Prognostic Value Of Programmed Death-ligand 1 Expression Research Articles

The prognostic value of programmed death-ligand 1 (PD-L1) expression in resected colorectal cancer without neoadjuvant therapy - differences between antibody clones and cell types

BackgroundProgrammed death-ligand 1 (PD-L1) expression on tumor cells is associated with poor prognosis in several malignancies, while partly contradictory and inconclusive results have been presented for colorectal cancer (CRC). This study aimed to evaluate PD-L1 as a prognostic biomarker in CRC by comparing three different antibody clones.MethodsPatients surgically treated for CRC between January 1st, 2007, and December 31st, 2015, in Kalmar County, Sweden, were retrospectively included. Tissue microarrays from 862 primary tumors without neoadjuvant treatment were assessed for immunohistochemical expression of PD-L1 in tumor cells (TC) and immune cells (IC) using clones 73-10, SP263, and 22C3. Cox regression proportional hazard models were used to estimate hazard ratios for overall survival (OS) and disease-free interval (DFI) in univariable and multivariable analyses, with 1% and 5% set as cut-offs for positive expression in TC and IC respectively.ResultsPD-L1 expression in TC was found in 89 (10%) cases for clone 73-10, 76 (9%) for clone SP263, and 38 (4%) for clone 22C3, while the numbers for IC were 317 (37%) cases for clone 73-10, 264 (31%) for clone SP263, and 89 (10%) for clone 22C3. PD-L1 expression in IC was associated with prolonged OS and DFI in univariable analysis for all three clones. The link to prolonged DFI remained in multivariable analysis for 73-10 and SP263, but only for 73-10 regarding OS. PD-L1 expression in TC was not prognostic of OS in any analysis, while it was associated with prolonged DFI for SP263, and a trend was seen for 73-10. The link to prolonged DFI remained for SP263 and was strengthened for 73-10 in multivariable analysis.ConclusionsThe prognostic value of PD-L1 expression in both IC and TC differs between antibody clones, with 73-10 and SP263 being more reliable for prognostic information than 22C3 in resected CRC.

Prevalence and prognostic value of PD-L1 expression and tumor mutational burden in persistent, recurrent, or metastatic cervical cancer.

To evaluate the prevalence and prognostic role of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in patients with non-immunotherapy-treated advanced cervical cancer. Clinical data were retrospectively collected from medical records between January 1, 2008, and December 31, 2016, at Asan Medical Center (Korea); archived tumor samples were assessed for PD-L1 expression (combined positive score [CPS] ≥1) and TMB (≥175 mutations/exome). Overall survival (OS) was defined as time from advanced diagnosis or initiation of first-line or second-line systemic therapy until death/last follow-up. The association of OS with PD-L1 expression and TMB were analyzed using the log-rank test and Cox proportional hazards model adjusted for covariates. Of 267 patients, 76.0% had squamous cell carcinoma (SCC), 24.0% had adenocarcinoma (AC)/adenosquamous carcinoma (ASC), 64.4% had PD-L1 CPS ≥1, and 32.6% had TMB ≥175 mutations/exome. PD-L1 CPS ≥1 and TMB ≥175 mutations/exome were more prevalent in SCC than in AC/ASC (73.9% and 37.2% vs. 34.4% and 17.7%). There was no association between OS and PD-L1 expression (CPS ≥1 vs. <1: adjusted hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.84-1.53 from advanced diagnosis); OS trended shorter for the subgroup with TMB ≥175 versus <175 mutations/exome (adjusted HR=1.29; 95% CI=0.95-1.75). Retrospective analysis of non-immunotherapy-treated patients with advanced cervical cancer demonstrated a higher prevalence of PD-L1 CPS ≥1 and TMB ≥175 mutations/exome in SCC versus AC/ASC. PD-L1 CPS ≥1 was not associated with OS; TMB ≥175 mutations/exome showed a trend toward shorter OS. Additional studies are needed to confirm these findings.

PD-L1 expression complements CALGB prognostic scoring system in malignant pleural mesothelioma.

