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. 2021 Sep 29;13(19):4910.
doi: 10.3390/cancers13194910.

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Mieke R Van Bockstal  1 , Maxine Cooks  2 , Iris Nederlof  3 , Mariël Brinkhuis  4 , Annemiek Dutman  5 , Monique Koopmans  6 , Loes Kooreman  7 , Bert van der Vegt  8 , Leon Verhoog  9 , Celine Vreuls  10 , Pieter Westenend  11 , Marleen Kok  3 , Paul J van Diest  10 , Inne Nauwelaers  12 , Nele Laudus  12 , Carsten Denkert  13 , David Rimm  14 , Kalliopi P Siziopikou  15 , Scott Ely  16 , Dimitrios Zardavas  17 , Mustimbo Roberts  16 , Giuseppe Floris  18   19 , Johan Hartman  20   21 , Balazs Acs  20   21 , Dieter Peeters  22   23 , John M S Bartlett  24   25   26 , Els Dequeker  12 , Roberto Salgado  27   28 , Fabiola Giudici  29 , Stefan Michiels  29   30 , Hugo Horlings  31 , Carolien H M van Deurzen  32
Affiliations

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Mieke R Van Bockstal et al. Cancers (Basel). .

Abstract

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive vs. negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs.

Keywords: PD-L1; SP142; TILs; TNBC; atezolizumab; distant metastasis; immune cells; interobserver variability; triple-negative breast cancer; tumor-infiltrating lymphocytes.

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Conflict of interest statement

J.M.S.B. received research funding from Thermo Fisher Scientific, Genoptix, Agendia, Nanostring Technologies Inc., Stratifyer GmbH and Biotheranostics Inc., as well as honoraria from NanoString Technologies Inc., Oncology Education, Biotheranostics Inc., and MedcomXchange Communications Inc. M.K. (Marleen Kok) received institutional funding from AZ, BMS, and Roche. M.K. (Marleen Kok) is an advisory board member of BMS, Daiichi, MSD, and Roche. C.H.M.v.D. received funding for this study from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Box-and-whisker plot, illustrating the PD-L1/SP142 scores of ten pathologists per proficiency test (PT) case. The range between the 25th and 75th percentiles is 0 for PD-L1-negative TNBCs and increases substantially for PD-L1-positive cases. Circles represent outliers; asterisks represent extremes. The thick line within each box is the 50th percentile (i.e., median, * outliers, ° extremes).
Figure 2
Figure 2
Photomicrographs (original magnification: 100×) of a TNBC in the proficiency set with low TILs (A) and no PD-L1/SP142-positive immune cells (B). The stroma of another TNBC shows high TILs levels (C) with several PD-L1/SP142-positive immune cells (D).
Figure 3
Figure 3
Scatter plot, illustrating the median PD-L1/SP142 score based upon the assessment by ten pathologists in relation to the consensus PD-L1 score in the proficiency test. Correlation is high (Spearman’s Rho = 0.956; p < 0.001).
Figure 4
Figure 4
Box-and-whisker plot illustrating the median TILs scores Px for the PD-L1-negative and PD-L1-positive subgroups in this study cohort of 49 TNBC metastases. PD-L1-positive TNBC metastases have significantly higher TILs levels (p = 0.004). Circles represent outliers; asterisks represent extremes, * outliers, ° extremes.
Figure 5
Figure 5
Box-and-whisker plot illustrating the median TILs scores Px per localization of the metastases in the study set. Although there is a trend towards higher TILs levels in lymph node metastases, there was no statistically significant association between both parameters (p = 0.136). Circles represent outliers; asterisks represent extremes. Bold lines within each box are the median P50. Skin and soft tissue metastases: n = 15. Brain metastases: n = 12. Lymph node metastases: n = 9. Metastases of other locations: n = 13 (including liver, bowel, kidney, and lung metastases), * outliers, ° extremes.
Figure 6
Figure 6
Line diagram showing the evolution between the agreement of the PD-L1 score of each pathologist with the median Px PD-L1 score in the proficiency set and the study set. The PD-L1 assessment of most pathologists showed a similar degree of agreement, except for P2 (higher agreement in the study set) and P5 (higher agreement in the proficiency set).
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