Dataset Information

Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization.

ABSTRACT: Targeting of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis with checkpoint inhibitors has changed clinical practice in non-small cell lung cancer (NSCLC). However, clinical assessment remains complex and ambiguous. We aim to assess whether digital image analysis (DIA) and multiplex immunofluorescence can improve the accuracy of PD-L1 diagnostic testing. A clinical cohort of routine NSCLC patients reflex tested for PD-L1 (SP263) immunohistochemistry (IHC), was assessed using DIA. Samples of varying assessment difficulty were assessed by multiplex immunofluorescence. Sensitivity, specificity, and concordance was evaluated between manual diagnostic evaluation and DIA for chromogenic and multiplex IHC. PD-L1 expression by DIA showed significant concordance (R² = 0.8248) to manual assessment. Sensitivity and specificity was 86.8% and 91.4%, respectively. Evaluation of DIA scores revealed 96.8% concordance to manual assessment. Multiplexing enabled PD-L1+/CD68+ macrophages to be readily identified within PD-L1+/cytokeratin+ or PD-L1-/cytokeratin+ tumor nests. Assessment of multiplex vs. chromogenic IHC had a sensitivity and specificity of 97.8% and 91.8%, respectively. Deployment of DIA for PD-L1 diagnostic assessment is an accurate process of case triage. Multiplex immunofluorescence provided higher confidence in PD-L1 assessment and could be offered for challenging cases by centers with appropriate expertise and specialist equipment.

SUBMITTER: Humphries MP

PROVIDER: S-EPMC7281311 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization.

Humphries Matthew P MP Bingham Victoria V Abdullahi Sidi Fatima F Craig Stephanie G SG McQuaid Stephen S James Jacqueline J Salto-Tellez Manuel M

Cancers 20200429 5

Targeting of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis with checkpoint inhibitors has changed clinical practice in non-small cell lung cancer (NSCLC). However, clinical assessment remains complex and ambiguous. We aim to assess whether digital image analysis (DIA) and multiplex immunofluorescence can improve the accuracy of PD-L1 diagnostic testing. A clinical cohort of routine NSCLC patients reflex tested for PD-L1 (SP263) immunohistochemistry (IHC), was as ...[more]

PMID: 32365629

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Project description:Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.

Project description:Tumor programmed cell death ligand-1 (PD-L1) expression is a key biomarker to identify patients with non-small cell lung cancer who may have an enhanced response to anti-programmed cell death-1 (PD-1)/PD-L1 treatment. Such treatments are used in conjunction with PD-L1 diagnostic immunohistochemistry assays. We developed a computer-aided automated image analysis with customized PD-L1 scoring algorithm that was evaluated via correlation with manual pathologist scores and used to determine comparability across PD-L1 immunohistochemistry assays. The image analysis scoring algorithm was developed to quantify the percentage of PD-L1 positive tumor cells on scans of whole-slide images of archival tumor samples from commercially available non-small cell lung cancer cases, stained with four immunohistochemistry PD-L1 assays (Ventana SP263 and SP142 and Dako 22C3 and 28-8). The scans were co-registered and tumor and exclusion annotations aligned to ensure that analysis of each case was restricted to comparable tissue areas. Reference pathologist scores were available from previous studies. F1, a statistical measure of precision and recall, and overall percentage agreement scores were used to assess concordance between pathologist and image analysis scores and between immunohistochemistry assays. In total, 471 PD-L1-evalulable samples were amenable to image analysis scoring. Image analysis and pathologist scores were highly concordant, with F1 scores ranging from 0.8 to 0.9 across varying matched PD-L1 cutoffs. Based on F1 and overall percentage agreement scores (both manual and image analysis scoring), the Ventana SP263 and Dako 28-8 and 22C3 assays were concordant across a broad range of cutoffs; however, the Ventana SP142 assay showed very different characteristics. In summary, a novel automated image analysis scoring algorithm was developed that was highly correlated with pathologist scores. The algorithm permitted quantitative comparison of existing PD-L1 diagnostic assays, confirming previous findings that indicate a high concordance between the Ventana SP263 and Dako 22C3 and 28-8 PD-L1 immunohistochemistry assays.

Project description:Anti-PD-1/PD-L1 immunotherapy could offer an alternative to traditional chemo- and/or radiotherapy to treat pediatric cancer patients. To unveil the potential benefit of this new therapeutic approach, the prevalence of PD-L1 and other relevant immune markers using quantitative digital image analysis (DIA) could help to clarify this point. A bridging study was first conducted using commercially available normal formalin-fixed paraffin-embedded (FFPE) tonsils to compare immunostaining patterns and intensities from PD-L1, tumor infiltrating lymphocyte (TIL) markers CD3, CD8, FoxP3, CD45RO, and macrophage marker CD68 in adult (n = 5) and pediatric (n = 10) samples. Then, commercially available pediatric FFPE tumor samples from five prevalent pediatric solid tumor indications: ganglioneuroblastoma (n = 7); neuroblastoma (n = 23); nephroblastoma (n = 30); osteosarcoma (n = 24); and rhabdomyosarcoma (n = 25) were immunostained and their images (n = 654) digitally analyzed using predefined algorithms. The qualitative analysis of staining patterns and intensities in all 15 tonsils for all 6 biomarkers was similar regardless of age category. Quantitative DIA showed that PD-L1 values varied across cancer-types, nephroblastoma having the lowest counts. PD-L1 counts in ganglioneuroblastoma, our pediatric indication with the highest average value, was approximately 12-times lower than in a similar nonsmall cell lung cancer study, an indication approved for anti-PD-1/PD-L1 immunotherapies. Variable values were measured for the TIL markers CD3, CD8, and CD45RO. FoxP3 was scant across all indications. The macrophage marker CD68 showed highest values in ganglioneuroblastoma, with lowest levels in nephroblastoma. In conclusion, the low PD-L1 levels uncorrelated with TIL values from the present biomarker morphological study suggest that a PD-L1 immunohistochemistry patient selection strategy used for anti-PD-1/PD-L1 monotherapy in adult tumors may not succeed in these pediatric indications.

Dataset Information

Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization.

Publications

Improving the Diagnostic Accuracy of the PD-L1 Test with Image Analysis and Multiplex Hybridization.

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