PD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d2268009e169">Background</h5> <p id="P2">In both the IMpassion 130 trial in the metastatic setting and in Keynote 522 in the neoadjuvant setting, triple negative breast cancer (TNBC) patients showed benefit from PD-1 axis immunotherapy. Here, we assess PD-L1 expression on both tumor and immune cells using quantitative immunofluorescence to assess association with benefit from neoadjuvant durvalumab concurrent with chemotherapy in TNBC. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d2268009e174">Methods</h5> <p id="P3">Pre-treatment core needle biopsies (n=69) were obtained from patients who participated in a Phase I/II clinical trial ( <a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02489448" id="d2268009e178" target="xrefwindow">NCT02489448</a>). The final analysis included 45 patients (pCR = 18, non-pCR = 27) due to technical issues and insufficient tissue. Slides were stained using a previously validated Ultivue DNA-based Ultimapper® kit (CD8, CD68, PD-L1, Cytokeratin/Sox10 and Hoechst counterstain). The PD-L1 expression was analyzed by molecular compartmentalization without segmentation using AQUA software (version 3.2.2.1) in three tissue compartments including tumor (cytokeratin positive cells), CD68 positive cells, and overall stroma. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d2268009e182">Results</h5> <p id="P4">In patients with pCR, PD-L1 expression was significantly higher in tumor cells, in CD68 positive cells and in the stroma compared to patients non-pCR. There was no difference in the amount of CD68 positive cells in the tumor or stromal compartments between cases with pCR and non-pCR. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d2268009e187">Conclusion</h5> <p id="P5">Expression of PD-L1 in tumor cells, immune cells in stroma, and co-localized with CD68 positive cells is associated with higher rates of pCR to durvalumab and chemotherapy in TNBC. </p> </div>

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Pembrolizumab for Early Triple-Negative Breast Cancer

Peter J. Schmid, Javier Cortés, Lajos Pusztai … (2020)

Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear.

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A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

S Loibl, M Untch, N Burchardi … (2019)

Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23–76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80–2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06–4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. ClinicalTrials.gov number: NCT02685059.