Prognostic Value Of PD-L1 Expression Research Articles

Prognostic value of PD-L1 expression for surgically treated localized renal cell carcinoma: implications for risk stratification and adjuvant therapies.

Background:We aimed to evaluate the prognostic role of programmed-death receptor ligand (PD-L1) in a multinational cohort of patients with localized renal cell carcinoma (RCC).Methods:Formalin-fixed paraffin-embedded blocks of 1017 patients from the Latin American Renal Cancer Group were analyzed. Tissue microarrays were immunostained for PD-L1 using a commercially available monoclonal antibody. Expression of PD-L1 in ⩾5% tumor cells was considered positive. PD-1 expression in immune cells was also assessed. All cases were reviewed twice based on antibody expression and compared with a positive control. Cox proportional hazard regression models were used to identify predictors of recurrence-free survival (RFS) and overall survival (OS).Results:A total of 738 cases with complete follow up met criteria. Median age was 57 [interquartile range (IQR): 49–64] years, and median follow up was 34 (IQR: 15–62.9) months. Median tumor size was 5 cm (IQR: 3.0–7.5 cm). Approximately 8.2% and 7.6% of tumors were PD-L1 and programmed cell-death 1 (PD-1) positive, respectively. PD-L1 and PD-1 positivity were significantly associated with higher tumor stage (both p < 0.001), and presence of tumor necrosis and lymphovascular multivariable analyses; PD-L1 positivity was found as a predictor of worse RFS [hazard ratio (HR) = 2.08, p = 0.05] and OS (HR = 2.61, p = 0.02).Conclusions:PD-L1 positivity was significantly associated with worse outcomes for patients with localized RCC at intermediate follow up. This marker may help stratify patients for stricter surveillance after surgical treatment and provide a basis for checkpoint-inhibitor therapy in the adjuvant setting.

Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels.

e14284 Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE). Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched and data were extracted independently by two researchers. Outcomes included pooled PD-L1 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed. Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p &lt; 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p &lt; 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p &lt; 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p &lt; 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p &lt; 0.001 for OS), pinteraction 0.124 for DFS and 0.005 for OS. Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.

P3.08-16 Prognostic Value of PDL-1 Expression and Correlation Between Primary Tissue and Brain Metastases in Oligometastatic NSCLC

Immunotherapy with anti-PD-1/PDL-1 agents in first-line metastatic non-small cell lung cancer (NSCLC) is chosen based on tumor cell PDL-1 expression. However, the incidence and prognostic value of PDL-1 expression in NSCLC patients with oligometastatic brain disease has never been characterized. We retrospectively analyzed in our SARDO clinical database NSCLC patients with only 1-3 brain metastases (oligometastastic) treated in our University Health Care Center CHUM from 2007-2014. Samples were stained with SP263 (Ventana) antibody against PDL-1. A membranous staining of >25% was considered positive, and scoring was performed by an experienced pathologist. Kaplan-Meier survival curves of all clinical data were performed in SPSS 25. In our cohort of 39 oligometastatic NSCLC patients treated before 2014, none received immunotherapy. A total of 49 specimens (biopsy or surgical) from either the primary or metastatic site were adequate and included in the study. In 10 cases, both primary and metastatic tissue were available for correlation. Overall PDL-1 positivity was 40.8% (20/49), with a positivity of 54.5% (12/22) in primary site samples and 29.6% (8/27) in metastatic brain tissue. Correlation of PDL-1 status between primary and metastatic site in a sub-group of 10 patients was 80% (8/10). Median overall survival (mOS) was significantly shorter for PDL-1 positive patients (8 mos) compared to PDL-1 negative patients (20 mos, p=0.05). 59% (23/39) of patients were aggressively treated for the primary tumor, and 86% (31/39) were aggressively treated for metastatic brain disease. When we controlled for treatment aggressivity of the primary tumor, mOS of PDL-1 positive patients treated aggressively was significantly shorter than mOS of PDL-1 negative patients treated aggressively (15 vs 22 mos, p=0.046). When the primary lung tumor was not addressed aggressively, mOS was the same regardless of the PDL-1 status (4 vs 4 mos). Median progression free survival (mPFS) tended to be longer in PDL-1 positive patients (6.0 vs 9.8 mos, p=0.254). PDL-1 status is concordant between primary and metastatic tissue in 80% of cases. PDL-1 expression is an adverse prognostic factor in NSCLC patients with oligometastatic brain disease, despite treating the patients aggressively for their primary lung cancer and their brain metastasis. In the future, giving early PD1/PDL-1 to oligometastatic PDL-1 positive NSCLC patients could significantly improve their outcome.