Programmed death ligand-1 (PD-L1) expression is a predictive biomarker in patients with lung cancer, but its role in malignant pleural mesothelioma (MPM) remains unclear. Evidence suggests that higher PD-L1 expression is correlated with worse survival. CALGB is the main scoring system used to predict the benefit of chemotherapy treatment. This study aimed to determine the prognostic value of PD-L1 expression and its addition to CALGB scoring system in patients with MPM. In this retrospective analysis, we evaluated samples with confirmed locally advanced or metastatic MPM. PD-L1 Tumor Proportional Score (TPS) was determined by immunohistochemistry at diagnosis. 73 patients were included in this study. A cutoff value of 15 was set for a high or low PD-L1 TPS. In total, 71.2% (n=52) and 28.8% (n=21) of individuals harbored low or high PD-L1 expression, respectively. PD-L1High was associated with worse median progression-free Survival (mPFS) [4.9 vs. 10.8 months; HR 2.724, 95% CI (1.44-5.14); p = 0.002] and Overall Survival (OS) [6.0 vs. 20.9 months; HR 6.87, 95% CI (3.4-8.7); p<0.001] compared to patients with PD-L1Low. Multivariate analysis confirmed that PD-L1 expression was an independent factor for PFS and OS in patients with MPM and CALGB score of 5-6. PD-L1 addition to CALGB scale improves its prognostic estimation of MPM survival and should be considered in future research.

Prognostic implication of PD-L1 in early-stage non-small cell lung cancer: a retrospective single-centre study.

The prognostic role of programmed death-ligand 1 (PD-L1) expression in patients with localised and locally advanced non-small cell lung cancer has not been fully elucidated. This information could help to better interpret recent and upcoming results of phase III adjuvant or neoadjuvant anti-PD-1/PD-L1 immunotherapy studies. In a cohort of 146 patients with early or locally advanced non-small cell lung cancer treated with curative intent (by surgery or radiotherapy), we investigated the prognostic value of PD-L1 expression and its correlation with other biological and clinical features. PD-L1 expression was stratified by quartiles. Primary endpoints were overall and disease-free survival. We also analysed the prognostic impact of the presence of actionable mutations, implemented treatment modality and completion of the treatment plan. Neither type of patient received neoadjuvant or adjuvant immunotherapy or target therapy. Of the 146 selected patients, 32 (21.9%) presented disease progression and 15 died (10.3%) at a median follow-up of 20 months. In a univariable analysis, PD-L1 expression ≥25% was associated with significantly lower disease-free survival (hazard ratio [HR]) 1.9, 95% confidence interval [CI] 1.0-3.9, p = 0.049). PD-L1 expression ≥50% did not lead to disease-free survival or overall survival benefits (HR 1.2 and 1.1, respectively; 95% CI 0.6-2.6 and 0.3-3.4, respectively; pnot significant). In a multivariate analysis, a stage >I (HR 2.7, 95% CI 1.2-6, p = 0.012) and having an inoperable tumour (HR 3.2, 95% CI 1.4-7.4, p = 0.005) were associated with lower disease-free survival. The population of patients with early-stage non-small cell lung cancer and PD-L1 expression ≥25% who were treated with curative intent during the pre-immunotherapy era exhibited a worse prognosis. This finding provides justification for the utilisation of adjuvant immunotherapy in this subgroup of patients, based on the current evidence derived from disease-free survival outcomes. However, for patients with PD-L1 expression <25%, opting to wait for the availability of the overall survival results may be a prudent choice.

Programmed death-ligand1 is a determinant of recurrence in alveolar echinococcosis

