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

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.

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.

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.

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.