1813P - Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC)

1813P - Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC)

PD-L1 Expression in Men with Penile Cancer and its Association with Clinical Outcomes

BackgroundIt has been hypothesized that PD-L1 expression in tumor cells and tumor-infiltrating immune (TII) cells may contribute to tumor progression by inhibiting antitumor immunity. ObjectiveTo investigate the association between PD-L1 expression in tumor cells and TII cells and clinical outcomes in penile cancer. Design, setting, and participantsA cohort of 222 men treated for penile squamous cell carcinoma (SqCC) at Örebro University Hospital between 1984 and 2008 with long-term follow-up (median 34 mo) was evaluated for PD-L1 expression in tumor cells and TII cells via immunohistochemistry. Outcome measurements and statistical analysisAssociation between clinicopathological features and PD-L1 expression was estimated using χ2 and Fisher's exact tests. For survival analyses, Kaplan-Meier curves with log-rank tests and multivariate Cox proportional hazards regression models were used. Results and limitationsWe found that 32.1% of the tumors and 64.2% of the TII cells expressed PD-L1. Our data demonstrate that penile SqCC patients with PD-L1–positive tumor cells or TII cells are at significant risk of lower cancer-specific survival and that the prognostic value of PD-L1 expression was strongest for tumor cell positivity. The use of tissue microarrays rather than whole sections may be viewed as a limitation. ConclusionsTumor PD-L1 expression independently identifies penile SqCC patients at risk of poor clinical outcomes. Patient summaryWe investigated how many patients with penile cancer had tumors that manufactured PD-L1, a protein that decreases the ability of the immune system to fight cancer. We found that up to one-third of penile tumors make this protein. Patients whose tumors make PD-L1 have more aggressive penile cancer and worse clinical outcomes.

Immunohistochemical expression and prognostic value of PD-L1 in Extrapulmonary small cell carcinoma: a single institution experience

BackgroundExtrapulmonary small cell carcinomas (ESCC) are rare but aggressive tumors. Relapses are common despite treatment with chemotherapy and/or radiotherapy. Prospective data for treatment of ESCC are lacking; treatment of these cancers usually incorporates lung small cell carcinoma treatment recommendations. Cancer staging remains the most important prognostic factor. Cancer immunotherapy targeting the PD-1/PD-L1 pathway has shown efficacy in multiple tumor types, and could be an appealing treatment strategy for these rare tumors.MethodsWe investigated PD-L1 expression by immunochemistry (IHC) in ESCCs diagnosed at University of Massachusetts Medical Center, from 1999 to 2016. 34 cases with sufficient material were selected for PD-L1 IHC analysis using clone E1L3N. PD-L1 expression was evaluated using the combined positive score (CPS). Retrospective chart review was performed. We evaluated the incidence and prognostic value of PD-L1 expression in ESCC at our institution.ResultsTwelve out 34 cases (35%) had PD-L1 CPS scores ≥1. Ten cases had CPS scores ranging 1–5, whereas 2 cases had CPS scores > 80. The overall response rate to the standard chemotherapy with/without radiotherapy in the PD-L1 positive group was 80% versus 67% for the PDL-1 negative group (p-value 0.67). The median overall survival for the PD-L1 positive group, regardless of stage, was 11.5 months versus 7 months for PD-L1 negative group (p-value 0.34). Patients with limited stage disease with positive PD-L1 had a median survival of 53 months compared to 15 months for patients with PD-L1 negative limited stage (p-value 0.80).ConclusionsThis study showed that at least one third of our ESCC tissue samples expressed PD-L1. There was a trend for higher response rates to the standard chemotherapy with/without radiotherapy and improved survival in PD-L1 positive patients. Further studies are required to understand the implications of immune dysregulation in these aggressive tumors. PD-L1/PD-1 inhibitors should be investigated in this group of patients.

