THRESHOLD VALUE METHOD DENSITY mammography, estradiol, AND ESTROGEN RECEPTORS 1 polymorphisms as predictors BREAST CANCER
ABSTRACT: Background: Breast cancer is the leading cause of women cancer mortality and the morbidity in worldwide as well as in Indonesia. The incidence rate continuously increases each year therefore breast cancer emerges as one of major health problems, therefore breast cancer emerges as one of major health problems. Despite of the fact that the detailed mechanism of breast carcinogenesis is not yet fully understood, estrogen is believed to play an important role in the development and progression of breast cancer by inducing cell proliferation and generating genotoxic metabolites. Estradiol is the main estrogen species produced in women and estrogen receptor α, encoded by ESR 1 gene, is the main estrogen receptor. The mixed results on success of anti-estrogen therapy are believed, in one hand, due to polymorphisms of the ESR 1. Mammographic densities reflect the differences in the number of stromal, epithelial, and fat tissue. In general, mammographic densities are equivalent to the cell proliferation, which is thought to be affected by estrogen. Women with higher mammographic density have greater risk to suffer from breast cancer. Objectives: To determine the role of mammographic density, estradiol level, and ESR1 polymorphisms as predictors of estrogenic factors associated breast cancer risk in Javanese ethnic population in Indonesia, and to create a model for calculating breast cancer risk using the percentage of mammographic densities that subsequently can be used as a reference for prevention as well as intervention to reduce breast cancer risk. Methods: We performed an observational study; data were collected prospectively using a cohort study design. Subjects were women who came to oncologic clinic for mammographic screening, with either high or low breast density. Subjects were then grouped into two, with and without breast cancer. The data were analyzed using relative risk and multivariate logistic regression. Results: There were 120 subjects. Sixty subjects were diagnosed as breast cancer based on triple tests. Among breast cancer patients, the largest age group was 40- 49 year-old (36.7%). Invasive ductal carcinoma is the most common type of breast cancer (80%) in our cohort. Fifteen breast cancer patients (25%) had a negative ER/PR/HER2/neu, known as triple negative cases. Subjects with percentage mammographic density (PMD) >50% had a greater relative risk for developing breast cancer by 1.55 times (95% CI, 1.066 to 2.270), compared to subjects with PMD <50%. Subjects with PMD 25-34% had a relative risk 1.67 (95% CI, 0.47 to 5.89). Women with PMD 35-49%, 50-64% and >65% had relative risk of 3.4 (95% CI, 1.16 to 9.97), 3.43 (95% CI, 31.19 to 9.88) and 3.45 (95% CI, 1.174 to 10.14%) times, respectively, compared to PMD <25%. The highest quartile of estradiol’s level did not have significant association with breast cancer risk compare with the lowest. CT and TT genotypes of ESR1 PvuII had a relative risk 1.9104 (95% CI, 0.9594 to 3.803) and 3.36 (95% CI, 1.729 to 6.526) times, respectively, compared to CC genotype. AG genotypes of ESR1 XbaI had relative risk 2.6800 (95% CI, 0.7273 to 9.88151) times than the GG genotype, whereas AA had relative risk 3.6393 (95% CI 1.01667 to 13.1050) times. By incorporating 6 factors i.e. : PMD, ESR1 PvuII polymorphisms, BMI, family history, age and menopausal status, we were able to develop a new breast cancer risk model known as GAMA DEJAVU (Gadjah Mada Mammographic Density Java ESR1 Pvu II ) that might be suitable for Javanese population although confirmation using larger data sets is warranted. Conclusion: Mammographic density is a novel independent risk factor for breast cancer. Polymorphisms of ESR1 PvuII and ESR1 XbaI are also a predictor for breast cancer with allele T/A proportion domination, concordant with the proportion of Asian women. Estradiol levels do not have a significant association with breast cancer risk. GAMA DEJAVU, the model of breast cancer risk calculation in Javanese ethnic population in Indonesia was developed by incorporating these results.
