Programmed Death-ligand 1 Immunohistochemistry Research Articles

Programmed Death-Ligand 1 Immunohistochemistry Assay Comparison Studies in NSCLC: Characterization of the 73-10 Assay.

Several programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays have been developed independently within clinical programs for therapeutic anti-programmed cell death protein 1 (anti-PD-1) or PD-L1 antibodies, necessitating assessment of assay comparability. We characterized the Dako PD-L1 IHC 73-10 assay used in clinical trials of avelumab (anti-PD-L1) or bintrafusp alfa (M7824; bifunctional immunotherapy) and compared it with the Dako PD-L1 IHC 22C3 pharmDx assay, an approved companion diagnostic for pembrolizumab monotherapy in patients with advanced NSCLC. Formalin-fixed, paraffin-embedded NSCLC tumor samples from a commercial source and from the JAVELIN Solid Tumor phase 1 trial of avelumab (NCT01772004) were stained using the 73-10 and 22C3 IHC assays with a standard protocol. Both assays displayed expected PD-L1 staining patterns. In 148 commercial NSCLC samples, the 73-10 assay stained greater than or equal to 1%, greater than or equal to 50%, and greater than or equal to 80% of tumor cells as PD-L1+ in 64.2%, 36.5%, and 23.6% of the samples, respectively, whereas the 22C3 assay stained 20.3% of the samples as greater than or equal to 50% PD-L1+. In 83 NSCLC clinical trial samples, the 73-10 assay stained 79.5% and 31.3% of the samples as greater than or equal to 1% and greater than or equal to 80% PD-L1+, respectively, whereas the 22C3 assay stained 59.0% and 21.7% as greater than or equal to 1% and greater than or equal to 50% PD-L1+, respectively. Efficacy of avelumab was similar in the subgroups classified with the 73-10 and 22C3 assays using greater than or equal to 80% and greater than or equal to 50% PD-L1+ cutoffs, with objective response rates of 26.9% and 33.3%, respectively. The 73-10 assay demonstrated high sensitivity for PD-L1 staining, and staining was comparable between the greater than or equal to 80% cutoff of the 73-10 assay and greater than or equal to 50% cutoff of the 22C3 assay.

Prevalence of PD-L1 expression in matched recurrent and/or metastatic sarcoma samples and in a range of selected sarcomas subtypes.

We assessed the frequency of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) in a cohort of 522 sarcomas from 457 patients, incuding a subset of 46 patients with 63 matched samples from local recurrence or metastases with primary tumours and/or metachronous metastases. We also investigated the correlation of PD-L1 with the presence and degree of tumour-infiltrating lymphocytes (TILs) in a subset of cases. IHC was performed using the PD-L1 SP263 companion kit (VENTANA) on tissue microarrays from an archival cohort. Evaluation of PD-L1 and TILs was performed on full sections for a subset of 23 cases. Fisher’s exact and Mann Whitney test were used to establish significance (P <0.05). PD-L1 positive expression (≥1%) was identified in 31% of undifferentiated pleomorphic sarcomas, 29% of angiosarcomas, 26% of rhabdomyosarcomas, 18% of myxofibrosarcomas, 11% of leiomyosarcomas and 10% of dedifferentiated liposarcomas. Negative expression was present in all atypical lipomatous tumous/well-differentiated lipoasarcomas, myxoid liposarcomas, synovial sarcomas, pleomorphic liposarcomas, and Ewing sarcomas. PD-L1 IHC was concordant in 81% (38 of 47) of matched/paired samples. PD-L1 IHC was discordant in 19% (9 of 47 matched/paired samples), displaying differences in the proportion of cells expressing PD-L1 amongst paired samples with the percentage of PD-L1-positive cells increasing in the metastatic/recurrent site compared to the primary in 6 of 9 cases (67%). Significant correlation between PD-L1 expression and the degree of TILs was exclusively identified in the general cohort of leiomyosarcomas, but not in other sarcoma subtypes or in metastatic/recurrent samples. We conclude that the prevalence of PD-L1 expression in selected sarcomas is variable and likely to be clone dependent. Importantly, we demonstrated that PD-L1 can objectively increase in a small proportion of metastases/recurrent sarcomas, offering the potential of treatment benefit to immune checkpoint inhibitors in this metastatic setting.