ObjectivesAlveolar echinococcosis (AE) recurrence is one of the major stakes in patients undergoing surgery, the main curative treatment. Preliminary data demonstrated an effect of programmed death-ligand1 (PD-L1) inhibitors on AE proliferation in animals. The current study aimed to analyze the prognostic value of PD-L1 expression in tissue samples of patients with AE undergoing surgery. MethodsA cross-sectional study of patients operated for AE between 2002 and 2017 was performed. Patients with recurrence were matched 1: 2 with patients without recurrence. The matching criteria were PNM staging (P = hepatic localization of the parasite, N = extra-hepatic involvement of neighboring organs, and M = absence or presence of metastasis), resection status, preoperative albendazole treatment, and lesion size. PD-L1 immunohistochemistry staining was performed in surgical liver specimens. The expression of PD-L1 was assessed in immune cells. Disease-free survival was calculated using the Kaplan-Meier method. ResultsAmong 68 consecutive patients, eight patients with recurrence were matched to 16 patients without recurrence. PD-L1 was overexpressed in patients with recurrence (recurrence: PD-L1 <1%: one, PD-L1 ≥1%: seven; no recurrence: PD-L1 <1%: nine, PD-L1 ≥1%: seven, P = 0.040). Moreover, patients with lower PD-L1 expression (<1%) showed better median disease-free survival (120 months, 95% confidence interval 104-135 vs 74, 95% confidence interval 44-104, P = 0.050). ConclusionThese findings highlight the proof of concept of PD-L1 in AE, but further data on its prognostic importance and the role of immune checkpoint blockade as a promising therapeutical strategy are needed.

Prognostic value of PD-L1 expression in recurrent renal cell carcinoma after nephrectomy: a secondary analysis of the ARCHERY study

BackgroundNephrectomy is a curative treatment for localized renal cell carcinoma (RCC), but patients with poor prognostic features may experience relapse. Understanding the prognostic impact of programmed death-ligand 1 (PD-L1) expression in patients who underwent nephrectomy for RCC may aid in future development of adjuvant therapy.MethodsOf 770 surgical specimens collected from Japanese patients enrolled in the ARCHERY study, only samples obtained from patients with recurrent RCC after nephrectomy were examined for this secondary analysis. Patients were categorized into low- and high-risk groups based on clinical stage and Fuhrman grade. Time to recurrence (TTR) and overall survival (OS) were analyzed.ResultsBoth TTR and OS were shorter in patients with PD-L1-positive than -negative tumors (median TTR 12.1 vs. 21.9 months [HR 1.46, 95% CI 1.17, 1.81]; median OS, 75.8 vs. 97.7 months [HR 1.32, 95% CI 1.00, 1.75]). TTR and OS were shorter in high-risk patients with PD-L1-positive than -negative tumors (median TTR 7.6 vs. 15.3 months [HR 1.49, 95% CI 1.11, 2.00]; median OS, 55.2 vs. 83.5 months [HR 1.53, 95% CI 1.06, 2.21]) but not in low-risk patients.ConclusionsThis ARCHERY secondary analysis suggests that PD-L1 expression may play a role in predicting OS and risk of recurrence in high-risk patients with localized RCC.Clinical Trial Registration: UMIN000034131.

Prognostic value of PD-L1 expression on immune cells or tumor cells for locally advanced esophageal squamous cell carcinoma in patients treated with neoadjuvant chemoradiotherapy.

Programmed death-ligand 1 (PD-L1) expression may influence the prognosis of patients with localized esophageal cancer. The current study compared the prognostic value of PD-L1 expression between tumor cells and immune cells. Archival esophageal tumor tissue samples were collected from patients who received paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) for locally advanced esophageal squamous cell carcinoma (ESCC) in three prospective phase II trials. PD-L1 expression on tumor and immune cells was examined immunohistochemically by using the SP142 antibody and scored by two independent pathologists. The association of PD-L1 expression with patient's outcomes was analyzed using a log-rank test and Cox regression multivariate analysis. A total of 100 patients were included. PD-L1 expression on tumor cells was positive (≥ 1%, TC-positive) in 55 patients; PD-L1 expression on immune cells was high (≥ 5%, IC-high) in 30 patients. TC-positive status was associated with poor overall survival (OS) (HR: 1.63, P = 0.035), whereas IC-high status was associated with improved OS (HR: 0.44, P = 0.0024). Multivariate analysis revealed that TC-positive, IC-high, and performance status were independent prognostic factors for progression-free survival and that IC-high and performance status were independent factors for OS. Furthermore, the combination of IC-high and TC-negative status was associated with the optimal OS, whereas that of TC-positive and IC-low status was associated with the worst OS. PD-L1 expression on tumor and immune cells may have different prognostic value for patients with locally advanced ESCC receiving neoadjuvant CRT. A combination of these two indexes may further improve the prognostic prediction.

