Assessment of risk factors and identification of potential biomarkers associated with breast cancer-related lymphedema in Malaysian breast cancer survivors

Although higher survival rates of breast cancer are achieved these days, breast cancer survivors are challenged with unwanted side effects following cancer treatment including breast cancer-related lymphedema (BCRL). BCRL is characterized by fluid retention and abnormal swelling in one or both arms that arises after obstruction of lymphatic vessels resulting from surgery insults or radiotherapy. The aim of this study was to identify risk factors and potential biomarkers associated with BCRL in the Malaysian breast cancer population. A set of questionnaires comprising demographic and medical history, quality of life assessment, and upper quadrant function were administered to 173 female breast cancer survivors. Anthropometry, arm circumference measurement, and ultrasound examination of the arms were performed on all participants to classify them into either lymphedema group or the non-lymphedema group (non-BCRL). Whole blood was collected and processed to obtain the serum to observe microRNA expression and functional protein in both groups. It was found that 20.5% (33/160) of the women in the study population were having arm lymphedema. Those with multiple breast cancer surgeries on the same site of the breast, had more than 10 lymph nodes excised, higher body mass index, higher waist-to-hip ratio, hypertension, and received fewer rehabilitation treatment were associated with increased odds of lymphedema. Diabetes mellitus was found to have a significant association with the development of early-onset lymphedema within the lymphedema group. MicroRNA profiling results demonstrated that miR-199a-3p and miR-151a-3p were associated with pathways involved in metabolic syndrome (MetS) including insulin resistance, mTOR and MAPK signalling pathways in the lymphedema group. One of the biomarkers of MetS, the adiponectin/leptin ratio was lower in the lymphedema group, indicates severe risk of MetS. Taken together, findings in the present study revealed a strong association between BCRL with MetS in the study population, hence provided a better understanding of secondary lymphedema in breast cancer survivors.