HER2 Immunohistochemical Expression and Fluorescent In Situ Hybridization (FISH) Testing in Clear Cell Carcinoma of the Gynecologic Tract

The DESTINY-PanTumor02 phase II trial, showing a remarkable response to fam-trastuzumab deruxtecan-nxki (Enhertu), has triggered an increase in HER2 testing for drug eligibility. We evaluated HER2 immunohistochemical (IHC) and FISH testing results and the extent of Enhertu use in gynecologic tract clear cell carcinomas (GT-CCC) at a tertiary care center. Sixty-five GT-CCC with HER2 IHC testing performed at our institution (2018 to 2024) were identified: 49 ovarian (OCCC), 14 endometrial (ECCC), and 2 peritoneal. The 2018 ASCO/CAP criteria were used for HER2 scoring (the standard during the time frame of this study). Overall HER2 IHC scores were: 0 [n=12 (18.5%)], 1+ [n=9 (13.8%)], 2+ [n=40 (61.5%)], 3+ [n=4 (6.2%)]. FISH confirmed amplification in 22.9% OCCCs and 25% ECCCs (18.8% of IHC 2+ and all IHC 3+). Cases with unusual staining patterns (USP; strong nuclear and cytoplasmic) did not show FISH amplification. HER2 0/1+ and cases with USP were more frequent in biopsies (41.7%) and metastatic tumors (45.5%) compared with resections (30.2%) and primary sites (29.6%). Intratumoral heterogeneity was seen in 7.7% of cases. Among HER2 3+ cases, only 1 patient received anti-HER2 therapy (Herceptin followed by Enhertu) and had a mixed response. Of the HER2 2+ with positive FISH, 4 received anti-HER2 therapy, and only 1 patient had a good response. Based on current HER2 eligibility guidelines, our study shows that more than half of GT-CCC cases, that is, IHC HER2+, would be eligible for anti-HER2 therapy. However, few patients in our cohort received this therapy. Further studies are needed to evaluate the efficacy of anti-HER2 therapy for advanced/recurrent GT-CCC.