The clinical impact of three validated PD-L1 immunohistochemistry assays as a prognostic factor in small cell lung cancer.

BackgroundEvidence of the clinical impact of programmed death-ligand 1 (PD-L1) expression in small cell lung cancer (SCLC) is scarce and conflicting, even though atezolizumab became the first PD-L1 inhibitor approved by the US Food and Drug Administration (FDA) in recent years for the initial treatment of extensive-stage (ES)-SCLC.MethodsWe investigated PD-L1 expression in SCLC tumors using the three validated PD-L1 immunohistochemistry (IHC) assays (SP263, SP142, and 22C3) and assessed the correlation between PD-L1 expression and clinicopathological factors to determine the prognostic value of PD-L1 expression. The three PD-L1 IHC analyses were prospectively used to assess tumor samples of patients with SCLC at diagnosis.ResultsOf the total of 59 patients, 47 patients received the active treatment beyond platinum-based chemotherapy at our institution. PD-L1 expression was positive in 39.0% with SP263, 37.3% with SP142, and 22.0% with 22C3. In a univariate analysis, the positive result of at least one of the three PD-L1 assays and the positive result of the SP142 assay were associated with longer overall survival (OS). A multivariable analysis confirmed that performance status, stage, and the SP142 assay were independent predictors of OS. In subgroup analysis, these results revealed more significant prognostic factors in ES than in limited-stage (LS). In patients with SCLC, especially those with ES, the expression of the SP142 assay is a significant independent prognostic factor.ConclusionsAlthough these results need to be further validated in larger cohorts, this information will benefit clinicians and patients in determining the immunotherapy for patients with ES-SCLC.

The clinicopathological significance and prognostic value of programmed death-ligand 1 in prostate cancer: a meta-analysis of 3133 patients.

Background: Programmed death-ligand 1 (PD-L1) is considered an adverse factor predicting poor prognosis in various cancers, but the significance of PD-L1 expression for the prognosis of prostate cancer (PCa) is still unclear. We aimed to investigate the clinicopathological significance and prognostic value of PD-L1 expression in PCa.Methods: Studies were retrieved from PubMed, Web of Science, Cochrane Library and Embase before March 23, 2020. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were obtained to assess the results. Begg’s test was applied to evaluate publication bias.Results: Fourteen studies involving 3133 cases were analyzed. The pooled data showed that both PD-L1 protein expression and PD-L1 DNA methylation (mPD-L1) were negatively associated with biochemical recurrence-free survival, with HRs of 1.67 (95% CI = 1.38-2.06, p < 0.001) and 2.23 (95% CI = 1.51-3.29, p < 0.001), respectively. In addition, PD-L1 overexpression was significantly related to advanced tumor stage (OR = 1.40, 95% CI= 1.13-1.75, p = 0.003), positive surgical margin (OR = 1.36, 95% CI = 1.03-1.78, p = 0.028), higher Gleason score (OR = 1.81, 95% CI = 1.35-2.42, p < 0.001) and androgen receptor positivity (OR = 2.20, 95% CI = 1.61-3.01, p < 0.001), while no significant correlation with age (p = 0.122), preoperative PSA (p = 0.796) or nodal status (p = 0.113) was observed.Conclusions: The study revealed that high expression of PD-L1 was related to unfavorable prognosis and advanced clinicopathological factors in PCa patients.

Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ≤1%: 95.4 months (95% CI: 51.8—not reached) vs. >1%: not reached, p = 0.03, log-rank). Patients with a PD-L1 TPS ≤1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4—not reached) vs. not reached, p = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ≤1%, hazard ratio: 0.29 (95% CI: 0.11–0.76), p = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.