Highlights of This Issue

Preclinical experiments demonstrate that interleukin-15 (IL-15) can control homeostasis and stimulate natural killer (NK) and antigen-specific CD8+ T cell activity without causing activation induced cell death or promoting T regulatory (Treg) cell function. Miller and colleagues conducted the first-in-human outpatient phase I dose escalation of subcutaneous (SC) rhIL-15 in refractory solid tumor cancer patients. SC rhIL-15 treatment was well tolerated and resulted in substantial increases in circulating NK and CD8+ T cells. These results will allow the export of IL-15 immunotherapy to an outpatient setting and testing of combinatorial strategies to improve cancer treatment.Treatment of cancer by targeting VEGF-A with bevacizumab has been extensively validated in the clinic; however, not all tumors respond to VEGF-A blockade. Angiopoietin-2 (Ang-2) and VEGF-A have complementary roles in regulating tumor angiogenesis and metastasis, suggesting that dual pathway inhibition is necessary to improve treatment outcomes. Vanucizumab is an investigational, first-in-class, bi-specific IgG1-like monoclonal antibody that simultaneously blocks VEGF-A and Ang-2 from interacting with their receptors. Hidalgo and colleagues conducted a first-in-human study that demonstrated an acceptable safety and tolerability profile for vanucizumab in patients with advanced solid tumors. Vanucizumab also demonstrated consistent pharmacokinetic and pharmacodynamic effects, and showed encouraging signs of antitumor activity that support further evaluation of vanucizumab in clinical trials.Adjuvant sunitinib prolonged disease-free survival over placebo in patients with locoregional renal cell carcinoma at high risk of recurrence postnephrectomy in the randomized phase III STRAC trial. In a prospectively designed exploratory analysis of tissue samples from a subset of patients in this trial, George and colleagues identify predictive biomarkers that could facilitate future patient selection for adjuvant sunitinib and mechanisms of interaction that might explain the durable treatment effect, potentially leading to future combination approaches. Tumor tissue expression levels of CD4, CD8, CD68, and PD-L1 were compared with efficacy outcomes. The observed association between higher CD8+ T-cell density in tumor tissue with longer disease-free survival with sunitinib, but not placebo, suggested predictive potential of CD8+ T-cell density, which warrants further independent cohort validation studies. The prognostic value of PD-L1 expression in primary tumors in this setting also should be further explored.The thymocyte differentiation antigen-1 (Thy1) is differentially expressed on the neovasculature of human PDAC compared to chronic pancreatitis and normal pancreas. To engineer a human Thy1-binding single-chain-antibody-ligand (Thy1-scFv) conjugated to microbubbles (MBThy1-scFv), Abou-Elkacem and colleagues designed and validated a clinically translatable Thy1-scFv for contrast-enhanced ultrasound molecular imaging of PDAC. The MBThy1-scFv was highly specific to murine/human Thy1, and in vivo ultrasound molecular imaging of PDAC-bearing mice demonstrated specific binding to Thy1. Ongoing translational studies are targeted at developing clinical-grade MBThy1-scFv which may improve visualization of PDAC and enable diagnosing at earlier disease state to ultimately improve survival of PDAC patients.

Prognostic value of PD-L1 expression in resected lung adenocarcinoma and potential molecular mechanisms.