Canadian Multicenter Project on Standardization of Programmed Death-Ligand 1 Immunohistochemistry 22C3 Laboratory-Developed Tests for Pembrolizumab Therapy in NSCLC.

The programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assay is used to select patients for first or second-line pembrolizumab monotherapy in NSCLC. The PD-L1 IHC 22C3 pharmDx assay requires an Autostainer Link 48 instrument. Laboratories without this stainer have the option to develop a highly accurate 22C3 IHC laboratory-developed test (LDT) on other instruments. The Canadian 22C3 IHC LDT validation project was initiated to harmonize the quality of PD-L1 22C3 IHC LDT protocols across 20 Canadian pathology laboratories. Centrally optimized 22C3 LDT protocols were distributed to participating laboratories. The LDT results were assessed against results using reference PD-L1 IHC 22C3 pharmDx. Analytical sensitivity and specificity were assessed using cell lines with varying PD-L1 expression levels (phase 1) and IHC critical assay performance controls (phase 2B). Diagnostic sensitivity and specificity were assessed using whole sections of 50 NSCLC cases (phase 2A) and tissue microarrays with an additional 50 NSCLC cases (phase 2C). In phase 1, 80% of participants reached acceptance criteria for analytical performance in the first attempt with disseminated protocols. However, in phase 2A, only 40% of participants reached the desired diagnostic accuracy for both 1% and 50% tumor proportion score cutoff. In phase 2B, further protocol modifications were conducted, which increased the number of successful laboratories to 75% in phase 2C. It is possible to harmonize highly accurate 22C3 LDTs for both 1% and 50% tumor proportion score in NSCLC across many laboratories with different platforms. However, despite a centralized approach, diagnostic validation of predictive IHC LDTs can be challenging and not always successful.

PD-L1 Assay Concordance in Metastatic Renal Cell Carcinoma and Metastatic Urothelial Carcinoma

Immune checkpoint inhibitors are now standard of care for many patients with metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC). Given real-world limitations in programmed death-ligand 1 (PD-L1) testing, concordance studies between PD-L1 assays are needed. We undertook comparisons of Dako 28-8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC. Thirty-two patients with mRCC and 18 patients with mUC who had received immune checkpoint inhibitor therapy were identified. Formalin-fixed paraffin-embedded tumor samples for patients with mRCC were evaluated with Dako 28-8 and Ventana SP142 PD-L1 immunohistochemistry assays. For patients with mUC, formalin-fixed paraffin-embedded tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 immunohistochemistry assays. The majority (29/32; 91%) of mRCC cases were concordant between assays. The majority (17/18; 94%) of mUC cases were also concordant between assays. There was strong concordance between PD-L1 assays chosen for comparison in both mRCC and mUC, with similar performance characteristics. One limitation is the small number of cases in this study; larger comparison studies are needed for this biomarker in mRCC and mUC.

PD-L1 expression in malignant pleural effusion samples and its correlation with oncogene mutations in non-small cell lung cancer.

