scholarly journals 60 Use of the Combined Positive Score (CPS) with the companion diagnostic PD-L1 IHC 22C3 pharmDx provides precise evaluation of PD-L1 expression across multiple tumor indications and cutoffs

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A68-A68
Author(s):  
Francisco Ponce ◽  
Stephanie Hund ◽  
Lindsay Peltz ◽  
Chris La Placa ◽  
Monika Vilardo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Urothelial Carcinoma ◽  
Tissue Samples ◽  
Testing Conditions ◽  
Multiple Tumor ◽  
Precise Evaluation ◽  
Tumor Tissues ◽  
Positive Score ◽  
Combined Positive Score ◽  
Meta Analyses

BackgroundThe Combined Positive Score (CPS)1 algorithm includes tumor and immune cells for determination of Programed Death-Ligand 1 (PD-L1) protein expression in tumor tissues and has been analytically and clinically validated for use with PD-L1 IHC 22C3 pharmDx across multiple indications and cutoffs.2 PD-L1 22C3 IHC pharmDx is a qualitative immunohistochemical assay using anti-PD-L1, Clone 22C3 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues using Autostainer Link 48. PD-L1 IHC 22C3 pharmDx is FDA-approved as an aid in identifying patients for treatment with KEYTRUDA® for six tumor indications at clinically validated CPS diagnostic cutoffs2: gastric or gastroesophageal junction (GC/GEJ) adenocarcinoma (CPS ≥ 1), cervical cancer (CPS ≥ 1), urothelial carcinoma (CPS ≥ 10), head and neck squamous cell carcinoma (HNSCC) (CPS ≥ 1), esophageal squamous cell carcinoma (ESCC) (CPS ≥ 10)3, and triple-negative breast cancer (TNBC) (CPS ≥ 10).MethodsPrecision of PD-L1 IHC 22C3 pharmDx using CPS was assessed for all six indications at the corresponding clinically validated diagnostic cutoffs and at additional exploratory cutoffs under normal, day-to-day testing conditions. Precision testing included Combined Precision (inter-instrument/operator/run (day)), Intra-Run Repeatability, and Observer (inter-/intra-) Scoring Reproducibility studies. FFPE specimens were stained with PD-L1 IHC 22C3 pharmDx and scored using CPS as described in the package insert.2 Four CPS cutoffs were evaluated: CPS ≥ 1 (GC/GEJ, urothelial carcinoma, ESCC, cervical cancer, HNSCC, TNBC), CPS ≥ 10 (GC/GEJ, urothelial carcinoma, ESCC, TNBC), CPS ≥ 20 (HNSCC), and CPS ≥ 50 (HNSCC). Data were analyzed using negative percent agreement (NPA), positive percent agreement (PPA), and overall agreement (OA) with two-sided 95% percentile bootstrap confidence intervals (CIs) based on PD-L1 binary status at the applicable cutoff(s). For each study, data from each CPS cutoff-indication pair were individually analyzed. Meta-analyses were also performed by pooling data from all indications per (i) study and cutoff, and (ii) per study for all tested cutoffs.ResultsNearly all agreement analyses (142/144) for each CPS cutoff-indication pair showed NPA/PPA/OA point estimates (PE) ≥ 90% and CI lower bounds (CILB) ≥ 85%. Meta-analyses showed PE ≥ 90% for NPA/PPA/OA and CILB ≥ 85% per study and cutoff, and per study for all tested cutoffs. Discordant comparisons accounted for <5% of total comparisons performed for each study type.ConclusionsCPS used with PD-L1 IHC 22C3 pharmDx provides precise evaluation of PD-L1 expression across multiple tumor indications and cutoffs under normal, day-to-day testing conditions.AcknowledgementsWe thank the IUSCC Cancer Center at Indiana University School of Medicine, for the use of the Tissue Procurement and Distribution Core, which provided Dako North America, Inc. service.The data and biospecimens used in this project were provided by US Biolab (Gaithersburg, MD, USA), Sofia Bio LLC (New York, NY, USA), Contract Research Ltd (Charlestown, Nevis), and Centre Hospitalier Universitaire (CHU) de Nice (Nice, France) with appropriate ethics approval and through Trans-Hit Biomarkers Inc. Tissue samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Tissue samples supplied by BioIVT (Hicksville, NY, USA).Trial RegistrationN/AReferencesCPS = (# PD-L1 staining cells (tumor cells, lymphotcytes, macrophages))/(Total # viable tumor cells )×100PD-L1 IHC 22C3 pharmDx [Instructions for Use]. Available at: www.agilent.com/library/eifu. Code SK006. Accessed July 2, 2021ESCC was analytically validated as a subtype of esophageal cancer [2].Ethics ApprovalN/AConsentN/A

