Kurzfassung

The immune system has also become an increasing focus of interest in breast cancer.An important target structure within the cancer immune-cell cycle are so-called "immune checkpoints". Immune checkpoint inhibitors (ICPi) block the interaction of certain cell surface proteins that serve as "brakes" on immune responses. Currently, the most relevant immune checkpoint in breast cancer is PD-1/PD-L1 (Postow et al. 2015; Ribas 2015). The response of PD-1 to T cells with PD-L1, which can be...The immune system has also become an increasing focus of interest in breast cancer.An important target structure within the cancer immune-cell cycle are so-called "immune checkpoints". Immune checkpoint inhibitors (ICPi) block the interaction of certain cell surface proteins that serve as "brakes" on immune responses. Currently, the most relevant immune checkpoint in breast cancer is PD-1/PD-L1 (Postow et al. 2015; Ribas 2015). The response of PD-1 to T cells with PD-L1, which can be expressed on both T cells and tumor cells, leads to the inhibition of T cell-mediated immunity against the tumor.
Building on these encouraging results, the phase III IMpassion130 study confirmed the clinical efficacy of atezolizumab in combination with nab-paclitaxel as first-line therapy in a cohort of 902 patients with metastatic or locally advanced TNBC (Schmid et al. 2018). Patients were randomized to either the experimental arm (atezolizumab in combination with nab-paclitaxel) or the placebo arm (nab-paclitaxel + placebo) in a 1:1 ratio. The results showed a significant prolongation of PFS in both the intention-to-treat (ITT) population and the PD-L1-positive subgroup: PFS was 7.2 months in the experimental arm compared with 5.5 months in the placebo arm (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.69-0.92; P=0.002). In the subgroup of PD-L1-positive (≥1% of immune cells) TNBC patients, PFS was 7.5 months compared with 5 months in the placebo arm. Atezolizumab in combination with nab-paclitaxel prolonged OS in PD-L1-positive patients (25.0 versus 15.5 months). Based on these results, atezolizumab in combination with nab-paclitaxel is now approved as first-line therapy for advanced PD-L1-positive TNBC. In a recent IMpassion130 analysis, Schmid et al showed that atezolizumab did not significantly increase OS in the overall cohort from 18.7 to 21 months at longer follow-up (HR 0.86; 0.72-1.02; P = 0.078) (Schmid et al. 2020). However, in PD-L1-positive patients, OS increased from 18 to 25 months (HR 0.71; 0.54-0.94). The authors concluded that a clinically meaningful overall survival benefit was found with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. They also postulated that atezolizumab plus nab-paclitaxel represents an important therapeutic option in disease with high unmet need. Surprisingly, the recently presented IMpassion131 trial combining atezolizumab with conventional paclitaxel in advanced TNBC did not improve PFS or OS compared with placebo + paclitaxel (Miles et al. 2017).
At the annual meeting of the American Society of Clinical Oncology, Cortes and coworkers presented the results of KEYNOTE-355, a randomized, double-blind, phase III trial of pembrolizumab + chemotherapy versus placebo + chemotherapy in previously untreated locally recurrent unresectable or metastatic triple-negative breast cancer (Cortes et al. 2020a). They showed that pembrolizumab in combination with multiple chemotherapy partners (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in patients with previously untreated locally recurrent unresectable or metastatic TNBC whose tumors expressed PD-L1. In addition, pembrolizumab + chemotherapy was generally well tolerated, with no new safety concerns. Recently, this study was published in full text (Cortes et al. 2020b). From their results, the authors concluded that the addition of pembrolizumab to standard chemotherapy has a role in the first-line treatment of advanced triple-negative breast cancer.
Based on these trial data in metastatic triple-negative breast carcinoma (TNBC), the two immune checkpoint inhibitors (ICPi) atezolizumab and pembrolizumab are approved as first-line therapy in PD-L1 positivity. Exploratory trials of the aforementioned ICPi are also being conducted in hormone receptor (HR)-positive and HER2-positive metastatic breast carcinomas. Both primarius and distant metastasis can be used for PD-L1 determination according to the approval. Concordance analyses of PD-L1 expression between primaries and metastases in breast carcinoma have only been performed on small numbers of cases to date and yield different results (Cimino-Mathews et al. 2016; Dill et al. 2017; Manson et al. 2019; Wang et al. 2020)..
This exploratory biomarker study aims to determine the concordance of PD-L1 positivity between primary and distant metastasis in breast carcinoma in the different molecular subtypes (TNBC, HR+, HER2+) in a larger collective with paired primary tumors and distant metastases each (n = 210) from 2006 to 2020.
For this purpose, tissue microarrays (TMAs) are produced at the Institute of Pathology of the University Medical Center Mainz, which are stained with an antibody against PD-L1 (DAKO 22C3) and evaluated. Following the analysis, which is performed with the TPS "tumor proportion score", CPS "combined positivity score" and IC score, a concordance analysis is performed to evaluate the correspondence of the respective PD-L1 status between the primarius and the corresponding distant metastasis.
These results are of interest for the indication of therapy with ICPi in advanced breast carcinoma.
 
References
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