Correspondence Address:
Sunil Vitthalrao Jagtap
Department of Pathology, KIMS University, Karad, Maharashtra
India

Full Text



For invasive breast cancer, various predictive and prognostic factors have been extensively studied. In India, breast carcinoma is on the rise. In newer modality of management, the target therapy forms the basis of effective treatment. Breast cancers which are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) are considered as triple-negative breast cancer (TNBC). These represent about 15%–20% of newly diagnosed cases. Compared with other forms of breast cancer, TNBC is associated with a younger age at diagnosis, advanced stage at diagnosis, increased risk of visceral metastasis, and poorer outcome.[1] These are not responsive to conventional receptor-target therapies also.

Breast cancer tissue is invaded by a mixed population of immune cells, including T-cells, B-cells, natural killer cells, and macrophages. The data regarding predictive validity of tumor-infiltrating lymphocytes (TILs) in several cancers are available. The number of CD4+ or CD8+ T-cells and CD4/CD8 ratio at tumor site have been studied in breast cancer for its prognostic value.

The CD4 antigen is a glycoprotein found on the surface of helper T-cells, regulatory T-cells, monocytes, and macrophages. The CD4+ T-lymphocytes are an essential part of adaptive immunity. The CD8 antigen is also a T-cell receptor glycoprotein. In general, both CD4+ and CD8+ TILs are necessary for effective tumor elimination. It is also suggested that CD8+ infiltration may inhibit tumor growth. In particular, a higher number of CD8+ TILs have been linked with disease-free survival and overall survival. The common consideration is that the presence of CD8+ T-cells along with the absence of CD4+ T-cells is associated with better overall survival.[2]

The limited number of studies to investigate the importance of the subsets of T-cells in TILs as a prognostic value has been carried out, especially in TNBC. Moreover, also location of these TILs has given less significance. Wang et al. in their study observed that the number of CD4+ or CD8+ T-cells at either location intratumoral stroma or tumor-host interface was not significantly associated with distant relapse-free or overall survival.[3]

However, the CD4/CD8 ratio at the tumor-host interface was significantly associated with both relapse-free survival and overall survival, whereas this association was not seen for the CD4/CD8 ratio within the intratumoral stroma.

CD8+ T-cell infiltrates are generally associated with better prognosis. CD4+ T-cells, which include T-regulatory cells, and tumor-associated macrophages have been associated with worse outcomes. A recent study assessed whether intratumoral T-cells and macrophages correlated with clinical outcome in patients with breast cancer. The study by DeNardo et al. on immunohistochemistry analysis of tissue microarrays derived from 179 treatment-naive breast tumors revealed that high levels of macrophages and CD4+ T-cells correlated with reduced overall survival, while high levels of CD8+ T-cells combined with low levels of macrophages and CD4+ T-cells correlated with increased overall survival.[2] Thus, CD8+ T-cells can control human breast cancer, but the presence of immunosuppressive cells, that is, CD4+ T-regulatory cells and macrophages reduces this action. It is noted by Schmidt et al. that intratumoral B-cells have also been associated with favorable prognosis in breast cancer. Interestingly, immunoglobulin-κ chain as a single marker has recently been shown to have similar predictive and prognostic value in breast cancer.[4]

The high intratumoral levels of interferon-gamma and CD8+ T-cells or TILs are associated with better clinical responses to anthracycline-based chemotherapy. Consistent with these studies, West et al. recently reported that in ER− breast cancer, high lymphocyte gene expression is associated with a remarkably high rate (74%) of pathological complete response to neoadjuvant anthracycline-based chemotherapy.[5] As TNBC lacks a therapeutic target, patients do not benefit from endocrine therapy or HER2-targeted therapy. Accordingly, TNBC remains an important challenge in today's clinical practice.[6],[7] Jana et al. observed that stromal expression of CD10 was found to be significantly associated with increasing tumor grade, increasing mitotic rate, and worsening prognosis and its role plays important in predict treatment failure in breast carcinomas receiving neoadjuvant therapy.[8]

CD8+ cells can be considered as an independent prognostic factor for survival improvement in TNBC patients. CD8-positive patients had mean survival of 3.5 years longer than those who lack the presence of CD8 and also significantly reduced lymph nodes involvement. T-lymphocytes and their subpopulations seem to have the probably promoting neoplastic progression rather than acting as an antitumor immune response.[9]

As stage and grade of tumor advances, CD4/CD8 ratio and CD30 expression levels are increased which give adverse prognosis and poor overall survival. However, when CD8+ expression is increased, it carries a favorable prognostic with improved overall survival status. The current meta-analysis studies support that integrating immunotherapy with conventional therapy for better survival outcome in early TNBC can be achieved. The various current studies on new CD markers expression will be helpful for prognostication and possible therapeutic intervention in invasive breast carcinoma and of interest in the field of target therapy.

References