PD-L1 Expression as a Biomarker in Gastric Cancer: Comparison
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Please note this is a comparison between Version 1 by Moonsik Kim and Version 2 by Wendy Huang.

Despite advances in diagnostic imaging, surgical techniques, and systemic therapy, gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Unfortunately, molecular heterogeneity and, consequently, acquired resistance in GC are the major causes of failure in the development of biomarker-guided targeted therapies. However, by showing promising survival benefits in some studies, the recent emergence of immunotherapy in GC has had a significant impact on treatment-selectable procedures. Immune checkpoint inhibitors (ICIs), widely indicated in the treatment of several malignancies, target inhibitory receptors on T lymphocytes, including the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and release effector T-cells from negative feedback signals. 

  • PD-L1
  • gastric cancer
  • immunotherapy
  • biomarker
  • IHC
  • biopsy

1. Introduction

Despite advances in diagnostic imaging, surgical techniques, and systemic therapy, gastric cancer (GC) is one of the most common cancers, with a high mortality rate from cancer around the world [1][2]. Unfortunately, morphological and molecular heterogeneity and, consequently, acquired resistance in GC are the major causes of failure in the development of biomarker-guided targeted therapies [2][3]. However, by showing promising survival benefits in some studies, the recent emergence of immunotherapy in GC has had a significant impact on treatment-selectable procedures (Figure 1) [4][5][6][7][8]. To protect the host from external antigens and autoimmune reactions, the immune system is regulated via a number of receptor–ligand interactions [2][9][10]. Immune checkpoint inhibitors (ICIs), widely indicated in the treatment of several malignancies, target inhibitory receptors on T lymphocytes, including the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and release effector T-cells from negative feedback signals [2][10][11]. Currently, with limited samples, it is important to identify target biomarkers for predicting response to ICIs [12][13]. PD-L1 immunohistochemistry (IHC), microsatellite instability (MSI)/mismatch repair (MMR), Epstein–Barr virus (EBV), and tumor mutational burden (TMB) have been proposed as predictive biomarkers to predict response to ICIs in patients with GC [12][14].
Diagnostics 13 02782 g001
Figure 1. Timeline of major milestones for immunotherapy and U.S. Food and Drug Administration (FDA)-approved Immune checkpoint inhibitors in gastric cancers. MSI-H, microsatellite instability-high; MMR-D, mismatch repair deficiency; GEJ, gastroesophageal junction; PD-L1, programmed death ligand 1; CPS, combined positive score; TMB-H, tumor mutational burden-high; mut/Mb, mutations/megabase; GC, gastric cancer; GEJC, gastroesophageal junction cancer; HER-2, human epidermal growth factor receptor 2.

