Expresión de ALDH1A1, PD-L1 y TILS en el cáncer de mama triple negativo y HER2 positivoasociación con variables clínico patológicas y supervivencia

Resumo

Triple negative (TN) and HER2 positive (HER2+) tumors have been associated with a more immunogenic tumor microenvironment, with a higher presence of tumor infiltrating-lymphocytes (TILs) and activation of PD-L1 pathway. Among other prognostic factors, a group of cells that exhibit tumorogenic, self-renewal and differentiation capacity, called cancer stem cells (CSC), have been described. Its presence has been related to resistance to treatment and relapse in breast cancer (BC). Aldehyde dehydrogenase 1 A1 (ALDH1A1) is a marker of CSC that has been proposed as a predictor of response and prognosis. A retrospective, historical cohort study was conducted in 75 patients diagnosed with early or locally advanced TN and HER2+ BC between 2008 and 2018 who had received neoadjuvant chemotherapy prior to surgery, and with a minimum follow-up period of 24 months. The expression of ALDH1A1, PD-L1 and TILs subtypes was assessed by immunohistochemistry. The relationship between ALDH1A1, PD-L1, and TILs, and its association with different clinicopathological characteristics and survival was analyzed. There were no differences in ALDH1A1 expression, PD-L1 expression and TILs infiltration between TN and HER2+ tumors, and their positive expression was related to smaller tumors. Different patterns of cytoplasmic expression of ALDH1A1 were identified. Nuclear expression of ALDH1A1 was described for the first time in BC, which was related to the presence of obesity and smaller tumor size, and might be associated with a favorable prognosis. TILs infiltration was identified in all the analyzed carcinomas, with TILs CD3+ and CD4+ subtypes being predominant. In addition, positive ALDH1A1 tumors exhibited a higher frequency of positive PD-L1 expression and greater presence of all evaluated TIL subtypes. The expression of PD-L1 was related to high TILs infiltration. On the other hand, triple-negative tumors with ALDH1A1 expression presented more frequently PD-L1 expression, high TILs infiltration and CD20+. This difference was not demonstrated in HER2+ cases. In HER2+ tumors, the expression of PD-L1 was related to the expression of androgen receptors, a dense inflammatory infiltrate, and the presence of CD20+ cells. Furthermore, positive ALDH1A1 was related to a higher rate of pathological complete response. Infiltration by HTILs was associated with a lower relapse rate. A smaller tumor size was related to fewer relapse and death. From these results it can be concluded that ALDH1A1 expression is related to PD-L1 expression and high TILs presence, and its identification could be a useful biomarker in TN and HER2+ breast cancer to select patients which might be candidates for certain therapies such as immunotherapy.