The Prognostic Value of PD-L1 Expression in Triple-Negative Breast Cancer: A Cohort Study and Systematic Literature Review

Context The prognostic value of programmed death ligand-1 (PD-L1) in triple-negative breast cancer (TNBC) is unclear. Objective To investigate PD-L1 expression for association with survival. Design Surgical specimens of primary TNBC were linked to data on recurrence-free survival (RFS). Tissue microarray averaging 3 tumor cores per case underwent immunohistochemical staining. Within each core, PD-L1 positivity was scored separately for tumor, stromal, and immune cells by averaging readings by two board-certified pathologists. Having at least one core with high (above 10%) PD-L1 staining (on tumor cells as primary risk, on stromal and immune cells as secondary risks) was evaluated for association with RFS using proportional hazards regression. Comparable survival analyses were identified by systematic search of MEDLINEindexed journals through March 2019. Results Patients (n=112) contributed 308 cores of TNBC. During follow-up, TNBC recurred in 24 subjects; another 4 subjects died without recurrence. Ten (8.9%) subjects had High PD-L1 expression on tumor cells, a feature associated with better RFS [hazards ratio 0.44 (95% Confidence Interval 0.19-0.97)] independently of age, distant metastasis, tumor size, lymphovascular invasion, and Ki-67. In contrast, High PD-L1 in stromal cells or immune cells was not associated with RFS. Among 22 similar studies, high PDL1 on tumor cells was associated with survival in 16 studies: 7 favorably, 8 unfavorably, and 1 with mixed results. Conclusions In this TNBC cohort, High PD-L1 on tumor cells conferred favorable prognosis. The lack of consensus across similar studies suggests that future studies should explore how timing, microenvironment, and glycosylation influence PD-L1’s association with survival.

PD-L1 Expression is Associated With Poor Prognosis in Renal Cell Carcinoma.

Programmed death ligand 1 (PD-L1) is a protein which, when interacting with its receptor programmed death 1, acts as a negative regulator of the antitumor T-cell-mediated immune response. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor-infiltrating immune cells (TIICs) in 346 RCC patients with long-term follow-up. PD-L1 positivity in tumor cells was associated with higher World Health Organization nucleolar grade (P<0.001), recurrence (P=0.011), and death due to RCC (P=0.031). PD-L1 positivity in TIICs was associated with higher nucleolar grade (P<0.001), higher T-stage (P=0.031), higher N-stage (P=0.01), recurrence (P=0.007), and death due to RCC (P=0.001). A significant positive association of time to cancer-specific death with both PD-L1-positive tumor cells and TIICs were also found. The data indicate that RCC patients with PD-L1-positive tumor cells and TIICs are at significant risk for cancer progression and the expression may be used as a complementary prognostic factor in the management of RCC patients.

Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma.

Purpose: Immunotherapy may be a potential alternative for patients with sinonasal squamous cell carcinoma (SNSCC). Data regarding potential immunotherapy targets, such as programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs), in SNSCC are limited. In this study, we assessed the prevalence and prognostic value of PD-L1 expression and TILs in p16-negative and p16-positive SNSCC.Patients and methods: Tissues from 96 patients with SNSCC were stained using immunohistochemistry against PD-L1, CD8, and Foxp3 to assess the immune environment. The correlations between PD-L1 expression, TILs, and p16 status were analyzed. Additionally, PD-L1, CD8, and Foxp3 expressions, as well as p16 status, were analyzed in relation to patient clinicopathological variables and prognosis.Results: Twenty-nine (30.2%) patients with SNSCC showed PD-L1 expression in >5% of tumor cells. PD-L1 expression was significantly correlated with poor differentiation and a high level of TILs. PD-L1 expression and the CD8+ and Foxp3+ T-cell infiltrates in p16-negative patients (n=78, 81.2%) and p16-positive patients (n=18, 18.8%) were not significantly different. PD-L1 expression and p16 status were not associated with overall survival (OS) and disease-free survival (DFS). Patients with high CD8+ or Foxp3+ cell infiltration had better clinical outcomes. A multivariate analysis confirmed that CD8 TILs were a significant independent and favorable prognostic factor for OS (p=0.023) and DFS (p=0.008).Conclusion: TILs can play a prognostic role in SNSCC. We did not find differences in immune marker expression between p16-positive and p16-negative SNSCC tissues. The high correlation between PD-L1 expression and TILs indicates that the PD-1/PD-L1 pathway is a promising immunotherapeutic target for SNSCC.

