Abstract
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 (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. Experimental Design: 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.
Original language | English (US) |
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Pages (from-to) | 6453-6463 |
Number of pages | 11 |
Journal | Clinical Cancer Research |
Volume | 26 |
Issue number | 24 |
DOIs | |
State | Published - Dec 2020 |
Funding
This work was supported by the NIH Medical Scientist Training Program (T32GM007281) and the University of Chicago Biological Sciences Division and Frank Family Endowment (to K.I. Zhou); and NIH K23 award (CA178203–01A1), UCCCC (University of Chicago Comprehensive Cancer Center) Award in Precision Oncology—CCSG (Cancer Center Support Grant; P30CA014599), Castle Foundation, LLK (Live Like Katie) Foundation Award, Ullman Scholar Award and the Sal Ferrara II Fund for PANGEA (to D.V.T. Catenacci).
ASJC Scopus subject areas
- Oncology
- Cancer Research