HER2 Immunohistochemical Expression and Fluorescent In Situ Hybridization (FISH) Testing in Clear Cell Carcinoma of
Khaled S Mohamed1, Preetha Ramalingam1, Barrett C Lawson1
1Departments of Anatomic Pathology.
Abstract:
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.
Insights
Increased HER2 testing for gynecologic tract clear cell carcinomas (GT-CCC) follows Enhertu trial success. While many GT-CCCs are HER2-positive and eligible for therapy, few patients receive it, indicating a need for further research.
Area of Science:
- Oncology
- Gynecologic Oncology
- Cancer Biomarkers
Background:
- Fam-trastuzumab deruxtecan-nxki (Enhertu) shows promise in a phase II trial, increasing HER2 testing for drug eligibility.
- Gynecologic tract clear cell carcinomas (GT-CCC) are a subset of gynecologic cancers with varying HER2 expression.
- Understanding HER2 testing patterns and anti-HER2 therapy use in GT-CCC is crucial for treatment optimization.
Purpose of the Study:
- To evaluate HER2 immunohistochemical (IHC) and FISH testing results in GT-CCC.
- To assess the utilization of Enhertu and other anti-HER2 therapies in this patient population.
- To determine the proportion of GT-CCC cases eligible for anti-HER2 therapy based on current guidelines.
Main Methods:
- Retrospective review of 65 GT-CCC cases (ovarian, endometrial, peritoneal) with HER2 IHC testing (2018-2024).
- HER2 scoring using 2018 ASCO/CAP criteria.
- FISH analysis for HER2 amplification in select cases.
- Review of anti-HER2 therapy use and response.
Main Results:
- Overall HER2 IHC scores: 0 (18.5%), 1+ (13.8%), 2+ (61.5%), 3+ (6.2%).
- FISH confirmed amplification in 22.9% of ovarian and 25% of endometrial CCCs (including 18.8% of IHC 2+ and all IHC 3+).
- Unusual staining patterns (USP) did not correlate with FISH amplification.
- Intratumoral heterogeneity observed in 7.7% of cases.
- Despite over half of GT-CCC cases being HER2-positive (IHC), very few patients received anti-HER2 therapy, with limited response observed.
Conclusions:
- A significant proportion of GT-CCC cases exhibit HER2 positivity, meeting criteria for anti-HER2 therapy eligibility.
- Underutilization of anti-HER2 therapies in eligible GT-CCC patients was noted.
- Further investigation is warranted to establish the efficacy of anti-HER2 therapies in advanced or recurrent GT-CCC.
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