Repurposing Gastric Cancer Biomarkers for Mucinous Ovarian Carcinoma: ERBB2 and Claudin 18.2 as Therapeutic Targets.

Abstract

Mucinous ovarian carcinomas (MOCs) have an upper-gastrointestinal cell phenotype (CK7+/SATB2-) similar to pancreatic ductal adenocarcinoma (PDAC) and gastric adenocarcinoma (GA). We aimed to develop an immunohistochemical panel that accurately discriminates MOC from GA. A secondary objective was to compare molecular and targetable tissue-based biomarkers across MOC, GA, and PDAC. Immunohistochemistry was performed on tissue microarrays representing 103 MOC, 265 PDAC, and 159 GA for markers of cell lineage (CK17, MEP1A, PAX8, CDX2, and HIK1083), key molecular alterations [TP53, Mismatch Repair deficiency (MMRd), CTNNB1, ARID1A, and SMAD4], as well as potential antibody targets (ERBB2 and Claudin 18.2). In situ hybridization was performed for Epstein-Barr virus-encoded RNA. A lasso-penalized nominal logistic regression model discriminated the 3 entities with low overall accuracy [77.8%, area under the curve (AUC)=0.91]. Discrimination from others was highest for PDAC (AUC=0.93) and MOC (AUC=0.92), but lowest for GA (AUC=0.87), and MOC was more similar to GA than to PDAC. MOC more frequently showed Claudin 18.2 PS2+ high (42%) and ERBB2 IHC3+ (25%) than GA (Claudin 18.2, 25%; ERBB2, 3%; MMRd, 19%) and PDAC (Claudin 18.2, 10%; ERBB2, 0%; MMRd, 2%). At least 1 potentially targetable alteration was present in 60% of MOC, 43% of GA, and 12% of PDAC. While our marker panel is of insufficient diagnostic accuracy to distinguish MOC from GA, based on the similarity between MOC and GA, consideration should be given to include MOC in clinical basket trials targeting ERBB2 and Claudin 18.2.