HER2 and FOLR1 Expression in Mesonephric and Mesonephric-Like Adenocarcinomas in the Gynecologic Tract

Mesonephric adenocarcinoma (MA) of the cervix and mesonephric-like adenocarcinoma (MLA) of the endometrium and ovaries are rare, aggressive tumors showing limited response to standard therapy. The DESTINY-PanTumor02 study demonstrated strong responses to Trastuzumab Deruxtecan (T-Dxd), an antibody-drug conjugate targeting HER2, in multiple HER2+ chemoresistant tumors, including gynecologic carcinomas. Mirvetuximab soravtansine (MIRV), which targets folate receptor-1 (FOLR1), is FDA-approved for platinum-resistant tubo-ovarian cancers with ≥75% moderate/strong staining, and emerging studies show meaningful responses to MIRV combination therapy even at lower FOLR1 expression. The National Comprehensive Cancer Network (NCCN) also recommends T-Dxd as second-line therapy for recurrent HER2 (2-3+) endometrial carcinoma. However, these biomarkers have not been adequately evaluated in MA/MLA. We assessed HER2 and FOLR1 immunohistochemical expression in 21 MA/MLA cases (13 endometrial, 5 ovarian, 3 cervical). HER2 was scored using endometrial cancer guidelines (EC) and American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) gastric/gastroesophageal criteria (GaC). FOLR1 scoring followed MIRV eligibility thresholds. HER2 expression was present in 14/21 tumors; HER2 (2+) was seen in two cases by both criteria, with no HER2 (3+) identified. The other 12 cases showed HER2 (1+) by EC criteria, while only four met 1+ by GaC criteria. FOLR1 met current MIRV treatment criteria in one case, while ten others showed expression ranging from 5% to 70%. Although most tumors did not meet current biomarker thresholds for Trastuzumab or MIRV monotherapy, detectable expression supports exploring anti-HER2 T-Dxd and MIRV combination treatments in selected MA/MLA cases.