BackgroundProgrammed death ligand 1 (PD-L1) tumor proportion score (TPS) is currently widely used for selection of immune therapies in non-small cell lung cancer (NSCLC). Most of samples for PD-L1 expression were obtained from tumor tissue. However, the feasible of malignant pleural effusion (MPE) cytological samples for PD-L1 detection is poorly reported. And the correlation between oncogene mutations and PD-L1 expression based on high-throughput sequencing is rarely studied.MethodsNSCLC MPE cytological samples and partially paired tumor tissue from our institution analyzed for PD-L1 immunohistochemistry (IHC) using the clone SP263 pharmDx kit and evaluated genomic aberrations in all patients using next generation sequencing (NGS).ResultsOne hundred and twenty-three MPE cell blocks and 29 paired tumor tissue were successfully tested for PD-L1 expression. PD-L1 TPS of ≥50% were seen in 18.7% (23/123) of all samples. The accordance of PD-L1 expression in tumor tissue and MPE samples was 86.2% (50% as cut-off value). PD-L1 TPS ≥50% tumors were significantly associated with EGFR wild-type (P=0.007), but, no correlation between other genes and PD-L1 expression. A trend of longer overall survival (OS) was observed in patients with PD-L1 TPS <50% than those TPS ≥50% (20.0 vs. 13.8 months, P=0.057). No difference of tumor mutational burden (TMB) was observed between patients with PD-L1 ≥50% and <50% (8.2/MB and 7.7/MB, P=0.47).ConclusionsOur results suggest that cytological material is feasible for PD-L1 IHC analysis. Gene alterations could partially contribute to select the samples that with different PD-L1 expression. No correlation between the PD-L1 expression and TMB.

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

BackgroundImmune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand...

The Co-Expression of Programmed Death-Ligand 1 (PD-L1) in Untreated EGFR-Mutated Metastatic Lung Adenocarcinoma.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is the standard first-line therapy for metastatic lung adenocarcinoma harboring sensitive EGFR mutations. Tumor surface programmed death-ligand 1 (PD-L1) is expressed in some metastatic EGFR-mutated lung adenocarcinoma, but its impact on the efficacy of EGFR-TKIs is unclear. We retrospectively investigated 117 untreated metastatic lung EGFR mutated adenocarcinoma patients with a PD-L1 immunohistochemistry test. The PD-L1 expression level was classified by tumor proportion scores (TPS). Forty-five patients had negative expression (TPS < 1%), 45 had a weak expression (TPS 1–49%), and 27 had a strong expression (≥50%). All patients recruited in this study received EGFR-TKIs as a first-line therapy. No significant differences were observed for objective response rates (68.9% versus 62.2% versus 73.1%, p = 0.807) and median time to treatment failure (TTF) (12.17 versus 13.17 versus 11.0 months, p = 0.443) of first-line EGFR-TKIS among the three groups of patients (negative versus weak versus strong). The median overall survival was 21.27 versus 20.63 versus 19.43 months among the three groups of patients (p = 0.77). Our results demonstrated that PD-L1 did not affect the efficacy of first-line EGFR-TKIs in metastatic EGFR mutated lung adenocarcinoma. Thus, EGFR-TKIs are suggested as the preferred clinical therapy for these patients, despite their PD-L1 levels.

Status of Programmed Death Ligand 1 (PD-L1) by Immunohistochemistry and Scoring Algorithms.

The detection of the Programmed Death Ligand 1 (PD-L1) protein by immunohistochemistry is currently the only approved test predictive of response to drugs targeting the PD1/PDL1 axis. The role of this test is debated since several reagents have been used as companion diagnostics for different drugs on diverse immunostaining platforms. In addition, different scoring systems for PD-L1 immunohistochemistry have been applied in the registration studies regarding single drugs. This review deals with the various issues that are related to the immunohistochemical test for PD-L1. We discuss currently unsolved problems such as the advantages and the flaws of PD-L1 immunohistochemistry; the choice of the best reagents and the best scoring system. Finally, we review the current experiences on the role of immunohistochemistry for PD-L1 in clinical trials with immune checkpoint inhibitors.

PD-L1 Testing in Gastric Cancer by the Combined Positive Score of the 22C3 PharmDx and SP263 Assay with Clinically Relevant Cut-offs.

