Changes and clinical impact of HER3 and ERBB3 expression in primary and recurrent ovarian cancer.

OBJECTIVE: Human epidermal growth factor receptor (HER) 3, encoded by the ERBB3 gene, transduces signals most effectively when dimerized with HER2. Although HER3 protein expression has been considered a poor prognostic factor in ovarian cancer, limited data exist on changes in HER3 protein expression and ERBB3 messenger RNA (mRNA) expression during recurrence. This study evaluated HER3/ERBB3 expression before and after recurrence and its association with prognosis using paired samples. We also evaluated HER2/ERBB2 expression. METHODS: We retrospectively analyzed 56 epithelial ovarian, fallopian tube, and primary peritoneal cancer patients who underwent primary cytoreduction and platinum-based chemotherapy at initial treatment and secondary cytoreduction at recurrence. HER2/HER3 protein expression was assessed by immunohistochemical staining. ERBB2/ERBB3 mRNA expression was quantified using the nCounter® Analysis System. RESULTS: The median age was 52 years. International Federation of Gynecology and Obstetrics stages I-IV included 16, 12, 22, and 6 patients, respectively. Histological subtypes included high-grade serous carcinoma (n=19), clear cell carcinoma (n=14), and other histological subtypes (n=23). The proportion of HER2-high and HER3-high tumors increased from 14.5% to 22.2% and from 62.5% to 72.2%, respectively, at recurrence, without statistical significance. Conversely, both ERBB2 and ERBB3 were significantly downregulated during recurrence. At initial treatment, HER3 did not correlate with prognosis, whereas ERBB3 was independently associated with favorable recurrence-free and overall survival. At recurrence, neither HER3 nor ERBB3 was prognostically significant. CONCLUSION: ERBB3 expression at initial treatment was associated with prognosis and significantly downregulated during recurrence. These findings suggest biological changes in HER3/ERBB3 associated with recurrence.