Predictive and prognostic features of early and locally advanced <i>PIK3CA</i>-mutated luminal HER2-negative breast cancer

Abstract

Background. Data on the prognostic role of the PIK3CA mutation in hormone receptor-positive (HR+) HER2-negative (HER2–) breast cancer (BC) are contradictory; nevertheless, there are indications of its negative predictive and prognostic significance. This dictates the need for early genetic testing of BC to predict the clinical course, select a primary therapy option and individualize systemic treatment with disease progression. Investigation of regulation of the tumor cell cycle, as well as the relationship between genetic markers, infiltration of tumor-infiltrating lymphocytes (TILs) and subpopulations of immune cells is strategically important for the search for drug therapy targets.Aim. To search for predictive and prognostic markers of the clinical course of PIK3CA-associated HR+ HER2– BC.Materials and methods. The clinical, morphological and molecular features of the tumor of 101 BC patients with PIK3CA mutations (100 women and 1 man) were analyzed. Early and locally advanced HR+ HER2– BC is present in 81 % of cases, where neoadjuvant chemotherapy (NAPCT) was performed in 28 % of patients. Primary metastatic disease was detected in 17 % of cases. An immunohistochemical evaluation was performed on sections from paraffin blocks using monoclonal antibodies to estrogen receptors, progesterone receptors, HER2, Ki-67, CD8, CD4, CD68, CD163, Bcl-2, p53, cyclin D1. TILs were evaluated when stained with hematoxylin and eosin. TILs were evaluated in the stromal component of the tumor. The correlation of clinical and morphological parameters with the type of mutation and clinical outcomes of treatment of patients with early and locally advanced HR+ HER2– BC was evaluated. The statistical analysis was performed using the IBM SPSS Statistics v. 22 statistical package.Results. In BC with the PIK3CA mutation, a low level of TILs infiltration was detected (1 point), which does not differ depending on the presence of mutations in exon 20 and exon 9 (p >0.05). However, the E545K mutation is characterized by a higher TILs level (2 points) (p = 0.05). CD4+ T-TILs and CD8+ T-TILs levels are statistically significantly higher with mutations in exon 20 compared to exon 9 of the PIK3CA gene (p = 0.017 and 0.013, respectively). At the same time, in comparison with other mutations, tumors with H1047R and E545K mutations (p = 0.05) were characterized by a higher level of CD4 and CD8 expression. Regardless of the mutated exon, a high level of CD68+ tumor-associated macrophages (Me = 80 %), was detected due to the CD163+ fraction of immunosuppressive M2-polarized tumor-associated macrophages (Me = 70 %). A feature of the regulation of the PIK3CA-mutated BC cell cycle is the high level of cyclin D1 expression, the absence of p53 expression and the positive expression of the antiapoptotic marker Bcl-2. The median disease-free survival in early and locally advanced HR+ HER2– BC with the PIK3CA mutation was 36 months (95 % confidence interval (CI) 24.720–47.280). The risk of progression was increased by NAPCT (hazard ratio 3.389; 95 % CI 1.530–7.504; p = 0.003). The risk of progression was reduced by age younger than 49 years (hazard ratio 0.54; 95 % CI 0.30–0.96, p = 0.0359) and the absence of expression of the antiapoptotic marker Bcl-2 (hazard ratio 0.36; 95 % CI 0.14–0.97; p = 0.0425).Conclusion. The data obtained indicate that BC with the PIK3CA mutation is a kind of biological subtype of HR+ HER2– BC, which shows the lack of significant efficacy of NAPCT, probably due to the immunosuppressive microenvironment and low TILs levels. At the same time, the predominant population was M2-polarized tumor-associated macrophages. Moreover, the administration of NAPCT and the positive expression of Bcl-2 reduce disease-free survival, which can be explained by the possible effect of increasing the invasiveness and migration potential of the tumor cell. It is important to continue investigation of identified clinical and morphological prognostic markers when planning and developing new strategies for the treatment of early and metastatic HR+ HER2– BC with the PIK3CA mutation, as well as the use of specific targeted therapy at early metastatic disease.