PurposeWe provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients.Materials and MethodsThe PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists.ResultsThe two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability.ConclusionTwo assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

Distribution and Expression of Programmed Death Ligand -1 (PD-L1) in Non-Small Cell Carcinomas of the Lung in a Tertiary Care Centre in South India.

Non-small cell lung carcinomas often present at an advanced stage with a grim prognosis. Immune checkpoint (ICP) inhibitors have drastically changed the scenario, and the response to ICP inhibitors is determined by analyzing the expression of PD-L1 by immunohistochemistry. PD-L1 immunohistochemistry helps in optimizing the treatment, and avoiding unnecessary exposure of patients to the toxic effects of the drugs that are ineffective and expensive in non-expressing tumors. This study was conducted to assess the prevalence of the expression of PD-L1 in non-small cell carcinomas of the lung diagnosed at our institution, which is a tertiary care center in South India. The PD-L1 immunohistochemistry of 77 cases of non-small cell carcinomas of the lung diagnosed over a period of two years were reviewed and analyzed (2018-2020). All tissues were fixed in 10% neutral buffered formalin and processed by standard methods, and the Ventana SP263 clone was used. Seventy-seven cases of non-small cell lung carcinomas were reviewed and studied for (PD-L1) expression. 35/77 (45%) of the cases had PD-L1 expression (≥ 1%) and 14 (18 %) had high (PD-L1) expression. Also there was a male preponderance of 2.3:1. High PD-L1 expression was seen mostly in patients above 60 years of age and was usually associated with high tumor grade. It is important to assess PD-L1 expression in non-small cell carcinomas of patients especially with higher tumor grade and older age groups that they may benefit from immune checkpoint inhibitor therapy.

Diabetes mellitus type 2 is associated with increased tumor expression of programmed death-ligand 1 (PD-L1) in surgically resected non-small cell lung cancer—A matched case-control study

ObjectivesProgrammed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics. MethodsA matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID: 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0: no staining; TPS1: <1%; TPS2: 1–49%; TPS3: ≥50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model. ResultsDiabetics (n=40) and nondiabetics (n=39) showed no differences in age, gender, cancer stage, and follow-up. NSCLCs were more likely PD-L1 positive in diabetics but with tumor positivity <50% (TPS0: 7.5 vs. 20.5%, TPS1: 35 vs. 25.6%, TPS2: 45 vs.23.1%, TPS3: 12.5 vs. 30.8%, respectively; P<0.05). In diabetics, squamous cell carcinomas (SCC) and adenocarcinomas were mainly TPS2 (65% vs. 20%) and TPS1 (50% vs. 26%), respectively. Peritumoral inflammation correlated with TPS (r=0.228), a relationship accentuated in diabetics (r=0.377, P<0.05) but diminished and non-significant in nondiabetics (r=0.136, P≥0.05). This association was stronger in SCC (r=0.424). Diabetes was associated with increased tumor recurrence (HR: 3.08; 95%CI: 1.027-9.23). ConclusionDiabetes is associated with an increase in peritumoral inflammation, PD-L1 positivity, and recurrence in NSCLC, more pronounced in SCC, suggesting the possibility of metabolic reprogramming and upregulation of PD-L1 by inducible pathways.

Reliability of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) on cytological smears in advanced non-small cell lung cancer: a prospective validation study.