Prognostic effect of programmed death-ligand 1 (PD-L1) in ovarian cancer: a systematic review, meta-analysis and bioinformatics study

BackgroundThe expression of PD-L1 has been reported in ovarian cancer. However, the prognostic role of PD-L1 expression in ovarian carcinoma remained controversial. This study was performed to assess the prognostic value of PD-L1 expression on ovarian cancer.MethodsThe PubMed, Embase, EBSCO, and Cochrane Library databases were searched to identify available publications. The pooled odds ratio (OR) or hazard ratios (HRs: multivariate analysis) with their 95% confidence intervals (95% CIs) were calculated in this analysis. A bioinformatics study based on The Cancer Genome Atlas (TCGA) sequencing and microarray datasets was used to further validate the results of PD-L1 mRNA expression. Kaplan-Meier (KM) survival curves were performed to evaluate the prognostic effect of PD-L1 mRNA expression.ResultsTwelve studies with 1630 ovarian cancers regarding PD-L1 immunohistochemical expression were identified. Meta-analysis showed that PD-L1 protein expression was not associated with tumor grade, clinical stage, lymph node status, tumor histology, overall survival (OS), and progression-free survival (PFS). TCGA data showed no association between PD-L1 mRNA expression and ovarian cancer. Further validation using microarray data suggested that no association between PD-L1 mRNA expression and OS was found in large independent patient cohorts (1310 cases). PD-L1 mRNA expression was significantly linked to worse PFS in 1228 patients with ovarian cancer (227458_at: HR = 1.55, 95% CI = 1.28–1.88, P < 0.001; 223834_at: HR = 1.41, 95% CI = 1.14–1.75, P = 0.0015).ConclusionsMeta-analysis showed that PD-L1 may not be a prognostic factor for ovarian cancer. But a bioinformatics study showed that PD-L1 expression was significantly associated with worse PFS of ovarian cancer. More clinical studies are needed to further validate these findings.

Reactive versus Constitutive: Reconcile the Controversial Results about the Prognostic Value of PD-L1 Expression in cancer.

The prognostic value of programmed death-ligand 1 (PD-L1) has been controversial in recent studies. PD-L1 is known to play a major role in suppressing the immune response, yet increasing studies have reported that PD-L1 expression has a favorable prognostic value for cancer patients. This raises the concern about how to understand PD-L1 expression: merely an immune inhibitory signal, or more likely a reactive process to T-cell response that indicates cytotoxic T lymphocyte (CTL) level in a tumor? To solve this dilemma, an integrative investigation is required. We compared the PD-L1 expression between tumor cells and immune cells, and characterized the inter- and intra-tumor correlation between CTL and PD-L1 expression. The prognostic values between PD-L1 and CTL is compared across 15 solid cancers and 11 independent cohorts of ovarian cancer. PD-L1 and PD-L1-adjusted CTL are analyzed in immunotherapy dataset receiving nivolumab. We observed unexpected high concordance between the prognostic value of PD-L1 and CTL across different cancers and cohorts. We found primarily reactive rather than constitutive PD-L1 expression in most tumors. We revealed that PD-L1-adjusted CTL level, rather than the expression of PD-L1, effectively predicts the responders to immune checkpoint inhibitors. This study highlights the importance of PD-L1 expression, as primarily a signature of reacting efficiency of pre-existing anti-tumor immunity, in balancing the tumor microenvironment. Importantly, it suggests that the reactive efficiency of PD-L1 is more useful to predict the response to immunotherapy.

Prognostic significance of programmed death ligand-1 immunohistochemical expression in esophageal cancer: A meta-analysis of the literature.

