PD-L1 diagnostics in the neoadjuvant setting: implications of intratumoral heterogeneity of PD-L1 expression in triple negative breast cancer for assessment in small biopsies

Stovgaard, Elisabeth Specht; Bokharaey, M; List-Jensen, Kamille; Roslind, Anne; Kümler, Iben; Høgdall, Estrid; Nielsen, Dorte; Balslev, Eva

doi:10.1007/s10549-020-05655-w

Cited by 30 publications

(31 citation statements)

References 21 publications

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“…Karnik et al 8 found high PD‐L1 expression in a higher tumor grade and high proliferative index apart from triple‐negative phenotype. Stovgaard et al 9 using 22C3 clone for PD‐L1 had 38% positivity comparable to our study group. They also investigated discrepancies in PD‐L1 using TMA rather than whole slides and found greater discordance between the results of IC compared to TC.…”

Section: Feature N = 197supporting

confidence: 90%

Assessment of PD‐L1 expression and tumor‐infiltrating lymphocytes (TILs) across molecular subtypes of triple‐negative breast cancer

et al. 2020

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Section: Feature N = 197supporting

confidence: 90%

Assessment of PD‐L1 expression and tumor‐infiltrating lymphocytes (TILs) across molecular subtypes of triple‐negative breast cancer

et al. 2020

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“…Future digital imaging analysis with double staining (tumor cells marker and PD‐L1) might overcome such challenge. PD‐L1 protein expression has been noted to be heterogeneous in melanoma, 21 triple negative breast carcinoma, 22 and NSCLC 23 . Our study also demonstrates that intratumoral heterogeneity of PD‐L1 expression does exist (Figure 2) and may contribute to discordant interpretation of PD‐L1 IHC.…”

Section: Discussionmentioning

confidence: 52%

Interobserver agreement in programmed cell death‐ligand 1 immunohistochemistry scoring in nonsmall cell lung carcinoma cytologic specimens

Sinclair

Kobalka

Ren

et al. 2020

Diagnostic Cytopathology

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BackgroundThe evaluation of PD‐L1 expression in nonsmall cell lung carcinoma (NSCLC) is becoming increasingly important given the effectiveness of PD‐L1 inhibitors. Although cytologic specimens have been shown to be compatible with surgical specimens to evaluate PD‐L1 immunohistochemistry (IHC), evidence of the reproducibility of PD‐L1 in cytologic specimens is lacking. The aim of this study is to evaluate interobserver agreement in PD‐L1 IHC in cytologic specimens.MethodsPD‐L1 IHC was performed on 86 NSCLC cytology specimens using Dako PD‐L1 IHC 22C3 pharmDx. The digitally scanned whole slide images (WSI) were read by five pathologists. Each case was given a Tumor Proportion Score (TPS) and the results were compared between the observers. The interobserver concordance was assessed using 1% and 50% as cutoffs.ResultsTPSs were highly correlated among observers (Spearman correlation coefficient, 0.86‐0.94). Using greater than 1% as a cutoff, interobserver agreement measured by Fleiss Kappa was 0.74 for all pathologists and Cohen's Kappa coefficient ranged from 0.49 to 0.83, consistent with moderate to substantial agreement. With a cutoff of greater than 50%, Fleiss Kappa was 0.79 for all pathologists and the kappa values ranged from 0.63 to 0.90, consistent with substantial to almost perfect agreement. Several pitfalls were identified by reviewing discordant cases, including staining in macrophages, stromal cells, and intratumoral heterogeneity.ConclusionOur data suggest that TPS of PD‐L1 IHC on cytology specimens is reproducible, with a better agreement when using 50% as the cutoff value. However, special attention is required when the TPS is near the 1% cutoff.

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“…Heterogeneity of PD-L1 expression and TMB could influence their roles as predictive biomarkers for ICI response. Heterogeneity of PD-L1 expression within tumors and between tumor sites has been described for multiple cancer types (16)(17)(18). In surgically resected GEAs, significant spatial discordance of PD-L1 expression was observed between primary tumors and lymph node metastases (19).…”

Section: Introductionmentioning

confidence: 96%

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy

Zhou

Peterson

Serritella

et al. 2020

Clinical Cancer Research

117

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Purpose: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICIs). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA.Patients and methods: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB-levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel.Results: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB-level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57-63% and 73-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival.Conclusions: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.

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PD-L1 diagnostics in the neoadjuvant setting: implications of intratumoral heterogeneity of PD-L1 expression in triple negative breast cancer for assessment in small biopsies

Cited by 30 publications

References 21 publications

Assessment of PD‐L1 expression and tumor‐infiltrating lymphocytes (TILs) across molecular subtypes of triple‐negative breast cancer

Assessment of PD‐L1 expression and tumor‐infiltrating lymphocytes (TILs) across molecular subtypes of triple‐negative breast cancer

Interobserver agreement in programmed cell death‐ligand 1 immunohistochemistry scoring in nonsmall cell lung carcinoma cytologic specimens

Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy

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