Genetic diversity of HPV in tissues of tumors of the reproductive organs in women.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17001-e17001
Author(s):  
Galina Andreevna Nerodo ◽  
Oleg Ivanovich Kit ◽  
Tatiana Zykova ◽  
Victoria A. Ivanova ◽  
Vera P. Nikitina ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Cervical Cancer ◽  
Vulvar Cancer ◽  
Uterine Cancer ◽  
Reproductive Organs ◽  
Cancer Tissue ◽  
Hpv 16 ◽  
Tissue Samples ◽  
Tumor Tissues ◽  
Cancer Tissues

e17001 Background: The purpose of the study was to determine the rate of various HPV genotypes detection in tissues of tumors of the female reproductive organs. Methods: FFPE and frozen tissue samples of cervical cancer (n=126), vulvar cancer (n=113) and uterine cancer (n=29) were studied. DNAs of HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 were determined by the Real-Time PCR. Results: HPV DNAs were found in 94.4% of samples of cervical cancer tissue, 65.5% - uterine cancer tissue and 28.3% - vulvar cancer tissue. HPV 16 and 18 were the most frequent (78.8%). HPV 16 in cervical cancer was detected in 60.9%, vulvar cancer – 59.0% and uterine cancer – 54.5%. On the contrary, HPV 18 was more frequent in uterine cancer (40.9%) and less frequent in cervical cancer (18.4%) and vulvar cancer (2.7%). Besides HPV 16 and 18, genotypes 31, 33, 35, 39, 45, 51, 52, 56 and 59 were found in tumor tissues as well (21.2% in total). HPV 35, 52 and 56 were the most frequently detected. Cervical cancer tissues showed the greatest genetic diversity of HPV and uterine cancer tissues – the lesser one (HPV 35 only, besides HPV 16 and 18). Combination of several HPV types was also more frequent in cervical cancer (37.0% of positive samples); in vulvar cancer – 18.8% and in uterine cancer – 15.8%. Conclusions: The results confirm HPV significance in carcinogenesis of cervical cancer, vulvar cancer and probably uterine cancer and show genetic diversity of HPV in different localizations of tumors of the female reproductive system.

scholarly journals Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1215
Author(s):  
Daisuke Takayanagi ◽  
Sou Hirose ◽  
Ikumi Kuno ◽  
Yuka Asami ◽  
Naoya Murakami ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Genetic Alterations ◽  
Specific Gene ◽  
Efficient Treatment ◽  
Hpv Status ◽  
Genetic Features ◽  
Positive Score ◽  
Combined Positive Score ◽  
Novel Therapeutic Strategies