2. Rationale and Performance

Honjo’s group first discovered PD-1 in 1992 [11][15]. PD-1 is mainly expressed in activated cytotoxic T-cells and other immune cells [5][11][16]. It is a cell surface (or transmembrane) protein encoded by the CD274 gene [2][17]. The interaction of PD-1, expressed on cytotoxic T lymphocytes, with PD-L1 on antigen-presenting cells is one of the main mechanisms of immune modulation, thereby allowing T-cell inactivation and tumor immune evasion [2][10][16][18]. Tumor cells with mutable neoantigens are recognized as ‘non-self’ by the immune system and are selectively targeted and removed by inducing an immune response [10]. To avoid removal, tumor cells can upregulate PD-L1 and PD-L2 expression following exposure to interferon-γ and other signaling and cytokines [10][11][16][17][19]. Furthermore, PD-L1 expression is increased in some immune cells within the tumor microenvironment, including dendritic cells, macrophages, antigen-presenting cells, and T-cells [17][20]. By this principle, the blockade of PD-1/PD-L1 interaction by monoclonal antibodies against either PD-1 (pembrolizumab and nivolumab) or PD-L1 (durvalumab, atezolizumab, and avelumab) appears to be a logical therapeutic strategy, particularly for a highly antigenic solid tumor, including GC [10][21].
The phase 2 KEYNOTE-059 trial (NCT#02335411), which enrolled 259 patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma suggested the safety and effectiveness of pembrolizumab as a third-line treatment [4][11]. In this single-arm, multicohort trial, the objective response rate (ORR) was 11.6% (30 of 259 patients), and complete responses (CRs) were noted in 2.3% of patients (6 of 259); the median (range) response duration was 8.4 (1.6+–17.3+) months [4][11]. Among 259 patients, 148 (57.1%) with PD-L1-positive tumors (combined positive score [CPS] ≥1, evaluated using the PD-L1 22C3 pharmDx Kit) had ORRs and CRs of 15.5% (23 of 148) and 2.0% (3 of 148), respectively. The median response duration was 16.3 (1.6+–17.3+) months. Based on these results, pembrolizumab, in 2017, was granted accelerated Food and Drug Administration (FDA)-approval as a third-line therapy for patients with locally advanced or metastatic G/GEJ adenocarcinoma whose tumors express a CPS of ≥1 using the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay [2][18]. Notably, pembrolizumab was approved, along with a companion diagnostic test, the PD-L1 IHC 22C3 pharmDx assay, for use on the Dako Autostainer Link 48 platform [4][18]. However, after accelerating FDA approval, pembrolizumab failed to demonstrate significant survival improvements in the following phase 3 trials (KEYNOTE-061 [NCT#02370498; efficacy as a second-line therapy] and KEYNOTE-062 [NCT#02494583; efficacy as a first-line therapy]) in patients with advanced G/GEJ adenocarcinoma showing a PD-L1 CPS of ≥1 [5][6][11][18].
Another phase 3 CheckMate-649 trial (NCT#02872116), which enrolled 1581 patients with untreated, unresectable, Human Epidermal Growth Factor Receptor 2 (HER2)-negative G/GEJ, or esophageal adenocarcinoma, demonstrated the acceptable safety profile and efficacy of nivolumab as a first-line treatment [7][18]. The CheckMate-649 trial demonstrated significant improvements in the overall survival (OS) and progression-free survival (PFS) for patients with a CPS of ≥5 (955 of 1581; 60.4%) determined using the PD-L1 28-8 pharmDx kit on the Autostainer Link 48 platform [7]. Specifically, the median OS was 14.4 months (95% confidence interval [CI]: 13.1–16.2) in the nivolumab plus chemotherapy group (n = 789) versus 11.1 months (95% CI: 10.0–12.1) in the chemotherapy-alone group (n = 792) (p < 0.0001) [7]. Moreover, the median PFS was 7.7 months (95% CI: 7.0–9.2) in the nivolumab plus chemotherapy arm versus 6.0 months (95% CI: 5.6–6.9) in the chemotherapy alone arm (p < 0.0001) [7]. Based on these results, in 2021, the FDA-approved, nivolumab plus fluoropyrimidine- and platinum-based chemotherapy as a first-line therapy for HER2-negative advanced or metastatic G/GEJ and esophageal adenocarcinoma [2]. Nivolumab was approved along with a companion diagnostic test, the PD-L1 IHC 28-8 pharmDx assay, for use on the Dako Autostainer Link 48 platform [2][18]. However, the phase 3 ATTRACTION-4 trial demonstrated that first-line nivolumab plus oxaliplatin-based chemotherapy resulted in a significant improvement in PFS, but not OS, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent G/GEJ adenocarcinoma with a tumor proportion score (TPS) of ≥1 (114 of 724; 15.7%) [22]. In this trial, PD-L1 expression was evaluated using the PD-L1 IHC 28-8 pharmDx assay and was scored using TPS, not CPS [22].
Recently, the interim results of the phase 3 KEYNOTE-811 trial (NCT#03615326) in enrolled patients with unresectable or metastatic, HER2-positive G/GEJ adenocarcinoma showed that first-line pembrolizumab plus trastuzumab and chemotherapy significantly reduced tumor size, induced CRs in some participants, and significantly improved ORR [8]. In this trial, PD-L1 expression was evaluated using the PD-L1 IHC 22C3 pharmDx assay and was scored using CPS (patients with a CPS of ≥1: 582 of 692, 84.1%) [8]. Although KEYNOTE-811 trial has proceeded, pembrolizumab plus trastuzumab and chemotherapy could potentially be a new first-line treatment option for patients with unresectable advanced or metastatic, HER2-positive G/GEJ adenocarcinoma.