Background:It is thought that expression of programmed death ligand-1 (PD-L1) in esophageal cancer (EC) might compromise patient survival. However, the association between PD-L1 expression and survival of patients with EC remains controversial.Methods:A meta-analysis combining eligible published studies was performed to evaluate the effect of PD-L1 expression in tumor cells detected by immunohistochemistry (IHC) on overall survival (OS) and disease-free survival (DFS) in patients with EC, using pooled hazard ratio (HR) with its 95% confidence interval (CI).Results:The pooled HR for 19 eligible studies (18 publications, n = 3306) suggested that PD-L1 overexpression had an unfavorable impact on OS (HR = 1.42, 95% CI: 1.09–1.86). No significant effect of PD-L1 overexpression on DFS was observed, and the combined HR was 1.08 (95% CI: 0.76–1.53) for 12 eligible studies (11 publications, n = 2260).Conclusion:PD-L1 expression in tumor cells detected by IHC was associated with worse OS in EC. However, the prognostic value of PD-L1 expression in tumor cells on OS in EC still needs further large prospective trials to be clarified.

Abstract P5-23-05: Prognostic value of PD-L1 expression in male breast cancer

Abstract Background Growing evidence have shown promise for targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling in several tumors. In female breast cancer, PD-L1 expression has been correlated with poor clinical outcome. However, whether PD-L1 has any indication for prognosis in male breast cancer (MBC) patients remains unknown. The purpose of this study was to examine the expression levels of PD-L1 in MBC and to identify the relationship between PD-L1 expression and patient survival. Methods We retrospectively identified 110 male breast cancer patients diagnosed between 2000 and 2013 at Salah Azaïz Cancer Institute. PD-L1 expression was evaluated by immunohistochemistry (IHC) using CD274 antibody. Specimens were scored as IHC low or high, when &amp;lt; 5% or ≥ 5% of cells were PD-L1 positive, respectively. The association between expression of PD-L1 and survival was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results Median follow up was 12.5 months [range 1-132 months]. High expression of PD-L1 was observed in 64.5% of MBC samples (71/110). PD-L1 expression was significantly associated with advanced clinical stage (p=0.012), higher histological grade (p=0.014), higher Ki67 expression (p=0.023) and hormone-receptor negative status (p=0.024). Patients with high PD-L1 expression had significantly shorter overall survival (OS) than patients with low expression (p=0.002, hazard ratio (HR) =5 [2.624–10.642]). Multivariate analysis identified PD-L1 as an independent prognostic factor for OS (p&amp;lt;0.001, HR = 0.775 [0.680–0.870]). Conclusion Our results indicate that high PD-L1 expression may be a prognostic indicator for reduced OS. Thus, PD-L1 expression is a promising novel biomarker with prognostic significance in MBC and may suggest a potential therapeutic target of anti-PD-L1 antibody therapy in MBC patients. Citation Format: Abdeljaoued S, Bettaieb I, Adouni O, Goucha A, Chiba D, Bouzaiene H, Ben Hassouna J, Boussen H, Rahal K, Gamoudi A. Prognostic value of PD-L1 expression in male breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-23-05.

Programmed death ligand 1 expression in esophageal cancer following definitive chemoradiotherapy: Prognostic significance and association with inflammatory biomarkers.

Immunotherapy with anti-programmed cell death protein 1 or programmed death ligand 1 (PD-L1) agents has demonstrated promising efficacy for the treatment of various types of malignancies. However, the role of PD-L1 as a tumor prognostic marker remains poorly understood. In the present study, the prognostic value of PD-L1 expression in esophageal carcinoma (EC) following definitive chemoradiotherapy (CRT) was investigated, and its associations with three systemic inflammation biomarkers, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) were further explored. A total of 104 patients with non-metastatic EC, who underwent definitive CRT between January 2009 and December 2012, were retrospectively analyzed. The expression of PD-L1 was examined by immunohistochemistry and the impact of PD-L1 expression level on overall survival (OS) was assessed. Furthermore, pretreatment neutrophil, lymphocyte, platelet and monocyte counts were obtained from routine blood tests to calculate the NLR, PLR and LMR. PD-L1 was overexpressed in EC compared with normal esophageal epithelium, with a positive expression rate of 37.5%. Additionally, patients with positive PD-L1 expression had a lower NLR than those with negative PD-L1 expression (P=0.001). On multivariate analysis, the positive staining of PD-L1 was significantly associated with improved OS (HR, 0.6; 95% CI, 0.372–0.965; P=0.035). Kaplan-Meier survival analysis showed a similar result (P=0.009). Additionally, sex (HR, 0.449; 95% CI, 0.229–0.880; P=0.020), clinical stage III (HR, 2.471; 95% CI, 1.171–5.212; P=0.018), and receipt of concurrent chemoradiation (HR, 0.590; 95% CI, 0.368–0.945; P=0.028) were all independent prognostic factors in EC treated with definitive CRT. The correlation of NLR with PD-L1 expression validated the relevance of immunity and inflammation. In summary, the present study demonstrated that positive PD-L1 expression is associated with improved survival in patients with EC treated with radical CRT, indicating that PD-L1 is a promising prognostic marker.