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Pathologic validation of artificial intelligence-powered prediction of combined positive score of PD-L1 immunohistochemistry in urothelial carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16518-e16518
Author(s):  
Jeong Hwan Park ◽  
Kyu Sang Lee ◽  
Euno Choi ◽  
Wonkyung Jung ◽  
Jaehong Aum ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Tumor Cell ◽  
Urothelial Carcinoma ◽  
Tumor Cells ◽  
Validation Cohort ◽  
Checkpoint Inhibitors ◽  
Medical Center ◽  
External Validation ◽  
Positive Score ◽  
Combined Positive Score

e16518 Background: Programmed death ligand 1 (PD-L1) expression is a reliable biomarker of immune-checkpoint inhibitors (ICI) in multiple cancer types including urothelial carcinoma (UC). A 22C3 pharmDx immunohistochemistry was particularly determined by using the combined positive score (CPS) in UC. A challenging issue regarding the manual scoring of CPS by a pathologist is in determining the representative area to read. This requires substantial time and effort and may lead to inter-observer variation. We developed an artificial intelligence (AI)-powered CPS analyzer, to assess CPS in whole-slide images (WSI) and validated its performance by comparing against a consensus of pathologists’ readings. Methods: An AI-powered CPS analyzer, Lunit SCOPE PD-L1, has been trained and validated based on a total of 3,326,402 tumor cells, lymphocytes, and macrophages annotated by board-certified pathologists for PD-L1 positivity in 1200 WSI stained by 22C3. After excluding the in-house control tissue regions, the WSIs were divided into patches, from which a deep learning-based model was trained to detects the location and PD-L1 positivity of tumor cells, lymphocytes, and macrophages, respectively. Finally, the patch-level cell predictions were aggregated for CPS estimation. The performance of the model was validated on an external validation UC cohort consisting of two institutions: Boramae Medical Center (BMC, n = 93) and Seoul National University Bundang Hospital (SNUBH, n = 100). Three uropathologists independently annotated the CPS of the external validation cohorts, and a consensus of CPS was determined by determination of their mean values. Results: The AI-model predicts CPS accurately in an internal validation cohort as the area under the curves (AUC) values to predict PD-L1-positive tumor cell, PD-L1-positive lymphocytes or macrophages, PD-L1-negative tumor cell, and PD-L1-negative lymphocytes or macrophages were 0.929, 0.855, 0.885, and 0.872, respectively. There was a significant positive correlation between CPS by AI-model and consensus CPS by 3 pathologists in the external validation cohort (Spearman coefficient = 0.914, P < 0.001). Concordance of AI-model and pathologists' consensus to call CPS ≥ 10 was 88.1%, which was similar to that of either 2 of 3 pathologists (84.5%, 86.5%, and 90.7%). The concordance rate was not significantly different according to data source (BMC: 88.2% versus SNUBH: 88.0%, P = 1.00), but was significantly different according to type of surgery [surgical resection (cystectomy, nephrectomy, and ureterectomy): 92.3% versus transurethral resection: 81.3%, P = 0.0244]. Conclusions: Lunit SCOPE PD-L1, AI-powered CPS analyzer, can detect PD-L1 expression in tumor cells, lymphocytes or macrophages highly accurately compared to uropathologists.

scholarly journals Pan-tumour analysis of the association between PD-L1 combined positive score (CPS) and response to pembrolizumab monotherapy

Pathology ◽  
2021 ◽  
Vol 53 ◽  
pp. S48
Author(s):  
Lingkang Huang ◽  
Jared Lunceford ◽  
Junshui Ma ◽  
Kenneth Emancipator
Keyword(s):  
Positive Score ◽  
Combined Positive Score

282 Pan-tumor analysis of the association between PD-L1 combined positive score and response to pembrolizumab monotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A308-A308
Author(s):  
Lingkang Huang ◽  
Jared Lunceford ◽  
Junshui Ma ◽  
Kenneth Emancipator
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Roc Analysis ◽  
Standard Of Care ◽  
Tumor Type ◽  
Operating Characteristics ◽  
Positive Score ◽  
Combined Positive Score ◽  
Line Of Therapy ◽  
Tumor Types

