Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma—A Large Multi-Institutional International Study

Abstract

The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen’s Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654–0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667–0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions.

Divergent Cellular Expression Patterns of PD-L1 and PD-L2 Proteins in Breast Cancer

“…Fortunately, studies on BC have shown relative concordance among assays, ranging from good to excellent [9,10]. However, pathologist interpretation is also subject to inter-and intra-observer variability, with concordance ranging from poor to excellent, depending on the setting [11,12]. More significant discordance and worse reproducibility were reported among low-expressing cases with PD-L1 around the cutoff of 1% [12], which is made more challenging when attempting to assess whether immune cells are in close enough proximity to the cancer cells to warrant inclusion in scoring.…”

“…However, pathologist interpretation is also subject to inter-and intra-observer variability, with concordance ranging from poor to excellent, depending on the setting [11,12]. More significant discordance and worse reproducibility were reported among low-expressing cases with PD-L1 around the cutoff of 1% [12], which is made more challenging when attempting to assess whether immune cells are in close enough proximity to the cancer cells to warrant inclusion in scoring. PD-L2 assessment may show similar susceptibility to interpretative differences, but a predictive scoring cutoff may prove less problematic to establish due to higher PD-L2 staining in cancer cells than in immune cells.…”

Reproducibility in PD-L1 Immunohistochemistry Quantification through the Tumor Proportion Score and the Combined Positive Score: Could Dual Immunostaining Help Pathologists?

“…These reproducibility studies are also very heterogeneous in terms of anti-PD-L1 IHC clones and platforms, the natures of cancers, the number of cases and pathologists, the use of physical glass slides or digital ones, the need for exact quantification of positive cells, or the use of semiquantitative scales and different statistical methods. Inter-and intra-observer reproducibility is reported with different agreements, from poor to excellent ones, but all the aforementioned methodological variations make the different studies difficult to compare [3][4][5][6][7][8][9][10][11][12][13][14][15].…”

“…Another potential issue in PD-L1 expression quantification could also be inter-and intra-pathologists' agreements in PD-L1 IHC quantification [3][4][5][6][7][8][9][10][11][12][13][14][15]. The evaluation of the reproducibility in assessing PD-L1 TPS and CPS using single PD-L1 IHC (S-IHC) but also using a more original dual IHC (D-IHC) method combining PD-L1 IHC with tumor nuclear marker IHC is the aim of the present study.…”

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

“…PD-L1 is the only biomarker approved for ICIs in TNBC, but there are many controversies surrounded its use in clinical practice. PD-L1 exhibits dynamic expression, heterogeneous distribution within the tumor area, and questionable reproducibility, particularly when borderline values are considered (114)(115)(116).…”