PD-L1 assessment in breast cancer immunotherapy: a critical overview

The advent of immune checkpoint inhibitors (ICIs) has recently made a breakthrough in several hematological and solid tumors including, among others, non-small-cell lung cancer, renal cell carcinoma, melanoma, urothelial carcinoma, and hepatocellular carcinoma [1–3]. These agents are able to enhance antitumor activity, leading to an increase in the cytotoxicity of T cells and the blocking of downregulators of immunity such as programmed cell death protein 1 (PD-1) and its ligand PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and lymphocyte activating-3 (LAG-3) [4]. ICIs have also been recently assessed in breast cancer (BC), as monotherapy or in combination with other anticancer agents. First, monotherapy with ICIs has reported disappointing results in unselected triple-negative BC (TNBC), with approximately one-quarter of patients achieving response [5]; in fact, the KEYNOTE-086 and the KEYNOTE-119 trials evaluating pembrolizumab monotherapy highlighted response rates lower than 10%, and these findings have also been confirmed by clinical studies evaluating other immunotherapies, such as single-agent atezolizumab [6]. Thus, several combination treatments have been investigated, based on the synergistic effect of ICIs plus other anticancer agents with different mechanism of action. Among these combinatorial strategies, and following the results of landmark trials, chemoimmunotherapy has entered into clinical practice as new front-line treatment in TNBC patients with metastatic disease and PD-L1 overexpression or elevated combined positive score (CPS) [7]. Moreover, a large number of phase I to III clinical trials are assessing immunebased combinations, with these studies having the potential to further shape the direction of firstand later-line therapy in this patient population. However, a high unmet need in BC immunotherapy remains the lack of biomarkers predictive of response to ICIs. In fact, if PD-L1 is considered the most reliable predictor, its assessment presents several limitations, and it is far from being standardized [8]. The expression of PD-L1 is typically detected on tumor cells (TC) or immune cells (IC), and in recent years, PD-L1 assessment has emerged as an important predictive biomarker of response to immunotherapy in several tumor types (e.g. nonsmall-cell lung cancer, head and neck cancer, and gastric cancer) [9,10]. As regards BC, PD-L1 status has been associated with a prognostic value, and high PD-L1 expression seems to predict worse clinical outcomes in triple-negative BC patients [11]. PD-L1 has been validated as a predictor of response to chemoimmunotherapy in metastatic BC and has entered into everyday clinical practice, following the results of recently published IMpassion130 and KEYNOTE-355 phase III clinical trials [12,13]. The IMpassion130 compared chemoimmunotherapy with atezolizumab–nab-paclitaxel versus placebo plus nabpaclitaxel as front-line treatment in TNBC patients with metastatic disease [12]; the coprimary endpoints were progressionfree survival (PFS) and overall survival (OS) in the intention-totreat (ITT) and in PD-L1-positive patients, with PD-L1 expression determined on IC and centrally evaluated per VENTANA SP142 immunohistochemistry assay (positive in the case of IC ≥1% and negative with IC <1%) [12]. The IMpassion130 highlighted a statistically superior and clinically meaningful benefit in terms of OS in patients with PD-L1 expression ≥1% receiving chemoimmunotherapy, leading to the approval of atezolizumab–nab-paclitaxel in this setting [12]. Similarly, the KEYNOTE-355 highlighted longer PFS and OS in metastatic TNBC patients with PD-L1 CPS ≥10 treated with pembrolizumab–chemotherapy versus placebo–chemotherapy [13]. In another study in the neoadjuvant setting, the KEYNOTE-522, the authors observed that in patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone, regardless of PD-L1 status [14]. Despite these trials have recently had an important impact in BC clinical practice worldwide, some fundamental issues regarding PD-L1 assessment should be highlighted. First, recent studies have suggested differences in terms of PD-L1 status according to primary tumors and secondary lesions in BC patients [15]. For example, a retrospective trial conducted by Rozenblit et al. compared PD-L1 expression between primary tumors (n = 179) and metastatic sites (n = 161) [15]. Interestingly, the authors reported higher PD-L1 expression in primary cancers compared with secondary lesions (63.7% versus 42.2%, respectively) by using the SP142 antibody [15]; in addi-