Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer

Humphries, Matthew P.; Hynes, Seán O.; Bingham, Victoria; Cougot, Delphine; James, Jacqueline; Patel-Socha, Farah; Parkes, Eileen E.; Blayney, Jaine K.; O’Rorke, Michael; Irwin, Gareth; McArt, Darragh G.; Kennedy, Richard D.; Mullan, Paul B.; McQuaid, Stephen; Salto-Tellez, Manuel; Buckley, Niamh E.

doi:10.1155/2018/2937012

Cited by 45 publications

(44 citation statements)

References 67 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this context, the adoption of digital pathology and software‐assisted methods may increase accuracy, reduce human error, and ultimately improve reproducibility of PD‐L1 assessment and interpretation . Recently, PD‐L1 expression measured by IHC and assessed by digital pathology platforms has been positively associated with outcome in two cohorts of patients with TN early BC treated with surgery and standard CT .…”

Section: Methodsmentioning

confidence: 99%

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

2019

View full text Add to dashboard Cite

In the light of recent advances in the immunotherapy field for breast cancer (BC) treatment, especially in the triple‐negative subtype, the identification of reliable biomarkers capable of improving patient selection is paramount, because only a portion of patients seem to derive benefit from this appealing treatment strategy. In this context, the role of programmed cell death ligand 1 (PD‐L1) as a potential prognostic and/or predictive biomarker has been intensively explored, with controversial results. The aim of the present review is to collect available evidence on the biological relevance and clinical utility of PD‐L1 expression in BC, with particular emphasis on technical aspects, prognostic implications, and predictive value of this promising biomarker. Implications for Practice In the light of the promising results coming from trials of immune checkpoint inhibitors for breast cancer treatment, the potential predictive and/or prognostic role of programmed cell death ligand 1 (PD‐L1) in breast cancer has gained increasing interest. This review provides clinicians with an overview of the available clinical evidence regarding PD‐L1 as a biomarker in breast cancer, focusing on both data with a possible direct impact on clinic and methodological pitfalls that need to be addressed in order to optimize PD‐L1 implementation as a clinically useful tool for breast cancer management.

show abstract

Section: Methodsmentioning

confidence: 99%

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

2019

View full text Add to dashboard Cite

show abstract

“…DIA of all DAB PD-L1 SP263 IHC stained cases was performed using the open source DIA program QuPath v0.1.2, developed at Queen's University Belfast [5,[17][18][19][20]. All IHC slides were scanned at 40× on an Aperio AT2 digital scanner (Leica Biosystems, Vista, CA, USA).…”

Section: Pd-l1 Ihc Image Analysismentioning

confidence: 99%

“…All IHC slides were scanned at 40× on an Aperio AT2 digital scanner (Leica Biosystems, Vista, CA, USA). A robust workflow and rigorous quality control steps were taken to remove unsuitable areas for analysis (e.g., necrosis, tissue folds, normal structures, and non-specific staining), this was confirmed by a second reviewer with frequent consultation, as described [5,[17][18][19][20]. Briefly, digital annotations were made, within which cell detection was conducted using default parameters within QuPath.…”

Section: Pd-l1 Ihc Image Analysismentioning

confidence: 99%

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

Humphries

Bingham

Sidi

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Anti-PD-L1 and anti-ErbB2 monoclonal antibody therapy in ErbB2 + mouse tumors PD-L1 is expressed in a wide range of cancer types and high PD-L1 expression is associated with improved clinical outcome in triple-negative breast cancers and Her2 + breast cancers likely as an indication of pre-existing immune responses triggering local adaptive resistance. 20,21 To understand the therapeutic potential of anti-PD-L1 antibody in Her2 + breast cancers, we tested PD-L1 expression on the rat ErbB2 + mouse TUBO cell line. Untreated TUBO cells did not express any significant level of PD-L1 expression ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy

et al. 2019

View full text Add to dashboard Cite

A significant proportion of human epidermal growth factor receptor 2 (Her2/ErbB2)-positive metastatic breast cancer patients are refractory to Her2-targeted trastuzumab-like therapy. Some of this resistance has been attributed to the upregulation of immune checkpoints such as programmed cell death-1 (PD-1) and its ligand, PD-L1 in Her2-positive breast cancer patients. Therefore, therapies targeting both the PD-1/PD-L1 interaction and oncogenic Her2 signaling are of significant clinical interest. Here, we constructed a mouse bispecific antibody targeting PD-L1 and rat Her2 (referred to as BsPD-L1xrErbB2) aiming to redirect the anti-PD-L1 response toward Her2-expressing tumor cells. BsPD-L1xrErbB2 demonstrated additive binding to interferon (IFN)-γ treated Her2 + TUBO tumor cells, but it did not affect the proliferation of tumor cells in-vitro. BsPD-L1xrErbB2 also blocked the PD-1/PD-L1 interaction. This bispecific antibody was constructed with a mouse IgG2a Fc backbone and interacted with Fcγ receptors and resulted in complement deposition (C3). ADCC and complement action could be potential mechanisms of action of this molecule. BsPD-L1xrErbB2 successfully reduced TUBO tumor growth and increased tumor rejection rate compared to the monovalent anti-PD-L1, monovalent anti-ErbB2 or the combination of anti-PD-L1 and anti-ErbB2 monotherapies. The enhanced anti-tumor effect of BsPD-L1xrErbB2 was dependent on CD8 + T lymphocytes and IFN-γ, as depletion of CD8 + T lymphocytes and neutralization of IFN-γ completely abolished the antitumor activity of the bispecific antibody. Consistently, BsPD-L1xrErbB2 treatment also increased the frequency of intratumor CD8 + T lymphocytes. Taken together, our data support a bispecific antibody approach to enhance the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade in Her2-positive metastatic breast cancers. ARTICLE HISTORY

show abstract

Automated Tumour Recognition and Digital Pathology Scoring Unravels New Role for PD-L1 in Predicting Good Outcome in ER-/HER2+ Breast Cancer

Cited by 45 publications

References 67 publications

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

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

Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy

Contact Info

Product

Resources

About