title: PD-L1 Expression and Intratumoral Heterogeneity Across Breast Cancer Subtypes and Stages: An Assessment of 245 Primary and 40 Metastatic Tumors.
abstract: Tumor expression of programmed cell death ligand 1 (PD-L1) is associated with immune evasion in a variety of malignancies, including a subset of triple-negative breast carcinomas, and may mark cancers as susceptible to PD-1/PD-L1 inhibitor therapies. We herein characterize PD-L1 expression in breast cancers across the full range of histomorphologies and investigate its intratumoral heterogeneity and fidelity across primaries and metastases. A total of 245 primary and 40 metastatic (20 nodal, 20 distant) breast carcinomas were evaluated with PD-L1 immunohistochemistry on tissue microarray. Tumor PD-L1 staining was seen in 12% of all primaries including 32% of triple-negative cancers. Staining was common in ductal cancers with medullary (54%), apocrine (27%), and metaplastic features (40%). However, diffuse (>50%) staining was rare (2% of all cancers and 5% of triple negatives). Immune staining was seen in 29% of all primaries and 61% of triple negatives. Tumor expression of PD-L1 was conserved in 94% of matched primary/metastasis pairs, while immune staining showed fidelity in 71%; the remaining cases acquired PD-L1 immune cell expression in the metastasis. Only half of cases with positive tumor staining showed concordance across all analyzed cores. These data demonstrate that PD-L1 expression is prevalent among high-grade, hormone receptor-negative breast cancers with a range of histomorphologies and shows fidelity between primary and metastatic sites in treatment-naive cancers, although acquisition of immune PD-L1 staining in metastases is not uncommon. There is considerable intratumoral heterogeneity in PD-L1 expression, undermining the suitability of core biopsy in the determination of PD-L1 status. Clinical trials are needed to determine PD-L1 staining thresholds required for therapeutic response, as diffuse staining is rare.
authors.affiliation: Departments of *Pathology ‡Oncology †School of Medicine, University of Virginia, Charlottesville, VA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Dill
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Gru
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Atkins
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Friedman
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Moore
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Bullock
authors.forename: Janet V
authors.initials: JV
authors.lastname: Cross
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dillon
authors.forename: Anne M
authors.initials: AM
authors.lastname: Mills
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D046888:Tissue Array Analysis
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human