Reproducibility of PD-L1 assessment in non-small cell lung cancer—know your limits but never stop trying to exceed them

Ilié, Marius; Hofman, Paul

doi:10.21037/tlcr.2017.10.13

Cited by 14 publications

(10 citation statements)

References 23 publications

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“…The concordance of PD-L1 measurements with other routinely used techniques, such as quantitative immunofluorescence (QIF), was high, with coefficients > 0.9 while providing the additional benefit of high reproducibility that was independent of the slide storage time [ 89 ]. Existing commercial PD-L1 IHC assays are semi-quantitative and require scoring by trained pathologists, which may introduce error due to inter-observer variability [ 92 , 93 ]. DSP might thus be used as a companion diagnostic tool that provides standardized, quantitative, and objective assessments of PD-L1 protein expression within spatially defined compartments in the tumour microenvironment.…”

Section: Digital Spatial Profilingmentioning

confidence: 99%

Transcriptional Spatial Profiling of Cancer Tissues in the Era of Immunotherapy: The Potential and Promise

Nerurkar

Goh

Cheung

et al. 2020

Cancers

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Intratumoral heterogeneity poses a major challenge to making an accurate diagnosis and establishing personalized treatment strategies for cancer patients. Moreover, this heterogeneity might underlie treatment resistance, disease progression, and cancer relapse. For example, while immunotherapies can confer a high success rate, selective pressures coupled with dynamic evolution within a tumour can drive the emergence of drug-resistant clones that allow tumours to persist in certain patients. To improve immunotherapy efficacy, researchers have used transcriptional spatial profiling techniques to identify and subsequently block the source of tumour heterogeneity. In this review, we describe and assess the different technologies available for such profiling within a cancer tissue. We first outline two well-known approaches, in situ hybridization and digital spatial profiling. Then, we highlight the features of an emerging technology known as Visium Spatial Gene Expression Solution. Visium generates quantitative gene expression data and maps them to the tissue architecture. By retaining spatial information, we are well positioned to identify novel biomarkers and perform computational analyses that might inform on novel combinatorial immunotherapies.

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Section: Digital Spatial Profilingmentioning

confidence: 99%

Transcriptional Spatial Profiling of Cancer Tissues in the Era of Immunotherapy: The Potential and Promise

Nerurkar

Goh

Cheung

et al. 2020

Cancers

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“…In summary, we show good concordance of PD-L1 22C3 IHC pharmDx TM results between cytology and site-matched resection specimens, and a negligible impact of CF on the performance of this assay compared to direct formalin fixation. We used digital image analysis as previously advocated for by others [29] to substantiate our results. Future research requires the assessment of clinical benefit derived from PD-L1/PD-1 inhibition after PD-L1 IHC performed with cytology specimens (i.e., clinical validation).…”

Section: Discussionmentioning

confidence: 98%

“…Disagreement found with a substantial proportion of CB cases from the 1–49% group in our cohort, which were negative (TPS <1%) upon evaluation of the LTR specimen, points to the difficulty of differentiating rare genuinely PD-L1-reactive tumor cells from mimics (e.g., macrophages or degenerated/necrotic cells) in a context where architectural information is diminished. Practical day-to-day experience and prior literature support that, especially in cases where tumor cell PD-L1 expression is low and strong membranous reactivity is present in tumor-infiltrating immune cells, false-positive results may occur [29]. The evaluation of additional markers on adjacent sections (e.g., p40 and TTF1) or as double stain on the same slide, while not a universal remedy and not tested as part of this study, can serve to mitigate the problem in these instances.…”

Section: Discussionmentioning

confidence: 99%

Implementation of PD-L1 22C3 IHC pharmDx<sup>TM</sup> in Cell Block Preparations of Lung Cancer: Concordance with Surgical Resections and Technical Validation of CytoLyt® Prefixation