Background: The prognostic role of PD-L1 expression in surgically resected lung adenocarcinoma (ADC) remains controversial. The present study was aimed to clarify the role of PD-L1 expression in predicting prognosis and to investigate its biological function in ADC.Materials and Methods: The association between PD-L1 expression and clinical outcomes in patients with resected ADC was analyzed using immunohistochemistry (IHC) in our cohort (n=104), externally validated by a meta-analysis of 13 published studies. The biological role of PD-L1 in ADC was explored using gene set enrichment analysis (GSEA).Results: Positive PD-L1 expression in tumor cells was observed in 38.5% (40/104). High PD-L1 expression levels were significantly correlated with poor overall survival (P=0.008). Furthermore, the meta-analysis also showed that positive PD-L1 expression was associated with shorter OS than negative PD-L1 expression (HR= 1.75, 95% CI: 1.26-2.42; P<0.001). In subgroup analysis stratified according to ethnicity, the pooled results demonstrated that increased PD-L1 expression was an unfavorable prognostic factor for Asian populations (HR= 2.11, 95% CI: 1.48-3.02; P<0.001), but not for non-Asian populations (HR=1.16, 95% CI: 0.63-2.11, P=0.64). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with positive lymph node metastasis (OR=1.74, 95% CI: 1.23-2.46; P=0.002) and male (OR=1.56, 95% CI: 1.02-2.37; P=0.04). GSEA revealed PD-L1 expression levels positively correlated with immune process or immune-related pathways.Conclusion: PD-L1 expression is an important negative prognostic factor in resected ADC. This finding has important implications for immunotherapy targeting the PD-1/PD-L1 pathway in patients with resected ADC.

Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma

BackgroundAnti-programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra- and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy. This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.MethodsIn primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+) T-cell density in primary tumors and PD-1 expression on CD8(+) T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients’ overall survival and disease-free survival.ResultsAmong 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors (45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+) T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes (both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression, PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.ConclusionThe expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

Abstract 1771: Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers

Abstract Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in patients (pts) with loco-regional high-risk renal cell carcinoma (HR=0.76, 95% CI: 0.59-0.98; P=0.03; median[m] DFS, 6.8 vs 5.6 years). Here, we report the results of a retrospective exploratory molecular biomarker analysis using nephrectomy biospecimens from the S-TRAC trial. Materials and Methods: Formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. Biomarker quantification was done by automated image analysis of the regions of interest (ROI). The analysis algorithm utilized an immunoscore approach applied to ROI, reflecting assessment of both the center and invasive margin of tumors (for PD-L1 and CD8 staining). DFS was compared between biomarker stratum by &amp;lt; median vs ≥ median values of a particular IHC parameter using Kaplan-Meier (K-M) analysis. Receiver Operating Characteristics (ROC) curves were generated to further assess the potential clinical utility of biomarkers for which significant (P &amp;lt; 0.05) results were obtained in K-M analysis. Results: In total, 191/615 (101, SU and 90, PBO) pts in the intent-to-treat population were included for IHC analysis. Baseline characteristics were similar in the subpopulations with and without IHC data. Shorter DFS was observed in the PBO group for pts with PD-L1+ vs PD-L1- tumors, although not statistically significant (HR=1.75; 95% CI: 0.89-3.46; P=0.103). In pts with PD-L1+ tumors, DFS was numerically longer for SU vs PBO (mDFS=6.17 vs 2.67 years) (HR=0.58; 95% CI: 0.26-1.29; P=0.175). In the SU group, pts with CD8+ T-cell density ≥ median (cutoff=269.5 CD8+ cells/mm2) had longer DFS (mDFS=not reached [NR]; 95% CI: 6.83-NR) than pts with CD8+ T-cell density &amp;lt; median (mDFS=3.47 years; 95% CI: 1.73-NR), and the difference was statistically significant (HR=0.40, 95% CI: 0.20-0.81; P=0.009), while CD8+ T-cell density showed no significant difference in DFS for PBO pts (HR=0.80, 95% CI: 0.42-1.50; P=0.484). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively, and the optimal cutoff was 222.22 cells/mm2 with an area under ROC curve of 0.622. Conclusions: Increased density of CD8+ T-cells in tumor tissue was associated with longer DFS in SU-randomized pts but not PBO, suggesting this may be predictive of treatment effect. Further validation in an independent cohort is warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic RCC should be further explored. Citation Format: Daniel J. George, Jean-Francois Martini, Yen-Hwa Chang, Michael Staehler, Jan Breza, Jean-Jacques Patard, Robert J. Motzer, Ahmed Magheli, Bernard Escudier, Giacomo Carteni, Paola Gerletti, Sherry Li, Michelle Casey, Brigitte Laguerre, Hardev S. Pandha, Allan J. Pantuck, Anup Patel, Maria Lechuga, Alain Ravaud. Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1771. doi:10.1158/1538-7445.AM2017-1771

A retrospective cohort study of PD-L1 expression in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SUPREME-HN).

