographic density measures between the two cohorts. General linear models and stepwise selection method were used to determine the risk factors associated with mammographic density within each cohort. Most of the anthropometric, reproductive and lifestyle risk factors examined were differentially distributed between the two cohorts. There was a significantly greater proportion of postmenopausal Swedish women (56%) compared to Malaysian women (51%). Hormone replacement therapy and oral contraceptive ever use was substantially higher among Swedish women (24% and 73%) than Malaysian women (14% and 29%). Mean dense volume was not significantly different between the two cohorts, but Swedish women had a significantly higher mean non-dense volume and lower percent volumetric density compared to Malaysian women. However, pre-menopausal Malaysian women had statistically significant higher dense volume than Swedish women (mean dense volume of 73.9cm3 compared to 70.4cm3). Among post-menopausal women, Malaysian women had significantly lower dense volume than Swedish women (mean dense volume of 54.7cm3 compared to 57.5cm3). In multivariable analyses, age, BMI and parity were associated with dense volume in both cohorts, but regular alcohol intake, height, changes in body shape over time, and menopausal status were only significantly associated with dense volume for Swedish women. In an age and BMI matched cohort, pre-menopausal Asian women had significantly higher dense volume than Caucasian women, whereas, post-menopausal Asian women had lower dense volume than Caucasian women. Population differences in height, body shape changes over time, and alcohol intake could explain, in part, the variation seen in mammographic density, and potentially breast cancer risk, across populations. Citation Format: Nadia Rajaram, Shivaani Mariapun, Mikael Eriksson, Jose Tapia, Pui Yoke Kwan, Weang Kee Ho, Faizah Harun, Nor Aishah Mohd Taib, Per Hall, Soo-Hwang Teo. Lifestyle determinants of mammographic density in Asian and Caucasian populations: A comparative analysis. [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 1740.