Diagnostic and Therapeutic Implications of Tumor-Infiltrating Lymphocytes in Breast Cancer

Abstract

In the age of personalized medicine, the multitude of scientific publications describing new biomarkers has raised a lot of criticism, as many of these results have been rather difficult to validate. As a consequence to this criticism, we are observing a considerable improvement in the design of clinical biomarker studies, which are increasingly based on large sample cohorts from clinical trials. The article by Loi et al that accompanies this editorial exemplifies this. Loi et al report a prognostic role for tumor-associated lymphocytes in triple-negative breast cancer in a large prospective clinical trial, evaluating more than 2,000 tumor samples from patients with nodepositive breast cancer treated within the Breast International Group (BIG) 02-98 trial. The main finding of the study was that in estrogen receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative breast cancer (n 256) an increased lymphocytic infiltrate was linked to a reduced relapse rate and improved survival. This association was independent of the type of chemotherapy and was not observed in hormone receptor–positive tumors (n 1,078). In the subgroup of HER2-positive tumors (n 297) there was a significant interaction with benefit from anthracycline-only chemotherapy. It should be noted, however, that trastuzumab was not part of the adjuvant treatment in BIG 2 to 98, which limits the interpretationof theresults intheHER2-positivesubset inthecontextofcurrent therapeutic approaches. The study by Loi et al shows that tumor-infiltrating lymphocytes can be evaluated as a distinctive histological parameter using the predefined standardized definitions of intratumoral lymphocytes, stromal lymphocytes and lymphocyte-predominant breast cancer (LPBC). We have evaluated the nearly identical parameters in tumor samples from the neoadjuvant GeparTrio study, with a slightly different definition of LPBC. In this study, we have shown that a pretherapeutic immunological infiltrate is a predictive factor for response to neoadjuvant therapy. In the neoadjuvant situation, an increased rate of pathological complete response was observed in different tumor subtypes including hormone receptor–positive tumors. In contrast, the survival effect in the study by Loi et al was present only in the triple-negative subgroup. This difference could be explained by the fact that pathological complete remission is a surrogate end point for survival for triple-negative, but not for hormone receptor–positive breast cancer. The results of this report are consistent with the functional model that is emerging from preclinical studies. Zitvogel et al has evaluated the interaction between tumor cells and the immune system in various cellular and animal models. From their research the concept is emerging that the response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. In a recent paper, it has been shown that in particular those cancer cells that are hyperploid become immunogenic due to an increased accumulation of calreticulin on the cell surface. Those results from preclinical models as well as translational studies suggest that the combination of standard chemotherapy with immunomodulatory concepts might be worth an evaluation in clinical trials. It should be noted that a similar prognostic effect of increased lymphocytic infiltrate in triple-negative tumors has been observed in another study by West et al using immunohistochemistry as well as gene expression analysis of inflammatory markers. Molecular immunological parameters, such as immunoglobulin kappa C and IL8 have been reported as prognostic parameters in breast cancer, suggesting that those parameters could form a basis for future molecular diagnostic tests. From a pathologist’s point of view, the concept of a tumor that has a predominant lymphocytic infiltrate is similar to the classical tumor type of medullary breast cancer that has been described by Moore and Foote already in 1949. In classical pathology several definitions for medullary breast cancer have been suggested including parameters such as a predominant lymphocytic infiltrate, a so-called syncytial cell architecture and a well-defined border of the tumor. It has been shown that this tumor type has a particularly good prognosis. However, true medullary carcinoma is extremely rare, a recent evaluation of 12,409 patients from International Breast Cancer Study Group trials has found only 127 medullary carcinomas (1%). In addition to medullary breast cancer, a prominent lymphoplasmacellular infiltrate is observed in certain types of hereditary breast cancer. Evaluation of tumor-associated lymphocytes by standard hematoxylin and eosin staining is extremely inexpensive and can be performed easily in the setting of the routine histopathological evaluation. Considering that medullary breast cancer is an old pathology concept and that tumor-associated lymphocytes are also relevant for BRCA-mutation–associated breast cancer, pathologists should perhaps get used to reporting this parameter as a part of the standard histological description of breast cancer. In addition, the parameters of stromal and intratumoral infiltrate should be added to the standard parameters evaluated in the context of clinical studies. This is already JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 7 MARCH 2013