3. Interpretation of PD-L1 IHC Assays in GC

To date, it has been typical to carry out IHC for evaluating PD-L1 expression [17]. When assessing PD-L1 expression, pathologists must pay attention to reproducibility and accuracy [17]. Criteria vary depending on the type of tumor. However, both the PD-L1 IHC 22C3 pharmDx and PD-L1 IHC 28-8 pharmDx assays share the CPS scoring system for assessing PD-L1 expression [2][18]. CPS is quantified as the number of PD-L1-stained cells (tumor cells, lymphocytes, and macrophages) and dividing the result by the total number of viable tumor cell subsequently multiplied by 100 [2][11][18]. For proper evaluation, at least 100 viable tumor cells must be present in the PD-L1-stained slide, and the maximum score is defined as 100 if the calculated results exceed 100 [2][11][18]. In CPS scoring system, partial linear or complete circumferential membrane staining (at any intensity) of invasive viable tumor cells is assessed, but not dysplasia or in situ carcinoma [2][11][18]. Conversely, membrane and/or cytoplasmic staining (at any intensity) of mononuclear inflammatory cells (including lymphocytes and macrophages) within tumor nests and adjacent supporting stroma is evaluated, but not eosinophils, neutrophils, and plasma cells. Additionally, normal cells, stromal cells (including fibroblasts), and cellular debris and/or necrotic cells are excluded from the numerator [18]. If the PD-L1 staining pattern shows heterogeneity, the final CPS should be determined by assessing the CPS results for each area within the entire tumor [18]. As previously mentioned, the interpretation of PD-L1 positivity should be according to the CPS cutoff point suitable for the assays used in the evaluation since two different PD-L1 assays have been approved as companion diagnostic assays on the basis of different CPS cutoff points [18]. CPS positivity is CPS ≥ 1 and CPS ≥ 5 in the PD-L1 IHC 22C3 pharmDx and PD-L1 and IHC 28-8 pharmDx assays, respectively [2][18]. In HER2-negative patients, the National Comprehensive Cancer Network Guidelines (NCCN) guidelines for GC version 2.2022 recommend fluoropyrimidine (fluorouracil or capecitabine), oxaliplatin, and nivolumab (CPS ≥ 5 when using the PD-L1 IHC 28-8 pharmDx assay) as preferred regimens of first-line therapy [14]. Another scoring method for PD-L1 IHC expression in other solid tumors, including metastatic non-small-cell lung cancer and melanoma, uses TPS for calculating the percentage of stained tumor cells out of the total tumor cells [2]. However, as TPS does not contain tumor-infiltrating immune cells when calculating the score, it may be inefficient in identifying responders [2][23]. Interestingly, a new tumor area positivity (TAP) score has recently been proposed for the evaluation of the VENTANA PD-L1 SP263 assay in G/GEJ adenocarcinoma and esophageal squamous cell carcinoma [24]. The TAP scoring system is measured as the percentages of the PD-L1-positive tumor cells plus immune cells are divided by the tumor area, which is occupied by all viable tumor cells and the tumor-associated stroma containing tumor-associated immune cells [24]. Partial linear or circumferential membrane staining (at any intensity) of tumor cells is evaluated, and cytoplasmic, membranous, and punctate staining of tumor-associated immune cells (at any intensity) is considered PD-L1-positive staining [24]. Liu et al. reported that the degree of agreement between the TAP (cutoff of 1%) and CPS (cutoff of 1%) was 100% positive percent agreement, 84.6% negative percent agreement, and 96.2% overall percent agreement [24]. Furthermore, they also suggested that the TAP scoring system is a simple, visual-based method as the average time spent on scoring is 5 min, and it can address the limitations of a cell-counting approach [24]. However, accumulating evidence based on clinical trials is required for the standardization of this scoring system.

