HUBUNGAN SINDROMA METABOLIK, OBESITAS, DAN KESINTASAN PASIEN KANKER PAYUDARA SUB-TIPE MOLEKULER HR+/HER2- NON-METASTATIK Kajian pada Biomarka Metabolik, Mitogenik, dan Epigenetik: Leptin, miR-222-3p, dan miR-143-3p

KARTIKA WIDAYATI, Prof.Dr.dr. Teguh Aryandono, SpB.(K).Onk; dr. Mardiah S. Hardianti, PhD., SpPD-KHOM

2021 | Disertasi | DOKTOR ILMU KEDOKTERAN DAN KESEHATAN

ABSTRAK Latar Belakang Sindroma metabolik (MetS) dan obesitas sering dikaitkan dengan munculnya berbagai penyakit termasuk kanker payudara. Kanker payudara dengan ekspresi reseptor hormon positif tanpa ekspresi human epidermal growth factor receptor-2 (HR+/HER2-) diketahui memiliki prognosis paling baik. Pengaruh metabolik terhadap kesintasan pasien kanker payudara HR+/HER2- belum diketahui. Tujuan Penelitian ini bertujuan menguji hubungan MetS dan obesitas dengan kesintasan kanker payudara HR+/HER2- serta menguji apakah leptin, miR-222-3p, dan miR-143-3p yang berperan pada proses metabolik dan mitogenik berhubungan dengan kesintasan kanker sub- tipe tersebut. Metode Penelitian dilakukan secara kohort retrospektif dengan mengambil data rekam medis pasien mulai tahun 2010-2020. Kriteria inklusi adalah tipe karsinoma invasif, stadium non-metastatik, IHC HR+/HER2-, sudah mendapat terapi hormon minimal 6 bulan sebelum dilakukan inklusi, menyelesaikan siklus terapi ajuvan lengkap, memiliki data surveillance evaluasi tumor setiap 6 bulan, dan memiliki data profil lemak, dan antropometrik pasca diagnosis. Data klinis semua ditarik dari rekam medis. MetS ditentukan berdasar kriteria NCEP-ATP III dengan modifikasi Asia. Obesitas ditentukan dengan kriteria Asia Pasifik. Leptin diperiksa dengan metode immunohistokimia. Kuantifikasi miR-222-3p dan miR-143-3p dilakukan secara RT-qPCR. MetS, obesitas, leptin, miR-222-3p, miR-143-3p bersama-sama parameter klinikopatologis dianalisis hubungannya terhadap Disease-Free Survival (DFS), dan Overall Survival (OS). Data dianalisis dengan Chi-square, Fisher exact test, Cox-proportional hazard model, dan Kaplan-Meier dengan signifikansi p<0,05. Hasil Terdapat 223 kasus kanker payudara HR+/HER2-. MetS dijumpai pada 56,1% kasus. MetS tidak mempengaruhi kesintasan. Obesitas berdasarkan BMI �¢ï¿½�¥ 25 juga tidak mempengaruhi kesintasan. Obesitas visceral (WHR �¢ï¿½�¥ 0,85) berkaitan dengan DFS singkat (HR 1,563; p = 0,073) dan OS singkat (HR 4,281; p = 0,028). Seratus tiga puluh enam blok parafin dari 223 kasus diperiksa marka molekular. Over-ekspresi leptin tidak berhubungan dengan DFS (HR 0,592, p = 0,099). Over-ekspresi miR-222-3p berkaitan dengan DFS (HR 0,350; p = 0,018) dan OS (HR 0,028; p = 0,309) yang lebih baik. Over-ekspresi miR-143-3p tidak berhubungan dengan DFS (HR 0,588; p = 0,089). Triple over-ekspresi-(leptin/miR-222-3p/miR-143-3p) merupakan penanda DFS lebih panjang (HR 0,086; p = 0,018). Kesimpulan MetS tidak berhubungan dengan kesintasan kanker payudara HR+/HER2- Obesitas visceral berhubungan dengan kesintasan lebih singkat. Over-ekspresi leptin tidak berhubungan dengan DFS. Over-ekspresi miR-222-3p berhubungan dengan kesintasan yang lebih panjang. Over-ekspresi miR-143-3p tidak berhubungan DFS. Triple over-ekspresi leptin/miR-222-3p/miR-143-3p memiliki DFS yang paling panjang. Kata kunci: breast cancer, luminal, metabolic syndrome, microRNA, obesity, prognosis

ABSTRACT Background Metabolic syndrome (MetS) and obesity are often associated with a risk of developing various diseases including breast cancer. Breast cancer with positive hormone receptor, negative human epidermal growth factor-2 (HR+/HER2-) sub-type has an excellent prognosis. The role of MetS and obesity on survival of breast cancer with less-aggressive sub-type has not been established yet, as well as the role of metabolic, mitogenic, and epigenetic markers such as leptin, miR-222-3p, and miR-143-3p. The aim of the study was to investigate the association of MetS, obesity, leptin, miR-222-3p and miR-143-3p as prognostic markers for survival of patients with HR+/HER2- breast cancer. Method The research was conducted retrospectively by taking patient medical record data from 2010-2020. Inclusion criteria were: invasive carcinoma, non-metastatic disease, HR+/HER2- sub-type, having received hormone therapy at least 6 months before inclusion, completed adjuvant therapy, had regular tumor evaluation and surveillance every 6 months, and have lipid profile and anthropometric data before systemic treatment initiated. Clinical data were all extracted from medical records. MetS was determined based on NCEP-ATP III criteria with Asian modifications. Obesity was determined by the Asia Pacific criteria. Leptin was examined by immunohistochemical methods. Quantification of miR-222-3p and miR-143-3p was performed by RT-qPCR. MetS, obesity, leptin, miR-222-3p, miR-143-3p all together with clinico-pathological parameters were analyzed for their contribution on Disease-Free Survival (DFS), and Overall Survival (OS). Data were analyzed with Chi-square, Fisher�¢ï¿½ï¿½s exact test, Cox regression and Kaplan-Meier for survival estimation, with p<0.05 was considered as statistically significant. Result There were 223 cases of HR+/HER2 breast cancer for analysis. MetS was found in 56,1% cases. MetS did not affect DFS nor the OS. Obesity, measured as BMI �¢ï¿½�¥ 25, did not affect survival. Visceral obesity measured as WHR �¢ï¿½�¥ 0.85 was associated with early recurrence (HR 1.563; p = 0.073) and short survival (HR 4.281; p = 0.028). There were 136 paraffine embedded tissues for molecular tests. Over-expression of leptin was not associated with DFS (HR 0.592, p = 0.099). Over-expression miR-222-3p was related to prolonged DFS (HR 0.350; p = 0.018) and OS (HR 0.028; p = 0.309). Over-expression of miR-143-3p was not associated with DFS (HR 0.588; p = 0.089). Triple over-expression-(leptin/miR-222-3p/miR-143-3p) was a marker of prolonged DFS (HR 0.086; p = 0.018). Conclusion MetS did not affect the survival of HR+/HER2 breast cancer. Visceral obesity was associated with poor survival. Over-expression of leptin was not significantly associated with DFS. Over-expression of miR-222-3p was a prognostic marker for good survival outcome. Over-expression of miR-143-3p was not significantly associated with DFS. Triple over-expression of leptin/miR-222-3p/miR-143-3p was associated with prolonged DFS. Keywords: breast cancer, luminal, metabolic syndrome, microRNA, obesity, prognosis

Kata Kunci : breast cancer, luminal, metabolic syndrome, microRNA, obesity, prognosis