BackgroundPD-L1 is expressed on both tumor and immune cells; however, the mechanism by which PD-L1 modulates the adaptive immune response on tumor versus immune cells may differ. Additionally, the prevalence of PD-L1 expression and the partitioning between tumor and immune compartments varies by tumor type. While PD-L1 expression on tumor or immune cells can be scored separately, the PD-L1 combined positive score (CPS) captures both tumor and immune cell expression in one aggregate score. We performed a retrospective, exploratory analysis of the effectiveness of CPS as an enrichment biomarker across several studies of pembrolizumab monotherapy in patients with multiple tumor types.MethodsPD-L1 expression was assessed using PD-L1 IHC 22C3 pharmDx. Expression was measured using CPS (defined as the number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of tumor cells, multiplied by 100) in tumor samples from single-arm (KEYNOTE-052 [UC], KEYNOTE-059 cohort 1 [G/GEJ], KEYNOTE-086 [TNBC], KEYNOTE-158 [cervical; SCLC], KEYNOTE-180 [EC], KEYNOTE-224 [HCC], KEYNOTE-427 [RCC]) and randomized (KEYNOTE-040 [HNSCC], KEYNOTE-045 [UC], KEYNOTE-061 [G/GEJ], KEYNOTE-119 [TNBC], KEYNOTE-240 [HCC]) pembrolizumab studies. Data were pooled across tumor types for pembrolizumab and for standard-of-care (in controlled studies), and then estimates of response rate, prevalence, and receiver operating characteristics (ROC) analysis were performed over various CPS cutpoints. CPS distribution by response, tumor type, and line of therapy were also assessed.ResultsThere were 3769 treated patients with available PD-L1 CPS (pembrolizumab, n=2678; standard-of-care, n=1091). The area under the ROC curve for ORR was 0.63 (95% CI, 0.61–0.66) for pembrolizumab and 0.48 (95% CI, 0.43–0.53) for standard-of-care when a positive association was evaluated between CPS and ORR (figure 1); individual cutpoints of 1, 10, 20, and 50 were examined (table 1). Figure 2 shows a boxplot of CPS distribution for response in pembrolizumab-treated patients.Abstract 282 Table 1Response Rates and Sensitivity at Individual CPS Cutpoints for Pembrolizumab-Treated PatientsAbstract 282 Figure 1ROC analysis of PD-L1 CPS for pembrolizumab versus standard-of-care therapyAbstract 282 Figure 2Boxplot of PD-L1 CPS distribution for responders versus nonresponders in pembrolizumab-treated patients by tumor type and line of therapy in order of descending median CPSConclusionsThis retrospective, exploratory pan-tumor analysis demonstrates that CPS is an effective scoring method for measuring PD-L1 expression and can be used as a predictive biomarker to identify patients likely to respond to pembrolizumab monotherapy. CPS demonstrated enrichment of response to pembrolizumab monotherapy across most, but not all, tumor types, including some tumor types for which efficacy favors pembrolizumab regardless of PD-L1 expression, and for which a companion diagnostic is therefore not needed. In the randomized studies, CPS did not show a consistent association with ORR for standard-of-care therapy.

scholarly journals PD-L1 Expression in Muscle Invasive Urothelial Carcinomas as Assessed via Immunohistochemistry: Correlations with Specific Clinical and Pathological Features, with Emphasis on Prognosis after Radical Cystectomy

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 404
Author(s):  
Ioan Alin Nechifor-Boilă ◽  
Andrada Loghin ◽  
Adela Nechifor-Boilă ◽  
Myriam Decaussin-Petrucci ◽  
Septimiu Voidăzan ◽  
...  
Keyword(s):  
Radical Cystectomy ◽  
Distant Metastases ◽  
Lymph Node Involvement ◽  
Histological Variant ◽  
Node Involvement ◽  
Positive Score ◽  
Checkpoint Inhibitor Therapy ◽  
N Stage ◽  
Combined Positive Score ◽  
Muscle Invasive

