PD-L1 Expression in Esophageal Squamous Cell Carcinoma: A Comparison of Three Leading Tests

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PD-L1 Expression in Esophageal Squamous Cell Carcinoma: A Comparison of Three Leading Tests

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers worldwide, with a 5-year survival rate below 20%. For patients in China—where ESCC makes up over 95% of esophageal cancers—this statistic hits especially hard. But there’s hope: immunotherapy drugs that target the PD-1/PD-L1 immune checkpoint have revolutionized treatment for squamous cell cancers. The key to unlocking these drugs? A reliable test for PD-L1, a protein that helps tumors hide from the immune system.

Yet for ESCC, there’s no widely accepted PD-L1 test. Different labs use different antibodies and platforms, which can lead to inconsistent results—and confused treatment decisions. To fix this, researchers from China’s National Cancer Center/Cancer Hospital (Chinese Academy of Medical Sciences) set out to compare three leading PD-L1 assays: 22C3 (the FDA-approved “gold standard” for non-small cell lung cancer), 28-8 (a complementary assay), and SP263 (a Europe-approved test). Their goal? Find out which works best for ESCC.

How the Study Was Done

The team analyzed tissue samples from 324 ESCC patients who had curative surgery between 2005 and 2013 (no pre-op chemo/radiation, no distant metastasis). They created tissue microarrays (TMAs)—small, standardized samples from areas of the tumor with lots of cancer cells—to ensure consistency.

They tested PD-L1 using three validated methods:

  • 22C3 and 28-8: Stained on the Dako Autostainer Link 48 platform (common in labs).
  • SP263: Stained on the Ventana BenchMark XT platform (another widely used system).

Two pathologists—blinded to patient data—scored each sample using the Combined Positive Score (CPS), which counts both tumor cells and immune cells with PD-L1. Samples were grouped as:

  • Negative (CPS < 1)
  • Weak-to-moderate positive (CPS 1–49)
  • Strongly positive (CPS ≥ 50)

What They Found

The results were clear: 28-8 and 22C3 were nearly identical. When comparing the two assays:

  • Negative samples (CPS < 1): 77.5% (28-8) vs. 77.2% (22C3)
  • Weak-to-moderate positive (CPS 1–49): 19.1% (28-8) vs. 19.4% (22C3)
  • Strongly positive (CPS ≥ 50): 3.4% (28-8) vs. 3.1% (22C3)

The overall percent agreement (OPA)—how often the two assays gave the same result—was 93.5% for the negative cutoff (CPS < 1) and 99.1% for strong positivity (CPS ≥ 50). Sensitivity (catching true positives) and specificity (catching true negatives) were also high: 85.1% and 96.0% for the negative cutoff, and 90.0% and 99.4% for strong positivity.

SP263, however, showed less agreement with 22C3. For the negative cutoff (CPS < 1), OPA was 81.5%—meaning 18.5% of samples gave different results. SP263 also found more PD-L1-positive cases (both weak and strong) than 22C3, likely because it stains cell membranes more intensely.

Why This Matters for Patients and Doctors

This study solves a big problem for ESCC care: it tells labs which PD-L1 test to use. The 28-8 assay is a reliable alternative to 22C3—critical because most clinics can’t afford multiple staining platforms. For example, if a lab uses the Dako Autostainer (for 22C3), they can easily switch to 28-8 without buying new equipment.

SP263’s higher positivity rate is trickier. While it might catch more potential candidates for immunotherapy, it also risks false positives. The team notes that tumor heterogeneity (PD-L1 isn’t evenly distributed in tumors) and the use of TMAs (instead of full tissue sections) could affect results. More research is needed to understand why SP263 differs—and whether its results translate to better patient outcomes.

The Bottom Line

For ESCC, the 28-8 PD-L1 assay is a strong stand-in for the 22C3 “gold standard.” This is a big win for standardizing care: consistent tests mean consistent treatment decisions, which save lives.

Of course, no study is perfect. The team used TMAs (which might miss some PD-L1 expression) and focused on surgically resected tumors (not biopsies). But this is the first research to compare PD-L1 assays in ESCC—and it’s a major step toward making immunotherapy more accessible for patients with this deadly cancer.

Guo L, Ji Y, Guo W, et al. Programmed cell death ligand 1 expression in esophageal squamous cell carcinoma: a comparative analysis of three different assays. Chinese Medical Journal. 2021;134(23):2890–2892.

doi.org/10.1097/CM9.0000000000001642

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