Introduction:Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assessment is mandatory for the single agent pembrolizumab treatment of patients with advanced non-small cell lung cancer (NSCLC). PD-L1 testing has been validated and is currently certified only on formalin-fixed paraffin-embedded materials but not on cytological smears. Unfortunately, a significant proportion of patients, having only cytological material available, cannot be tested for PD-L1 and treated with pembrolizumab. In this study, we aimed to validate PD-L1 IHC on cytological smears prospectively by comparing clone SP263 staining in 150 paired histological samples and cytological smears of NSCLC patients.Methods:We prospectively enrolled 150 consecutive advanced NSCLC patients. The clone SP263 was selected as, in a previous study of our group, it showed higher accuracy compared with clones 28-8 and 22-C3, with good cyto-histological agreement using a cut-off of 50%. For cyto-histological concordance, we calculated the kappa coefficient using two different cut-offs according to the percentage of PD-L1 positive neoplastic cells (<1%, 1–49% and ⩾50%; <50%, ⩾50%).Results:The overall agreement between histological samples and cytological smears was moderate (kappa = 0.537). However, when the cyto-histological concordance was calculated using the cut-off of 50%, the agreement was good (kappa = 0.740). With the same cut-off, and assuming as gold-standard the results on formalin-fixed paraffin-embedded materials, PD-L1 evaluation on smears showed specificity and negative predictive values of 98.1% and 93.9%, respectively.Conclusion:Cytological smears can be used in routine clinical practice for PD-L1 assessment with a cut-off of 50%, expanding the potential pool of NSCLC patients as candidates for first-line single agent pembrolizumab therapy.

PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee.

The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.

Multicentre study on the consistency of PD-L1 immunohistochemistry as predictive test for immunotherapy in non-small cell lung cancer

AimsInvestigate the impact of interlaboratory- and interobserver variability of immunohistochemistry on the assessment of programmed death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC).MethodsTwo tissue microarrays (TMAs) were constructed...

A community‐based lung cancer rapid tissue donation protocol provides high‐quality drug‐resistant specimens for proteogenomic analyses

BackgroundFor the advancement of cancer research, the collection of tissue specimens from drug‐resistant tumors after targeted therapy is crucial. Although patients with lung cancer are often provided targeted therapy, post‐therapy specimens are not routinely collected due to the risks of collection, limiting the study of targeted therapy resistance mechanisms. Posthumous rapid tissue donation (RTD) is an expedient collection process that provides an opportunity to understand treatment‐resistant lung cancers.MethodsConsent to participate in the thoracic RTD protocol was obtained during patient care. When death occurred, tumor and paired non‐tumor, cytology, and blood specimens were collected within 48 hours and preserved as formalin‐fixed and frozen specimens. Tissue sections were evaluated with hematoxylin and eosin staining and immunohistochemistry (IHC) against multiple biomarkers, including various programmed death ligand 1 (PD‐L1) clones. Next‐generation sequencing was performed on 13 specimens from 5 patients.ResultsPostmortem specimens (N = 180) were well preserved from 9 patients with lung cancer. PD‐L1 IHC revealed heterogeneity within and between tumors. An AGK‐BRAF fusion was newly identified in tumor from a donor with a known echinoderm microtubule‐associated protein‐like 4 to anaplastic lymphoma kinase (EML4‐ALK) fusion and history of anaplastic lymphoma kinase (ALK) inhibitor therapy. RNA expression analysis revealed a clonal genetic origin of metastatic cancer cells.ConclusionsPost‐therapy specimens demonstrated PD‐L1 heterogeneity and an acyl glycerol kinase to B‐rapidly accelerated fibrosarcoma (AGK‐BRAF) fusion in a patient with an EML4‐ALK–positive lung adenocarcinoma as a potential resistance mechanism to ALK inhibitor therapy. Rapid tissue donation collection of postmortem tissue from lung cancer patients is a novel approach to cancer research that enables studies of molecular evolution and drug resistance.

Clinicopathologic Significance and Immunogenomic Analysis of Programmed Death-Ligand 1 (PD-L1) and Programmed Death 1 (PD-1) Expression in Thymic Epithelial Tumors.