4. Interchangeability of PD-L1 Assays in GC

The interchangeability between the PD-L1 IHC 22C3 pharmDx and the PD-L1 IHC 28-8 pharmDx assays is very high [25][26]. Ahn et al. compared two PD-L1 assays in the same formalin-fixed, paraffin-embedded (FFPE) tissue blocks from 55 cases with GC and demonstrated that all PD-L1-positive cases using the PD-L1 IHC 22C3 pharmDx assay were also positive using the PD-L1 IHC 28-8 pharmDx assay, regardless of which CPS cutoff was used (≥1, ≥10, and ≥50) [25]. Moreover, they provided a high correlation between them in a comparison of the quantitative CPS of the two assays (Spearman correlation value = 0.978, p < 0.001) [25]. However, nonspecific background staining can be observed in the PD-L1 IHC 28-8 pharmDx assay. When the PD-L1 IHC 28-8 pharmDx assay was used in comparison with the PD-L1 IHC 22C3 pharmDx assay, nonspecific cytoplasmic staining, but not membranous staining, was observed in the muscular tissues and tumor cells [25]. Moreover, Narita et al. evaluated a pairwise comparison of two assays in the same FFPE tissue microarray (TMA) from 226 cases with GC. They reported that 87% of the pairs were concordant, and 11% had a higher expression using the PD-L1 IHC 22C3 pharmDx assay [26]. With a CPS of ≥ 5, the concordance between them was strong (kappa score = 0.881), specifically, 25 and 22 cases were positive using the PD-L1 IHC 22C3 pharmDx and PD-L1 IHC 28-8 pharmDx assays, respectively [26]. Conversely, Yeong et al. suggested that CPSs using the PD-L1 IHC 28-8 pharmDx assay were consistently observed at higher rates than that using the PD-L1 IHC 22C3 pharmDx assay in 362 cases with GC (344 cores of TMA, 18 whole slides) (70.3% versus 49.4%, p < 0.001 at CPS ≥ 1; 29.1% versus 13.4%, p < 0.001 at CPS ≥ 5; 13.7% versus 7.0%, p  =  0.004 at CPS ≥ 10) [27]. However, in their study, PD-L1 expression was determined by multiplex IHC/immunofluorescence using the Opal Multiplex fIHC kit (Akoya Biosciences, CA, USA) [27]. Moreover, Kim et al. demonstrated that the concordance for the different IHC assays (VENTANA PD-L1 SP263, PD-L1 IHC 22C3 pharmDx on the Dako automated staining platform, and PD-L1 IHC 22C3 pharmDx on the Ventana platform) was very low across all cutoffs in the biopsy or resection specimens (biopsy, kappa coefficient [κ] = 0.17–0.453; resection, κ = 0.02–0.311) [28]. Therefore, based on the results of several studies, even when using the same sample, PD-L1 expression can be observed differently depending on the antibody, staining method, and platform/machine [25][26][27][28][29].

5. Discordance between Biopsy and Resection Specimens and Inter-Observer Variation

As previously mentioned, as PD-L1 staining patterns may exhibit intratumoral heterogeneity, there may be discrepancies in PD-L1 CPS results between paired biopsy and resection specimens [28][29]. Kim et al. reported that the overall positive agreement for PD-L1 results, when the CPS cutoff was 1, in paired biopsy and resection samples from 99 cases with GC was 100% (VENTANA PD-L1 SP263; κ = 1.000), 86% (PD-L1 IHC 22C3 pharmDx on the Dako automated staining platform; κ = 0.693) and 93% (PD-L1 IHC 22C3 pharmDx on the Ventana platform; κ = 0.820), respectively [28]. Additionally, Heo et al. presented that cases with PD-L1 CPS ≥1 were observed in 32.1% (36 of 112) paired biopsy and 47.3% (53 of 112) resection samples as measured by digital image analysis using the PD-L1 IHC 22C3 pharmDx assay [29]. Interestingly, in their study, 41 (36.6%) discrepant cases between biopsy and resection were determined by digital image analyses (κ = 0.254, p = 0.0048), while 31 (27.7%) discrepant cases were determined by pathologists (κ = 0.432, p < 0.0001) [29]. Furthermore, Yamashita et al. showed that cases with PD-L1 CPS ≥ 1 observed in 46.6% (89 of 191) paired biopsy and 70.1% (135 of 191) resection samples using the E1L3N antibody for PD-L1 [30]. In their study, the accordance of cases with only a single biopsy tissue was significantly lower (48.8%) than that of cases with multiple biopsied tissues (68.9%) (p < 0.05) [30]. Therefore, owing to the high levels of intraumoral and intertumoral heterogeneity in GC, PD-L1 expression in paired biopsy and resection specimens of GC may show relatively low concordance. Considering the difference in interpretation between digital image analyses and pathologists, inter-observer variation may also exist. Multiple biopsies can be more helpful than a single biopsy for reducing discrepancies in PD-1 CPS results between biopsy and resection [30]. Notably, Schoemig-Markiefka et al. suggested that sampling and analysis of four or more biopsies with a total area of approximately 4.5 mm2 may obtain similar results to resection specimens [31]. To evaluate inter-observer variation, Park et al. compared the CPS results of 55 cores of TMA obtained from five pathologists [32]. The PD-L1 IHC 22C3 pahrmDx assay had a higher concordance among pathologists than the VENTANA PD-L1 SP263 assay (CPS ≥ 1, κ = 0.389 versus κ = 0.224; CPS ≥ 10, κ = 0.256 versus κ = 0.140) [32]. They suggested that continuous training for PD-L1 interpretation is significant as trained pathologists showed higher agreement between the two assays than untrained pathologists [32].

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