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.