In 2000, the authors of The Hallmarks of Cancer suggested that the complexity of cancer could be reduced to six hallmarks explaining the transformation of a normal cell into a cell with malignant potential. A decade later, the complexity of the biology of cancer cells and their ability to escape host defenses were better encompassed with the addition of four new hallmarks. One of these new traits is the ability of cancer cells to evade the immune surveillance.
The concept of cancer immunoediting consists of a dual role both in promoting host protection against cancer and facilitating tumor immune escape; immunoediting establishing the basis for new individualized cancer immunotherapies. During cancer immunoediting, three essential phases have been proposed: elimination, equilibrium, and escape. In the elimination phase, including innate and adaptive immune responses, cancer cells are eliminated by a competent immune system. Tumor cells that have escaped immune elimination may then enter an equilibrium phase where editing occurs. In the last phase, escape, tumors that have been shaped into a less-immunogenic state progressively grow in an immunosuppressive tumor microenvironment and clinical symptoms of cancer then emerge.
The role of the immune system in breast cancer (BC) biology is complex, both promoting tumor growth and mediating eradication of the disease. Although BC has traditionally been considered poorly immunogenic, several groups have reported a relationship between stromal lymphocytic infiltration with several clinic-pathological parameters including response to therapy and outcome (J Clin Oncol 2015;33:983-91, Ann Oncol 2015;26:259-7).
Studies carried out in melanoma show that CD4+ and CD8+ T cells reactive to peptides arising from cancer-specific mutations (termed “neoantigens”) can be identified in tumor infiltrates (Nat Med 2015;21: 81-5). In BC, it has been reported that T cells extracted from tumors are specific to antigens present in the tumor from which they derive, although these antigens were not defined. In addition, increasing tumor mutational burden and expression on T cell effector function are variably correlated across different tumor types including BC (Cell 2015;160:48-61). It therefore appears the repertoire of mutant peptides produced by tumor cells is a key determinant for tumor immune recognition.
Moreover, chemotherapy and radiotherapy may affect the tumor immune infiltrate. Increasing evidence suggests their efficacy may be determined by T cell-dependent, tumor-specific immune responses (Cancer Immunol Res 2015;3:518-25). In addition, the mechanism of action of targeted anticancer therapeutics, such as the HER2-targeting agent trastuzumab, involves both the innate and adaptive immune systems.
TILs as a Biomarker
In the past decade, several gene-expression signatures were developed and showed additional prognostic information to the well-characterized clinic-pathological factors for patients with estrogen receptor (ER)-positive, HER2-negative tumors (N Engl J Med 2015;373:2005-14).
Tumor-infiltrating lymphocytes (TILs) are mononuclear immune cells that infiltrate tumor tissue and have been described in several tumor types including BC. TILs are commonly measured on histological slides after haematoxylin and eosin staining. They are located either in the stroma or within the tumor. Both stromal and intratumoral TILs are composed of different types of cells (i.e., T cells, B cells, NK cells, macrophages) in variable proportions, T cells being the most abundant cells. Recommendations for the standardization of TIL evaluation in BC have recently been published by international investigators (Ann Oncol 2015;26:259-7). These recommendations suggest evaluating stromal TILs rather than intratumoral TILs, since stromal TILs are clinically more informative and their assessment is more reproducible. The level of TILs differs between the different BC subtypes: in one of the largest studied cohorts of women with lymph-node-positive disease, the median percentage of stromal TILs was 10 percent, 15 percent and 20 percent in ER-positive/HER2-negative, in HER2-positive and in ER-negative/HER2-negative tumors respectively (J Clin Oncol 2013;31:860-7).
In the past 5 years, TILs have been evaluated in nearly 16,000 patients in prospective studies with available clinical follow-up data (J Clin Oncol 2013;31:860-7, JAMA Oncol 2015;1:448-54). High levels of TILs have consistently been associated with a good prognosis in patients with early stage TNBC and HER2-positive BC. Indeed, accumulating data have shown a robust linear correlation between an increase in lymphocytic infiltration over time and improved recurrence-free survival (RFS) for patients with TNBC as reported in various retrospective and prospective trials (Breast International Group (BIG) 2-98 trial, the FinHER trial, the Eastern Cooperative Oncology Group (ECOG) 2197 and ECOG 1199 trials, and the National Epirubicin Adjuvant Trial (NEAT)/BR9601 trial). Similarly, a relationship between RFS and TILs was shown for patients with HER2-positive tumors in the NeoALTTO trial (JAMA Oncol 2015;1:448-54) and the HER2-positive patient cohorts.
Moreover, a high level of TILs is associated with increased pathological complete response (pCR) rate. In addition, the presence of TILs after neoadjuvant chemotherapy in the residual disease is also prognostic for metastasis-free and overall survival in the TNBC subgroup. These findings have boosted interest in the development of immunotherapeutic agents for BC. Multiple clinical trials of anticancer vaccines and immune checkpoint inhibitors are currently ongoing.
Recently, very promising results for the TNBC subgroup were obtained from four trials evaluating the efficacy of anti-PD-1/PD-L1 antibodies in the advanced breast cancer setting. The first trial was a phase Ia study assessing Atezolizumab, an anti-PD-L1 antibody, in patients with PD-L1-positive TNBC tumors (Cancer Research 2015;75(9 Supplement):PD1-6), whereas a 19 percent overall response rate was observed for the 21 patients assessed. Interestingly, 27 percent of patients remained disease free at 24 weeks. The KEYNOTE-012 trial, a phase Ib study testing pembrolizumab (MK-3475) in patients with PD-L1 positive advanced stage TNBC. The overall response rate was 18.5 percent at the time of reporting. The KEYNOTE-028 trial, assessing pembrolizumab in patients with PD-L1-positive advanced stage ER-positive, HER2-negative BC, reported a rather low response rate (12%) (Cancer Research 2016;76(4 Supplement):S5-07). Finally, the Javelin Phase Ib trial evaluated the anti-PD-L1 antibody Avelumab in patients with advanced BC patients. The objective response rate was 5.4 percent in the whole cohort and 8.8 percent in patients with TNBC (Cancer Research 2016;76(4 Supplement):S1-04). In HER2-positive BC, several trials are currently ongoing.
These results highlight the fact that biomarkers are needed to improve patient selection. Although the expression of PD-L1 seems to predict better responses to anti-PD1/PD-L1 agents, no validated biomarkers are yet available to predict accurately whether a patient will benefit from immune-checkpoint inhibitors.
Other immune modulators including OX40 and CD40 agonists, IDO and TIM3 inhibitors given alone or in combination with anti-PD1 or PD-L1 antibodies are being investigated in clinical trials.
Although the responses to immune checkpoint inhibitors are generally low when they are given as single agents, some patients do not progress for a long period of time. There is a clear need to identify patients who will benefit from immunotherapy. Intensive research on the identification of biomarkers is ongoing. Immunotherapy in breast cancer is still at its early stages of development; learning how to combine them with the other treatments will be crucial for their success.
LUIS TEIXEIRA, MD, PHD; FRANçOISE ROTHé, PHD; MICHAIL IGNATIADIS, MD, PHD; AND CHRISTOS SOTIRIOU, MD, PHD, are with the Breast Cancer Translational Research Laboratory J.-C. Heuson, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium. Teixeira is also with the Breast Disease Unit, Department of Medical Oncology, Hôpital Saint-Louis, Paris.