###### Abstract  
Background: In the present study, we evaluated the prognostic value of TILs as well their relation with clinicopathological factors in patients affected by HER-2 positive breast cancer. **Methods**: We evaluated 47 patients with a histologically confirmed diagnosis of invasive breast carcinoma showing an immunohistochemistry confirmed (score 3+) amplification of the c-erbB-2 gene for the presence of TILs and categorized in three predefined groups of low (0-10% immune cells in stromal tissue within the tumor), intermediate (11-40%), and high TILs (>40%). **Results**: Low, intermediate and high TILs were found in 17/47 (36%), 23/47 (49%) and 7/47(15%) cases, respectively. It was found that 6/47 cases treated with adjuvant chemotherapy plus trastuzumab underwent progression of the disease; none of these cases exhibited high TILs. It was found that 12/47 patients with a prognostically unfavorable stage of III and IV showed low and intermediate levels of TILs, while high TILs were never observed. A significant association between intermediate/high-levels of TILs, elevated KI 67 index and hormone receptors nuclear staining was observed. High concordance in TILs distribution was observed between preoperative breast biopsies and surgical samples. **Conclusions**: We observed a positive correlation between the TILs and the response to both adjuvant and neoadjuvant treatments in HER-2 positive BC. High TILs were also related to increased KI-67 index and to the expression of hormone receptors. breast cancer; HER2; tumor infiltrating lymphocytes; KI-67; hormone receptors; immune microenvironment; target therapy +
Footnote †: journal: Medicalcountries [1; 2; 3]. With respect to age groups, the incidence of BC tends to increase up to the menopausal years (around 50-55 years), slow down and then start to rise again after the age of 60 [2]. BC does not represent a homogeneous disease, but a wide spectrum of neoplasms characterized by huge differences in terms of clinical behavior, prognosis and response to treatments [1; 2; 3]. In recent years several studies have been carried out in order to identify a series of morphological or molecular parameters that were related to the patient's prognosis (i.e., the clinical course of the disease and the overall survival) or to the response to specific treatments (predictive factors) [1]. Some of these fall into both categories, such as the expression of estrogen receptors (ERs), HER-2, the proliferation index and genetic signatures [4]. The immunogenicity of BC has not traditionally been taken into account either in clinical practice or in scientific research, unlike other types of malignancies, such as melanoma, lung cancer and gynecological neoplasms, for which new therapies, able to stimulate the antitumor immune response have recently been introduced in clinical practice with a significant impact on prognosis [5; 6; 7; 8]. However, in recent years numerous clinical studies have been conducted in order to better understand whether the individual immune response was able to influence the clinical behavior of BC and, in other words, whether it was possible to assign to each mammary neoplasms an \"immunological grade\" that had prognostic and/or predictive significance of therapeutic response [9]. The presence of tumor-infiltrating lymphocytes (TILs), within the tumor and/or in peritumoral sites, has been recognized as an important immunological biomarker that reflected the antitumor immune response in BC, as well as in other malignancies, including ovarian and endometrial carcinomas [9; 10; 11]. Several studies have attempted to determine the prognostic value of TILs in breast cancer. In detail, increased TIL levels have been linked to better response to neoadjuvant chemotherapy and with improved survival for patients with triple negative tumors (TNBC) and HER2-positive BC [12]. On the other hand, the prognostic and predictive value of TILs in luminal breast cancer remains poorly understood [12].