Objectives: Thymic epithelial tumors (TETs) are rare malignant tumors that exhibit heterogeneous histology and clinical behavior. As immune check point inhibitors, drugs targeting anti-programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown remarkable results against many cancers; thus, the importance of PD-1/PD-L1 immunohistochemistry as a predictive or prognostic biomarker has grown. However, limited data on PD-L1 and PD-1 expression in TETs have been reported; moreover, these results have been variable. Here, we examined the expression of PD-1/PD-L1 proteins in TETs and analyzed the clinicopathologic significance of this expression.Patients and Methods: A tissue microarray was constructed using 368 samples of TETs, each in triplicate. Immunohistochemistry for PD-L1 (SP263 assay) and PD-1 in TETs and CD8 in thymic carcinoma (TC) was performed; next, correlations with clinicopathologic characteristics were analyzed. PD-L1high was designated as ≥50% of tumor proportion score; PD-1high and CD8high were defined as ≥5% and 1% of tumoral immune cells, respectively.Results: The cohort consisted of 308 patients with thymomas and 60 patients with TC. PD-L1 positivity was identified in 90.6% (328/362, ≥1%) of TETs, PD-1 expression of intra-/peritumoral T cells was identified in 53.6% (194/362) of TETs and CD8 positivity was identified in 11% (7/60, ≥1%) of TC. Of the 362 patients, 141 (39.0%) exhibited high PD-L1 expression (PD-L1high). The PD-L1high thymoma group was correlated with high Masaoka-Koga stage (p < 0.001), type B3 histology (p < 0.001), and myasthenia gravis (p < 0.001). This group exhibited poor overall survival (OS, p = 0.003, log-rank) and worse disease-free survival (DFS, p = 0.042, log-rank). No survival differences were detected between PD-L1high and PD-L1low groups in TC. Additionally, there was no correlation between PD-1 expression and survival in patients with TETs. Multivariate analysis revealed that PD-L1high expression was an independent poor prognostic factor (p = 0.047, HR 2.087, 95% CI, 1.009–4.318) in thymomas.Conclusions: To our knowledge, this is the largest study on TETs published in English literature. This study provides useful information regarding the prognosis of and potential therapeutic options for patients with TETs.

929P - Biomarker analyses of ramucirumab in patients with platinum refractory urothelial cancer from RANGE, a global, randomized, double-blind, phase III study

BackgroundRANGE previously reported positive progression-free survival1 and a trend towards improved overall survival (OS)2 in ramucirumab (RAM) treated patients. Exploratory biomarker analysis of efficacy by programmed death-ligand 1 (PD-L1) expression revealed a hazard ratio (HR) for OS of 0.519, p=0.0048 in patients with a PD-L1 combined positive score (CPS)≥10 compared to HR of 0.999, p=0.9955 in patients with a PD-L1 CPS<10. We aim to understand prognostic and predictive factors related to survival outcomes in RANGE, and to identify patients who may benefit from RAM therapy using PD-L1 immunohistochemistry and gene expression analysis, defining molecular subtypes, and tumour microenvironment signatures. MethodsArchival tumour specimens that met assay stability requirements (238/530 ITT patients in RANGE) were analyzed with the 22C3 PD-L1 antibody with CPS based on tumour cell (TC) and immune cell (IC) staining. RNA expression analysis on archival tumour tissue (394/530 ITT patients) was done by GenomeDx (RNA microarray)3. PD-L1 groups, urothelial carcinoma molecular subtypes, and immune4 and stromal phenotypes5 were determined and analyzed for association with OS outcome. ResultsOverall, RAM had the greatest improvement in OS in patients with TC≥1, IC≥4 or CPS≥10 PD-L1 status. OS was also more improved in patients with basal subtypes, with considerable overlap noted between basal subtypes and TC≥1, IC≥4, or CPS ≥10 PD-L1 status. In the subgroup with both basal/basal claudin-low subtype and CPS≥10 PD-L1 status, median OS was 9.2 months with RAM and 6.0 months with placebo (stratified hazard ratio 0.47; 95% confidence interval: 0.27-0.84, p=0.01, n=79). ConclusionsOur analysis suggested significant improvement in OS in RAM treated patients with platinum refractory urothelial carcinoma, and with both basal subtype and positive PD-L1 status.