In the present study, we analyzed Programmed Death Ligand-1 (PD-L1) expression in radical cystectomy (RC) specimens from patients with muscle-invasive urothelial carcinoma (UC), in order to assess any correlations with specific clinicopathological features and its potential prognostic value. A multi-institutional study was performed within the departments of urology and pathology at the Mureș County Hospital, Romania, and Centre Hospitalier Lyon Sud, France. Sixty-nine patients with MIBC were included, for whom tumor histology (conventional versus histological variant/differentiation), tumor extension (T), lymph node involvement (N), and distant metastases (M) were recorded. PD-L1 immunostaining was performed using the 22C3 clone and was interpreted using the combined positive score (CPS) as recommended (Dako Agilent, Santa Clara, CA, USA). Positive PD-L1 immunostaining was more prevalent among UCs with squamous differentiation compared to conventional UCs and trended towards an improved OS (p = 0.366). We found the T stage to be a risk factor for poor survival in PD-L1-positive patients (HR 2.9, p = 0.021), along with the N stage in PD-L1-negative patients (HR 1.98, p = 0.007). No other clinicopathological factor was found to be significantly associated with PD-L1 positivity. Thus, we confirm the need for PD-L1 immunostaining prior to initiating immune checkpoint inhibitor therapy for a more accurate assessment of the patients’ chances of responding to treatment.

scholarly journals The Origin of Tumor DNA in Urine of Urogenital Cancer Patients: Local Shedding and Transrenal Excretion

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 535
Author(s):  
Anouk E. Hentschel ◽  
Rianne van den Helder ◽  
Nienke E. van Trommel ◽  
Annina P. van Splunter ◽  
Robert A. A. van Boerdonk ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Bladder Tumor ◽  
Great Promise ◽  
Tumor Tissues ◽  
Catheter Urine ◽  
Tumor Dna ◽  
Urogenital Cancers

In urogenital cancers, urine as a liquid biopsy for non-invasive cancer detection holds great promise for future clinical application. Their anatomical position allows for the local shedding of tumor DNA, but recent data indicate that tumor DNA in urine might also result from transrenal excretion. This study aims to assess the origin of tumor-associated DNA in the urine of 5 bladder and 25 cervical cancer patients. Besides natural voided urine, paired urine samples were collected in which contact with the local tumor was circumvented to bypass local shedding. The latter concerned nephrostomy urine in bladder cancer patients, and catheter urine in cervical cancer patients. Methylation levels of GHSR, SST, and ZIC1 were determined using paired bladder tumor tissues and cervical scrapes as a reference. Urinary methylation levels were compared to natural voided urine of matched controls. To support methylation results, mutation analysis was performed in urine and tissue samples of bladder cancer patients. Increased methylation levels were not only found in natural voided urine from bladder and cervical cancer patients, but also in the corresponding nephrostomy and catheter urine. DNA mutations detected in bladder tumor tissues were also detectable in all paired natural voided urine as well as in a subset of nephrostomy urine. These results provide the first evidence that the suitability of urine as a liquid biopsy for urogenital cancers relies both on the local shedding of tumor cells and cell fragments, as well as the transrenal excretion of tumor DNA into the urine.

scholarly journals RNA-sequencing identified miR-3681 as a negative regulator in the proliferation and migration of cervical cancer cells via the posttranscriptional suppression of HGFR

RSC Advances ◽  
2019 ◽  
Vol 9 (39) ◽  
pp. 22376-22383 ◽  
Author(s):  
Fan Shi ◽  
Yingbing Zhang ◽  
Juan Wang ◽  
Jin Su ◽  
Zi Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Rna Sequencing ◽  
Negative Regulator ◽  
Tumor Tissues ◽  
Differentially Expressed Mirnas ◽  
Cervical Cancer Cells ◽  
And Migration ◽  
Cancer Tissues ◽  
Proliferation And Migration

In this study, RNA-sequencing was used to investigate the differentially expressed miRNAs between cervical cancer tissues and matched adjacent non-tumor tissues.

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