Anti-Tumour TreatmentCheckpoint inhibitors in breast cancer – Current status
Introduction
The overall survival rate for patients with breast cancer (BC) has improved in the past three decades, because of advances in cancer detection and locoregional therapy as well as improvements in systemic treatment i.e., chemotherapy, endocrine therapy, and new molecular targeted drugs. Due to these advances, the 5-year, 10-year, and 15-year relative survival rates for BC are 89%, 83%, and 78%, respectively [1].
Recent advances in immunotherapy in other cancer types e.g. melanoma and non-small cell lung cancer highlight the potential for immunotherapy [2], [3]. BC has historically been considered immunologically silent [4]. Nonetheless, a robust body of literature now suggests that BC, particularly the more aggressive subtypes, does elicit host antitumor immune responses, and that the robustness of responses correlate with prognosis [5]. In triple negative breast cancer (TNBC), substantial evidence shows that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved overall survival (OS) [6] and increased metastasis free survival [7], [8]. Meta-analyses have shown that TILs were significantly correlated with a favorable prognosis in TNBC [9]. In addition, the presence of PD-L1 is significantly associated with response to immunotherapy [10] and TNBC frequently overexpresses programmed death-ligand protein (PD-L1) [11].
The most striking evidence of effective immunotherapy in BC has been the development of the monoclonal antibody trastuzumab directed against the human epidermal growth factor receptor 2 (HER2) protein. In addition to targeting the kinase signaling pathway, trastuzumab also functions via recruitment of natural killer (NK) cells and activation of antibody-dependent cytotoxicity (ADCC) [12]. Finally, chemotherapeutics as anthracyclines, platinum-based agents and cyclophosphamide may induce immunogenic cell death [13], [14].
Therefore, there is great interest in exploring the potential role of immunotherapy in patients with BC [15], [16].
The basal-like and HER2-enriched subtypes have been found to harbor higher genomic instability and be more immunogenic than luminal A carcinomas [5]. Emerging evidence indicates that genomic instability and thus a higher mutational load causes production of higher tumor-specific antigen levels eliciting stronger immune responses [17], [18], [19]. In TNBC, multiple studies suggest an important influence of host anti-tumor immunity on response to chemotherapy and prognosis making this subtype most relevant for investigating immunotherapy [7], [19], [20], [21], [22], [23].
In HER2-positive patients receiving neoadjuvant treatment with taxanes and trastuzumab, a positive correlation between number of NK cells and pCR has been demonstrated [24]. More recently, Luen et al. [19] in a secondary analysis of the CLEOPATRA study evaluating docetaxel + trastuzumab + pertuzumab/placebo in HER2-positive advanced BC found a positive correlation between number of TILs and OS. No correlation to progression free survival (PFS) was found [19]. These studies may provide a rationale for integrating immunotherapies into the care of HER2-positive BC [25]. The rational for immunotherapies in ER-positive BC cancer is very limited [15].
Under normal physiologic conditions, a plethora of suppressive pathways in the immune system exist to promote self-tolerance and protect against autoimmunity [26]. Tumors have been shown to exploit these pathways in order to prevent antitumor responses and escape immune detection and elimination [27], [28]. The pathways are highly regulated by immune checkpoints. The two immune-checkpoint receptors that have been most studied in the context of clinical cancer immunotherapy, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are both inhibitory receptors. CTLA-4 is expressed on T cells where it primarily regulates the amplitude of the early stages of T cell activation by down-modulating the activity of effector T cells (Teff cells) and enhancing the immunosuppressive T regulatory cells (Tregs) [27]. PD-1 is also expressed on T cells and signals through the PD-1 pathway limit T cell activation and effector T cell responses and, thus, immune responses within the tumor microenvironment [29]. Immune checkpoint inhibitors are antibodies against CTLA-4, PD-1 or its ligand (PD-L1). The inhibitors modulate the interaction between tumor cells and cytotoxic T lymphocytes which are thought to be exhausted in their function [30]. Targeting CTLA-4 or PD-1/PD-L1 reverses the exhaustion of cytotoxic T lymphocytes leading to elimination of tumor cells via re-induction of the “natural” function of the T cell population [31].
The use of immune checkpoint inhibitors (CPIs) is a promising anticancer therapeutic strategy which aims at blocking specific immune regulatory checkpoints to enhance the endogenous antitumor immunity. The present review summarizes data on clinical studies of CPIs in BC.
Two monoclonal antibodies that inhibit CTLA-4 are currently either approved by The United States Food and Drug Administration (FDA) or under investigation. Ipilimumab, a fully humanized monoclonal IgG1 antibody (Supplementary Table 1) has been approved both as monotherapy and in combination with nivolumab for treatment of malignant melanoma [2], [32], [33], [34]. Tremelimumab, a fully human IgG2 monoclonal antibody has been tested in a variety of tumor types [35] (Supplementary Table 1).
PD-1 pathway signaling is a result of binding to the inhibitory surface receptor PD-1 expressed on immune cells such as T, B and NK cells. Its ligands PD-L1/B7-H1 and PD-L2/B7-DC are displayed on cancer cells, and antigen-presenting cells such as activated monocytes and dendritic cells [27]. Two PD-1 inhibitors, nivolumab and pembrolizumab, are investigated in BC (Supplementary Table 1).
PD-L1 is the best characterized of the two known PD-1 ligands, PD-L1 and PD-L2. It can be expressed by tumor cells as well as by T and B cells, macrophages and dendritic cells [27]. Targeting PD-L1 may result in different biological effects than targeting PD-1. In addition to binding PD-1, PD-L1 exerts negative signals on T cells by interaction with B7 [36]. PD-L1 antibodies prevent this interaction. In addition, PD-L1 antibodies do not prevent PD-1 from interaction with PD-L2 - although the significance of this interaction remains unknown [37]. Altogether five PD-L1 inhibitors are evaluated in BC (Supplementary Table 1). Among these, atezolizumab (MPDL3280A), avelumab (MSB0010718C) and durvalumab (MEDI4736) have been approved for other cancer types.
Section snippets
Search strategy
Articles included in this review were retrieved by searching PubMed (1966–2017), EMBASE (1980–2017), American Society of Clinical Oncology Annual Meeting (ASCO) (2013–2017) and San Antonio Breast Cancer Symposium (SABCS) (2013–2017). We (AP and DN) searched for studies using the following search terms: “checkpoint inhibitor” and “breast cancer” (PubMed 383, EMBASE 70). In addition, we searched for the specific drugs (Supplementary Table 1) and “breast cancer”: ipilimumab (PubMed 18; EMBASE
Reported studies with CTLA-4 inhibitors in early breast cancer
Studies including CTLA-4 directed therapy in BC are given in Table 1. Only one pilot study on ipilimumab monotherapy in early stage BC has been reported [38]. Nineteen women with primary BC for whom a mastectomy was planned were treated preoperatively with cryoablation, a single dose of ipilimumab or both modalities. Ipilimumab and especially combination therapy were found to be associated with increased Th1-cytokine production, peripheral T-cell proliferation/activation and intratumoral
Discussion
Few clinical trials on monotherapy demonstrated modest efficacy of PD-L1/PD-1 blockade in primarily TNBC [41], [44], [47], [49], [50]. Anyhow, response rates have been potentially better than one might expect and interestingly, when responses occurred, they were often durable. In the preoperative setting preliminary encouraging results suggest that the combination of chemotherapy and CPI might significantly increase pCR and thus have the potential to increase survival [64], [65], [66]. It
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
All authors declare no conflicts of interest and this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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