Expression of PD-L1 in periampullary adenocarcinoma: Relationship with morphological type, the immune microenvironment and prognosis.

268 Background: Overall survival for patients with periampullary adenocarcinoma, including pancreatic cancer, continues to be poor. Pancreatic cancer is characterized by a largely immunosuppressive microenvironment, but blockade of the programmed death ligand 1 (PD-L1) pathway has still not been effective. Reports on the prognostic value of PD-L1 expression in pancreatic and in particular periampullary cancer are sparse. The aim of this study was therefore to analyze PD-L1 expression in periampullary adenocarcinoma, with specific reference to morphological type, tumor-infiltrating immune cells, and survival. Methods: PD-L1 expression in tumor cells (TC) and immune cells (IC) was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, 65 of intestinal(I)-type and 110 of pancreatobiliary(PB)-type. Correlations with various immune cells were calculated with non-parametric tests. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. Results: TC PD-L1 expression was not associated with any clinicopathological factors nor with survival. IC PD-L1 ( &gt; 10%) expression was higher in I-type than in PB-type tumors (p &lt; 0.001), and correlated with defect mismatch repair (p = 0.012) and lymph node negativity (p = 0.016). IC PD-L1 was not prognostic in PB-type tumors. High IC PD-L1 was associated with a prolonged survival in the entire cohort (HR = 0.59, CI 0.40-0.88), and in I-type tumors (HR = 0.38, CI 0.18-0.81), but not after adjustment for other prognostic factors. In I-type tumors, high IC PD-L1 correlated with high density of T cells (CD3+, CD8+, FoxP3+), but not with B cell or macrophage density. There were no significant associations between IC PD-L1 expression and any other immune cells in PB-type tumors. Conclusions: High PD-L1 expression in IC is associated with a T cell dense tumor microenvironment and a prolonged survival in I-type, but not in PB-type, periampullary adenocarcinoma, thus indicating that the effect of immune-modulating therapies may differ by morphological type.

PD-L1 expression and its effect on clinical outcomes of EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Objective:Epidermal growth factor receptor (EGFR) activation was reported to upregulate programmed death-ligand 1 (PD-L1) expression in lung cancer cells and subsequently contribute to immune escape, indicating its critical role in EGFR-driven lung tumors. This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer (NSCLC). The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).Methods:In total, 73 patients with surgically resected NSCLC and EGFR mutations were identified. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density were assessed by immunohistochemistry. A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen (26.0%) patients were positive for PD-L1 expression, which was significantly associated with concomitant KRAS mutation (P = 0.020) and marginally associated with higher CD8+ TILs density (P = 0.056). Positive PD-L1 expression was associated with markedly inferior overall survival (OS) in multivariate analysis (P = 0.032). The combination of PD-L1 and CD8+ TILs expression could be used to stratify the population into three groups with distinct prognoses. A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS [hazard ratio (HR) = 0.90; 95% confidence interval (CI), 0.42–1.38] or progression-free survival (HR = 1.03; 95 CI, 0.73–1.33) in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs. Conclusions:PD-L1 expression tended to correlate with CD8+ TIL expression, concomitant KRAS mutation, and poor survival in surgically resected EGFR-mutant NSCLC. PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.