Lou

Kinoshita

et al. 2020

Acta Cytologica

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Background: Programmed death ligand-1 (PD-L1) assessed by immunohistochemistry (IHC) is used as biomarker for pembrolizumab therapy in advanced stage lung cancer patients. However, data permitting direct performance comparison between cytology and surgical specimen types are limited since both specimens from a single tumor site are infrequently available. In addition, alcohol fixation used with cytology specimens requires technical validation of the PD-L1 IHC assay before clinical use. We here report our experience with implementation of the PD-L1 22C3 IHC pharmDxTM assay for cytologic samples at a large tertiary cancer center. Study Design: Archival formalin-fixed (FF), paraffin-embedded cell blocks (CBs) and subsequent lung tumor resections (LTRs) from the same anatomical site were used for a direct comparison of PD-L1 tumor proportion scores (TPSs). TPS values were independently determined by one surgical lung pathologist and two cytopathologists blinded to the specimen pairs. An interim analysis was performed to facilitate the pooling of expertise among observers. After PD-L1 22C3 IHC pharmDxTM implementation for FF cytology specimens, dual-processed samples were used for a prospective technical validation of CytoLyt® prefixation (CF). Digital image analysis was performed for a subset of dual-processed specimens. Results: Eighty-one CBs and LTRs were included for comparison of the specimen types. PD-L1 assessment in CBs had an accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 88.9/72.8, 66.7/73.5, 95.2/72.3, 80.0/65.8, and 90.9/79.1% for the ≥50/≥1% cutoff, respectively. The intraclass correlation coefficient was 0.84 (95% confidence interval [CI]: 0.76, 0.90), and it improved after interim analysis (before: 0.79 and after: 0.92). The overall concordance between CF and FF for the categories defined by the ≥50/≥1% cutoff values was 90.4% (95% CI: 79.0, 96.8). Similar assay performance was confirmed by digital analysis. Conclusions: PD-L1 22C3 IHC pharmDxTM shows good reliability if used with CB preparations. CF does not impact assay results significantly. Clinical validation with outcome data is needed, and digital methods of assessment should be further investigated.

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“…Pathologist assessment of tissues is done primarily by visual inspection and includes review of the tissue morphology, and positivity of one or two proteins, or of two to three genes targeting DNA or RNA molecules. Its application to assessments of expression in cellular subgroups is also inconsistent because it relies solely on visual interpretation which may vary greatly between individuals ( Hirsch et al, 2017 ; Ilie and Hofman, 2017 ; Rimm et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Multiplex Immunofluorescence and Multispectral Imaging: Forming the Basis of a Clinical Test Platform for Immuno-Oncology

Hoyt

2021

Front. Mol. Biosci.

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As immuno-oncology (I/O) emerges as an effective approach in the fight against cancer, multispectral imaging of multiplex immunofluorescence (mIF) is maturing as an analytical platform. The timing is fortuitous. Due to health economic considerations surrounding the use of I/O, there is an urgent need for tests that accurately predict response to the growing list of available therapies. Multispectral mIF provides several advantages over other biomarker modalities by enabling deeper interrogation of the intricate biology within the tumor microenvironment, including detection of cell-to-cell spatial interactions that correlate with clinical outcomes. It also provides a practical path for generating reliable and reproducible results in a clinically suitable, high-throughput workflow. In this article, we (1) describe the principles behind multispectral mIF; (2) provide advice and recommendations on assay development and optimization and highlight characteristics of a well-performing assay; and (3) discuss the requirements for translating this approach into clinical practice.

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Reproducibility of PD-L1 assessment in non-small cell lung cancer—know your limits but never stop trying to exceed them

Cited by 14 publications

References 23 publications

Transcriptional Spatial Profiling of Cancer Tissues in the Era of Immunotherapy: The Potential and Promise

Transcriptional Spatial Profiling of Cancer Tissues in the Era of Immunotherapy: The Potential and Promise

Implementation of PD-L1 22C3 IHC pharmDx<sup>TM</sup> in Cell Block Preparations of Lung Cancer: Concordance with Surgical Resections and Technical Validation of CytoLyt® Prefixation

Multiplex Immunofluorescence and Multispectral Imaging: Forming the Basis of a Clinical Test Platform for Immuno-Oncology

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