Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer

Programmed death-ligand 1 (PD-L1) expression is required for benefit from immune checkpoint inhibitors in metastatic triple negative breast cancer (TNBC). In contrast, in the neoadjuvant setting patients benefited regardless of PD-L1 expression. We hypothesized that, in stages II-III breast cancers, low levels of PD-L1 expression may be sufficient to confer sensitivity to therapy and focal expression could be missed by a biopsy.

In this study, we examined intratumor spatial heterogeneity of PD-L1 protein expression in multiple biopsies from different regions of breast cancers in 57 primary breast tumors (n = 33 TNBC, n = 19 estrogen receptor-positive [ER-positive], n = 5 human epidermal receptor 2-positive [HER2 +]). E1L3N antibody was used to assess PD-L1 status and staining was scored using the combined positivity score (CPS) with PD-L1 positive defined as CPS ≥ 10.

Overall, 19% (11/57) of tumors were PD-L1 positive based on positivity in at least 1 biopsy. Among TNBC, PD-L1 positivity was 27% (9/33). The discordance rate, defined as the same tumor yielding PD-L1 positive and negative samples in different regions, was 16% (n = 9) in the whole study population and 23% (n = 7) in TNBC. Cohen's kappa coefficient of agreement was 0.214 for the whole study and 0.239 for TNBC, both of which falling into a non-statistically significant fair agreement range. Among all PD-L1 positive cases, 82% (n = 9/11) had positivity in only one of the tissue assessments.

These results indicate that the overall 84% concordance is driven by concordant negative results. In PD-L1 positive cancers, within-tumor heterogeneity in PD-L1 expression exists.