DENSITAS MAMOGRAFI METODE NILAI AMBANG, KADAR ESTRADIOL, DAN POLIMORFISME RESEPTOR ESTROGEN 1 SEBAGAI PREDIKTOR KANKER PAYUDARA

Lina Choridah, dr., Sp.Rad, Prof. Dr. dr. Teguh Aryandono, Sp.B(K) Onk.

2013 | Disertasi | S3 Kedokteran Umum

Latar Belakang: Kanker payudara adalah penyebab utama morbiditas dan mortalitas kanker pada wanita di seluruh dunia maupun di Indonesia. Angka kejadian semakin meningkat tiap tahun sehingga menjadi salah satu masalah kesehatan yang krusial. Meskipun mekanisme kerja secara pasti belum diketahui, estrogen diduga memegang peranan penting terjadinya kanker payudara melalui mekanisme proliferasi dan metabolit genotoksik. Reseptor estrogen utama adalah reseptor estrogen α, dikodekan sebagai gen ESR1. Variasi keberhasilan terapi anti estrogen diduga karena adanya polimorfisme gen ESR1. Densitas mamografi merefleksikan perbandingan jumlah stroma, epithelial, dan jaringan lemak. Secara umum densitas mamografi dikaitkan dengan proliferasi sel yang diduga merupakan efek estrogenik. Wanita dengan densitas mamografi tinggi memiliki faktor risiko kanker payudara yang lebih kuat. Tujuan: Mengetahui peranan densitas mamografi, kadar estradiol, dan polimorfisme ESR1 sebagai prediktor kanker payudara terkait faktor estrogenik pada populasi etnis Jawa di Indonesia, serta menyusun model perhitungan risiko kanker payudara dengan memperhitungkan persentase densitas mamografi sehingga dapat digunakan sebagai acuan upaya preventif dan intervensi untuk menurunkan risiko kanker payudara. Metode: Penelitian observasional, pengumpulan data secara prospektif menggunakan rancangan cohort study. Subjek penelitian adalah wanita yang menjalani mamografi di klinik onkologi dengan densitas tinggi dan rendah. Subyek dikelompokkan menjadi dua, dengan dan tanpa kanker payudara. Data hasil penelitian dianalisis menggunakan risiko relatif (RR) dan analisis multivariat regresi logistik. Hasil: Didapatkan 120 subjek penelitian, 60 subyek ditetapkan sebagai penderita kanker payudara berdasar triple test. Kelompok umur terbanyak kanker payudara 40-49 tahun (36,7%). Karsinoma duktal infiltratif merupakan tipe terbanyak (80%). Lima belas subyek (25%) memiliki ER/PR/HER2/neu negatif atau dikenal sebagai kanker payudara triple negative. Subyek dengan persentase densitas mamografi (PDM) >50% memiliki RR 1,55 (IK 95% 1,066-2,270) terhadap kanker payudara dibanding densitas < 50%. Subyek dengan PDM 25-34% memiliki RR 1,67 (IK 95% 0,47-5,89) dibanding PDM <25%. PDM 35-49%, 50- 64% dan > 65% memiliki RR 3,4 (IK 95% 1,16-9,97), 3,43 (IK 95% 31,19-9,88), dan 3,45 (IK 95% 1,17-10,14) dibanding PDM <25%. Kadar estradiol tinggi tidak memiliki hubungan yang bermakna dengan risiko kanker payudara. Genotip CT dan TT gen ESR1PvuII memiliki RR terhadap kanker payudara sebesar 1,91 (IK 95% 0,95-3,80) dan 3,36 (IK 95% 1,729-6,526) dibanding CC. Genotip AG gen ESR1 XbaI memiliki RR 2,68 (IK 95% 0,72-9,88) sedangkan AA 3,63 (IK 95% 1,01-13,10) dibanding GG. Berdasarkan penggabungan 6 faktor yaitu PDM, polimorfisme gen ESR1 PvuII, IMT >25 kg/m2, riwayat keluarga, kelompok umur, dan status menopause, dikembangkan suatu model baku emas sekaligus model terbaik risiko kanker payudara yang dinamakan GAMA DEJAVU (Gadjah Mada Densitas Mamografi Jawa PvuII) yang mungkin sesuai untuk etnis Jawa, diperlukan konfirmasi menggunakan data yang lebih besar. Kesimpulan: Densitas mamografi merupakan novel independent risk factor kanker payudara pada populasi di Indonesia. Polimorfisme ESR1 PvuII dan ESR1 XbaI juga merupakan prediktor kanker pada etnik Jawa dengan proporsi menunjukkan adanya dominasi alel T/A sesuai dengan proporsi wanita Asia. Kadar estradiol tidak memiliki hubungan yang bermakna dengan risiko kanker payudara. GAMA DEJAVU, model perhitungan risiko kanker payudara pada populasi etnis Jawa di Indonesia dikembangkan berdasarkan hasil-hasil dari penelitian ini.

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.

Kata Kunci : densitas mamografi, kadar estradiol, DNA polimorfisme, kanker payudara