6040 Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. Targeting the PD-1/PD-L1 axis has resulted in clinically meaningful antitumor activity and improved overall survival (OS) in R/M HNSCC patients. Tumoral PD-L1 expression correlates with response to blocking PD-1/PD-L1 antibodies. We investigated the prognostic value of PD-L1 expression in R/M HNSCC patients. Methods: Archival tumor samples from R/M HNSCC patients diagnosed between March 2011 and June 2015 at 12 institutions in 6 countries were stained for PD-L1 and clinic-demographic data were abstracted from medical records. Tumoral PD-L1 protein expression was assessed with the validated Ventana SP263 assay and scored as high (≥25% of tumor cells [TC]) or low/negative ( &lt; 25% of TC). Extracted data included demographic and tumor characteristics, treatment patterns, and clinical outcomes. Descriptive analyses were conducted and survival estimated by the Kaplan-Meier method. OS was defined from the diagnosis index date of R/M disease to time of death. Results: As ofSeptember 26, 2016 (interim analysis), data were available for 143 patients of whom 138 were eligible for analysis. Median age was 62.0 years (range, 28.0−88.0), 76.8% were male, and 84.0% were white. PD-L1 protein expression was high in 43 patients (31.2%), low/negative in 91 (65.9%), and unknown in 4 (2.9%). Median OS (8.2 vs. 8.8 months; P = 0.94) and progression-free survival (PFS) from the start of first-line (6.0 vs. 5.6 months; P = 0.29) or second-line therapy (7.1 vs. 1.8 months; P = 0.11) did not significantly differ between PD-L1 high and low/negative patients, respectively. There were no significant differences in OS based on PD-L1 status within subgroups defined by age, race, tobacco or alcohol use, primary tumor site, performance status, metastatic disease at diagnosis, or treatment with platinum-based chemotherapy. Conclusions: Interim analyses indicate that PD-L1 status is not associated with OS or PFS in R/M HNSCC patients.

Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study

BackgroundEpithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. MethodsImmunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). ResultsInter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1–5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. ConclusionE1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.

MTE08.01 Immunotherapy in Early and Locally Advanced NSCLC: Challenges and Perspectives

MTE08.01 Immunotherapy in Early and Locally Advanced NSCLC: Challenges and Perspectives

PD-L1 expression in human cancers and its association with clinical outcomes.

PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

Prognostic Role of Programmed Death Ligand-1 Expression in Breast Cancer: A Systematic Review and Meta-Analysis.

Cancer therapies that target the PD-1/PD-L1 pathway are in ongoing phase I/II clinical trials for several tumor types. However, the prognostic value of PD-L1 expression in breast cancer is unclear. We assessed the prognostic role of PD-L1 expression in breast cancer. We searched Medline/PubMed for eligible studies of the association between PD-L1 expression and patient survival in breast cancer published before 7 December 2015. The effect size was the hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS), recurrence-free survival (RFS) and metastasis-free survival (MFS). Odds ratios (OR) with 95% CIs were also extracted to evaluate associations between PD-L1 expression and patient clinicopathological features. We included five studies with 7,802 total patients in this meta-analysis. The pooled OR associated high PD-L1 expression with predictors of poor-prognosis: high tumor grade, negative ER status, negative PR status, positive HER2 status and lymphovascular invasion. High PD-L1 protein expression was associated with shorter OS (HR = 3.22, 95% CI: 1.86-5.59; P < 0.0001), shorter RFS (HR = 1.38, 95% CI: 1.03-1.86; P = 0.03) and shorter MFS (HR = 3.33, 95% CI: 2.30-4.82; P < 0.00001); whereas high PD-L1 mRNA expression was associated with longer OS (HR = 0.86, 95% CI: 0.75-1.00; P = 0.05) and longer RFS (HR = 0.57, 95% CI: 0.36-0.91; P = 0.02). The findings of these studies were significantly heterogeneous; the results should be interpreted cautiously. In breast cancer, high PD-L1 protein expression appears to be a negative prognostic factor, whereas high PD-L1 mRNA expression appears to be a favorable prognostic factor.

Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas

Activation of the programmed death 1 (PD1)/PD1 ligand (PDL1) pathway is important for tumor cells to escape from immune control. The clinical efficacy of therapeutic modulation of the PD1-PDL1 pathway has been recently shown in classical Hodgkin lymphoma (cHL), but little is known about the frequency and diagnostic and prognostic importance of PDL1 expression in lymphomas. The available anti-PDL1 antibody clones E1L3N and SP142 were compared, and a large cohort of Hodgkin lymphomas (n=280) and B-cell lymphomas (n=619) was examined for PDL1 using E1L3N. The results were correlated with the expression of other phenotypic markers, interphase fluorescence in situ hybridization data of the 9p24.1 region (PDL1 locus), and the clinical outcome. PDL1 was expressed on more than 5% of tumor cells in 70% of cHL, 54% of nodular lymphocyte-predominant Hodgkin lymphoma, and 35% of primary mediastinal B-cell lymphomas; in the latter, PDL1 expression correlated with PDL1 gains (ρ=0.573). PDL1 was expressed in 31% of primary diffuse large B-cell lymphomas (DLBCLs), whereas most other entities did not express PDL1. In cHL, expression of PDL1 correlated with increased numbers of granzyme+ T cells (ρ=0.251) and CD68+ macrophages (ρ=0.221) but with decreased numbers of FoxP3+ T cells (ρ=0.145). In activated B-cell-like DLBCL, PDL1 positively correlated with PD1+ T cells, whereas an inverse correlation with FoxP3+ T cells was seen in the germinal center B-cell-like DLBCL. PDL1 expression can be diagnostically valuable in some gray zones around DLBCL and cHL; it identifies an "immune escape" cluster of cHL and activated B-cell-like DLBCL with increased granzyme+ and PD1+ T cells and macrophages and decreased regulatory T cells.

Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors

Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.

3025 Prognostic value of PDL1 expression in stage III Non-Small Cell Lung Cancer (NSCLC) treated by chemo-radiotherapy (CRT)

3025 Prognostic value of PDL1 expression in stage III Non-Small Cell Lung Cancer (NSCLC) treated by chemo-radiotherapy (CRT)

Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma

The aberrant expression of programmed cell death 1 ligands 1 and 2 (PD-Ls) on tumor cells dampens antitumor immunity, resulting in tumor immune evasion. In this study, we investigated the expression of PD-Ls in human hepatocellular carcinoma (HCC) to define their prognostic significance after curative surgery. Immunohistochemistry was used to investigate PD-Ls expression as well as granzyme B+ cytotoxic and FoxP3+ regulatory T cell infiltration on tissue microarrays containing 240 randomly selected HCC patients who underwent surgery. The results were further verified in an independent cohort of 125 HCC patients. PD-Ls expression on HCC cell lines was detected by Western blot assay. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-L2 also had a poorer survival, the difference in recurrence was not statistically significant. Multivariate analysis identified tumor expression of PD-L1 as an independent predictor for postoperative recurrence. No correlation was found between PD-Ls expression and granzyme B+ lymphocyte infiltration, whereas a significant positive correlation was detected between PD-Ls expression and FoxP3+ lymphocyte infiltration. In addition, tumor-infiltrating cytotoxic and regulatory T cells were also independent prognosticators for both survival and recurrence. The prognostic value of PD-L1 expression was validated in the independent data set. Our data suggest for the first time that PD-L1 status may be a new predictor of recurrence for HCC patients and provide the rationale for developing a novel therapy of targeting the PD-L1/PD-1 pathway against this fatal malignancy.