Lymphocyte Infiltration in Breast Cancer: A Key Prognostic Factor That Should Not Be Ignored

Abstract

Worldwide, breast cancer is the second most common cause of cancer-related death in women. The course of this disease is almost asymptomatic at the early stage, and thus, the majority of patients are diagnosed in later stages when most have lost the chance for cure. Currently, only human epidermal growth factor receptor 2 (HER2) and hormone receptors—including estrogen receptors (ER) and progesterone receptors—are routinely used to identify subsets of patients with a differential benefit from specific therapies. However, the expression of these biomarkers overlap and the prognostic and predictive value of these markers in combination needs to be well defined. For a long time, the role of the immune system in fighting breast cancer has been investigated, but results have so far been disappointing.It has also become apparent that both innate and adaptive immunity have a dark side and can promote tumor progression as well as mediate tumor destruction. In fact, the inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, which creates a conundrum when examining mechanisms of action. This results from tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. The article by Mahmoud et al analyzing the role of the immune system and, more specifically, the influence of density and distribution of the tumor-infiltrating lymphocytes (cytotoxic CD8 ) in a large cohort of unselected, well-characterized invasive breast cancer with a long follow-up provides us with an illustration of the critical role of CD8 lymphocytes in primary breast cancers described in other tumor types. Using immunohistochemistry staining of tissue microarray cores, Mahmoud et al assessed tumor-infiltrating CD8 lymphocytes from unselected breast tumors from 1,334 patients with long-term follow-up and established a cutoff point ( 2 CD8 infiltrating lymphocytes for total number and distant stromal or 1 CD8 lymphocytes for intratumoral and adjacent stromal). The total number of infiltrated CD8 cells was positively correlated with tumor grade (P .001) and inversely correlated with patient’s age at diagnosis as well as ER and progesterone receptor expression (P .001). Using univariate analysis, a significant association has been observed between a better patient survival and a high number of total CD8 cells (P .041) as well as distant stromal CD8 counts (P .001). Surprisingly, no association was found between survival and the number of CD8 T cells infiltrating the tumor or the adjacent stroma. Remarkably, using multivariate analysis in a model that included age, tumor size, nodal stage, grade, vascular invasion, HER2 status, ER status, and adjuvant treatment, Mahmoud et al showed that a high number as the total CD8 cytotoxic lymphocytic count was an independent prognostic factor associated with longer survival (P .001). Interestingly, distant stromal CD8 T-cell positivity conferred a positive independent prognostic value in the same model, independent of tumor size, stage, grade, vascular invasion, and HER2 status. Leukocyte infiltration into tumors is now considered one of the hallmarks of cancer development, and the classic view of the role of immune cells in cancer has been supplanted by a more complex view of leukocytes having both proand antitumor properties. Several studies have shown that the presence of a lymphocytic infiltrate in cancer tissue is associated with improved outcome and that the immune system participates in the control and elimination of tumor cells. However, an efficient immune reaction requires lymphocytes to be at the right place at the right time. In many types of cancers, massive infiltration of CD8 cells, a crucial component of antitumor immunity, tends to have a better prognosis. Conversely, tumors with marked infiltration of regulatory T cells tend to have a worse prognosis. Thus, both the quantity and quality of TIL are crucial determinants of the outcome of antitumor immune responses. In breast cancer, a relationship between host defense mechanisms and prognosis has been widely discussed for decades. In a pioneering study, Aaltomaa et al showed that lymphocytic infiltrates were related to a good outcome in breast cancer, especially in rapidly proliferating tumors. In addition, a close association between diffuse inflammation and good outcome was described, especially for grade 3 breast carcinomas. Furthermore, medullary breast cancer has been identified as being closely related to the basal-like tumor type, which suggests that the described poor outcome of the basal subtype may be improved by the immune system. Retrospective studies in breast cancer have revealed that increased presence of T regulatory cells and high ratios of CD4/CD8 or T lymphocytes in primary tumors or in draining lymph nodes correlate with tumor grade, stage, and overall patient survival. Thus, some facets of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 15 MAY 2