Correlation between the Expression of PD-L1 and Clinicopathological Parameters in Triple Negative Breast Cancer Patients.

Triple-negative breast cancer (TNBC) is a heterogenous group of tumors with no estrogen receptor (ER), progesterone receptor (PR) and Cerb-B2/HER2 expression. Programmed death ligand-1 (PD-L1) is a transmembrane protein located on both non-tumor and tumor cells and it has been shown to be associated with the escape of tumor cells from the immune system. PD-L1-targeted therapy alone or in combination is now an alternative strategy in several aggressive tumor types. In this respect, TNBC is a potential candidate having limited treatment options and poor outcome. Sixty-one breast cancers with no expression of ER, PR and Cerb-B2/HER2 were chosen to study PD-L1 immunohistochemistry. PD-L1 staining and its correlation with main clinicopathological parameters were evaluated. The percentage of PD-L1 positivity was 37.7% and 47.5% in tumor and tumor microenvironment, respectively. The positivity rate was higher in breast carcinomas with medullary features (83.3%) and metaplastic carcinoma (66.6%) subgroups. PD-L1 expression of tumors was positively correlated with their Ki-67 score and PD-L1 positivity of the tumor microenvironment. No significant relationship was found between the other variables. PD-L1 expression rate was remarkable both in the tumor and the tumor microenvironment of TNBCs. Larger cohorts of TNBC are required to further describe their PD-L1 expression characteristics and help standardize PD-L1 immunohistochemistry assays in these tumors.

1714P - PD-L1 expression as a potential therapeutic target and prognostic biomarker in well-differentiated and dedifferentiated liposarcoma

BackgroundFor liposarcoma (LPS), the mainstay of treatment is still surgical resection. Recently, some researchers suggested that immune checkpoint inhibitor may have a clinical activity in well-differentiated (WD) and dedifferentiated (DD) LPS. We aimed to evaluate the expression level of programmed death ligand 1 (PD-L1) and determine its relationship with clinical outcomes in WD/DD LPS. MethodsAll patients diagnosed with WD/DD LPS at Asan medical center from 1989 to 2017 were identified and their clinical information were obtained from our medical database. PD-L1 testing was performed with previously-collected surgery or biopsy tissue by Immunohistochemistry (IHC). ResultsTotal 152 patients who were pathologically diagnosed with WD (n=74) or DD (n=78) LPS and had available tissue for PD-L1 IHC assay were included in this retrospective analysis. The median age was 58 years (range, 19—87) with males comprising 59.2%. By primary site, abdomen-pelvis (69.7%) was most frequently involved. Most patients (98.7%, n=150) were presented with localized disease at the time of diagnosis and every patient with localized disease except one with high-perioperative risk (n=149) underwent curative-intent surgical resection. PD-L1 positive (tumor proportion score ≥1%) rate was 31.1% and 51.3% in WD and DD LPS, respectively. In WD LPS, PD-L1 positivity, as well as abdomen-pelvis origin, R1/2 resection, and no adjuvant radiotherapy, was associated with shorter recurrence-free survival (RFS) (vs. PD-L1 negativity, 31.3 vs. 99.8 months; P=0.014) and remained significant in the multivariate analysis (HR, 2.7, P=0.028). In DD LPS, on the other hand, PD-L1 expression had no statistical significance in multivariate model for RFS. Overall survival was not properly compared due to the small number of death events. ConclusionsOur findings indicate that decent portion of WD/DD LPS patients were positive for PD-L1 expression, and it might be a negative prognostic biomarker in surgically-resected WD LPS. This provides a rationale for future clinical trials of immune checkpoint inhibitor for patients with PD-L1-positive WD/DD LPS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

359P - Reproducibility and concordance of 4 clinically developed programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays in triple negative breast cancer (TNBC)

359P - Reproducibility and concordance of 4 clinically developed programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays in triple negative breast cancer (TNBC)