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Tumor infiltrating lymphocytes (TIL) and androgene receptors (AR) in triple – negative breast cancer (TNBC) – new biomarkers on horizon?

Triple Negative Breast Cancer (TNBC) makes a clinically heterogeneous group of tumors, with the common feature of the most aggressive and deadliest breast cancer subtype. TNBC patients have higher rates of tumor disease return and worse overall survival than other breast cancer subtypes. The molecular feature of TNBC is the lack of immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR), as well as HER2 receptors. Approximately 12-17% of breast cancer patients have TNBC and they fall into the group of patients with poor prognosis, with no effective endocrine therapy or HER2-mediated drugs. Due to the frequency of mutations (resulting in immune response inducing neo-antigens), the increase in the number of infiltrating lymphocytes (TILs) (evidence of immune detection) and the increased expression of PD-L1 protein (inhibits T-cell anti-tumor response), TNBC represents a potential target for immunotherapy (especially PD-L1 targeted therapy). The TILs have prognostic value in TNBC, predictive of the effect of preoperative chemotherapy, and may be associated with the effectiveness of the use of immunotherapy with checkpoint inhibitors. There are currently controversies over the estimation of TILs role in breast cancer, both localization and quantification. Namely, it appears that the stromal TILs have a higher prognostic value than the intratumor TILs, and the cut-off value is also unclear (high versus low expression). The role of lymphocyte count in the blood is also unclear as a prognostic factor in TNBC. The predicted value of TILs in TNBC was investigated, depending on the type of chemotherapy applied and the greater expression of TILs was shown to be associated with a better outcome. More pronounced TILs are associated with a higher rate of complete pathological response to preoperative chemotherapy in TNBC. The basic expression of TILs may be associated with a better response to the use of a checkpoint inhibitor atezolizumab. Androgen Receptors (AR) belong to a group of nuclear receptors, as well as ER and PR. AR is structurally similar to progesterone receptor and progestins at higher concentrations block AR. AR are expressed in over 70% of breast cancer. Also, part of the TNBC has an expressed AR, although there is no expressed ER or PR. In literature, the presence of AR in TNBC ranges from 10-54%. Negative AR expression is significantly associated with higher clinical stage, higher mitotic index, higher grade and high Ki-67 proliferation index, and significantly more AR negative tumors are seen in the group of tumors with positive basaloid immunophenotype and basaloid morphology. At present, there are good results of clinical studies with the application of immunotherapy, PD-1 and PD-L1 inhibitors, pembrolizumab and atezolizumab, in TNBC. Also, early clinical studies have shown promising results in the use of antiandrogens in the advanced TNBC.

breast cancer ; biomarkers ; tumor infiltrating lymphocytes ; androgene receptors

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