HER2 expression in squamous cell carcinoma of the vulva: A systematic review and meta-analysis.

Abstract

e17653 Background: Vulvar cancer is a rare gynecologic malignancy comprising 1–3% of all cases. No established standard exists for advanced disease. Recent activity of HER2-directed antibody–drug conjugates in solid tumors (ORR ~37%) highlights the need to better characterize HER2 expression in vulvar cancer. The aim of this study was to determine prevalence of HER2 expression in vulvar cancer through a systematic review and meta-analysis. Methods: We performed a systematic search of Medline, Embase, CENTRAL, and the Cochrane Database of Systematic Reviews from inception to May 2025. Eligible studies included ≥10 vulvar cancer cases with HER2 assessment by immunohistochemistry and/or in situ hybridization. Vulvar Paget’s was excluded. Two reviewers independently screened studies. A random-effects model was used to estimate pooled HER2-positivity. Heterogeneity was assessed using Cochran’s Q and Higgins’s I². Publication bias was explored with Egger's test. Results: Of 506 records, nine retrospective studies including 769 patients with predominantly squamous cell carcinoma histology (98%, n=752) across 5 countries met inclusion criteria. Median age at diagnosis of vulvar cancer was between 55 and 78, reported in three studies. Lymph-node involvement was reported in six studies including 361 patients, where lymph node status was positive in 48% (n=173). Molecular profiling was limited. Among three studies with known TP53 status (n=206), 59% expressed TP53 (n=122), and among two studies with known human papillomavirus (HPV) status (n=128), 21% (n=27) were HPV positive. Six studies were American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)-compliant. Pooled HER2 expression across ASCO/CAP compliant studies was 2% (95%CI 1%, 3%) and for ASCO/CAP non-compliant studies was 21% (95% CI: 2%, 52%). The overall pooled estimated proportion of HER2 positive expression was 5% (95% CI: 0.4%, 14%). There was substantial heterogeneity across studies with an I² value of 90.2% [95% CI: 84.1%; 93.9%], but no significant publication bias was observed (Egger’s test p = 0.364). HER2 positive status was associated with nodal involvement and presence of distant metastases (2 studies; n=73 patients), as well as with adenocarcinoma histology (1 study; n= 143 patients). HER2 expression was not associated with survival in three studies that reported clinical outcomes. Conclusions: HER2 positive expression in squamous cell carcinoma of the vulva appears uncommon but may be underestimated. Standardized assessment using contemporary ASCO/CAP criteria is needed to clarify the prevalence of HER2-low, ultra-low versus HER2-positive disease to inform potential use of HER2-targeted therapy among patients with vulvar cancer.