Clinical significance of cadherin-6 expression in primary and recurrent epithelial ovarian cancer and its association with outcomes: A potential therapeutic target for epithelial ovarian cancer (206)

Objectives: Cadherin-6 (CDH6) is a membrane glycoprotein, and aberrant expression of CDH6 has been reported in several human carcinomas, suggesting a possible role in metastasis and invasion. Recently, antibody-drug conjugates (ADCs) targeting CDH6 have drawn attention to new cancer therapies and demonstrated their antitumor activity in preclinical models of epithelial ovarian cancer (EOC). However, limited data are available regarding the frequency of CDH6 expression and its relationship to clinical factors in EOC. Our goal was to understand the clinical significance of CDH6 expression in EOC. Methods: We performed immunohistochemical (IHC) staining on CDH6 expression in a total of 232 EOC surgical samples (including 181 primary tumors and 51 recurrent tumors). CDH6 IHC was performed using the Leica BOND III staining platform with an anti-CDH6 antibody (HPA007456, ATLAS ANTIBODIES). The CDH6 IHC scoring standard refers to the HER2 detection guidelines for gastric cancer (0, 1+, 2+, 3+). We define a score greater than or equal to 1 as positive for the expression of CDH6. Results: We investigated 181 patients with primary EOC for CDH6 expression through IHC. Total 117 (64.6%) patients tested positive. In which, 18 (15.4%), 84 (71.8%) and 15 (12.8%) cases were scored as 1+, 2+ and 3+, respectively. We then investigated the relationship between CDH6 expression and clinical-pathologic features in EOC. CDH6 expression was observed more frequently in high-grade serous carcinomas (89.0%, p < 0.0001), stage III/IV tumors (84.8%, p < 0.0001) and gross residual tumors in primary surgery (84.7%, p < 0.0001). CDH6-positive patients showed shorter progression-free survival (PFS) and overall survival (OS) (p < 0.0001 and p = 0.0006) than that of CDH6-negative patients in all EOC patients. In addition, patients with CDH6 3+ had shorter PFS and OS than that of patients who had 0, 1+ and 2+ (p =0.028 and p = 0.015) in the high-grade serous subgroup. We also investigated the expression of CDH6 in 51 recurrent EOC; 38/51 (74.5%) recurrent tumors tested positive for CDH6 expression, and nine (23.7%), 17 (44.7%) and 12 (31.6%) received scores of 1+, 2+ and 3+, respectively. CDH6 expression from recurrent tumors was observed in 18/24 (75.0%) high-grade serous, 11/16 (68.8%) clear cell, 4/5 (80.0%) endometrioid and 5/6 (83.3%) other histotypes. Conclusions: CDH6 expression is frequently observed in primary and recurrent EOC of all histotypes, especially in high-grade serous carcinoma. The frequency of CDH6 expression is consistent between primary and recurrent tumors. CDH6 is a promising therapeutic target for the treatment of EOC. Objectives: Cadherin-6 (CDH6) is a membrane glycoprotein, and aberrant expression of CDH6 has been reported in several human carcinomas, suggesting a possible role in metastasis and invasion. Recently, antibody-drug conjugates (ADCs) targeting CDH6 have drawn attention to new cancer therapies and demonstrated their antitumor activity in preclinical models of epithelial ovarian cancer (EOC). However, limited data are available regarding the frequency of CDH6 expression and its relationship to clinical factors in EOC. Our goal was to understand the clinical significance of CDH6 expression in EOC. Methods: We performed immunohistochemical (IHC) staining on CDH6 expression in a total of 232 EOC surgical samples (including 181 primary tumors and 51 recurrent tumors). CDH6 IHC was performed using the Leica BOND III staining platform with an anti-CDH6 antibody (HPA007456, ATLAS ANTIBODIES). The CDH6 IHC scoring standard refers to the HER2 detection guidelines for gastric cancer (0, 1+, 2+, 3+). We define a score greater than or equal to 1 as positive for the expression of CDH6. Results: We investigated 181 patients with primary EOC for CDH6 expression through IHC. Total 117 (64.6%) patients tested positive. In which, 18 (15.4%), 84 (71.8%) and 15 (12.8%) cases were scored as 1+, 2+ and 3+, respectively. We then investigated the relationship between CDH6 expression and clinical-pathologic features in EOC. CDH6 expression was observed more frequently in high-grade serous carcinomas (89.0%, p < 0.0001), stage III/IV tumors (84.8%, p < 0.0001) and gross residual tumors in primary surgery (84.7%, p < 0.0001). CDH6-positive patients showed shorter progression-free survival (PFS) and overall survival (OS) (p < 0.0001 and p = 0.0006) than that of CDH6-negative patients in all EOC patients. In addition, patients with CDH6 3+ had shorter PFS and OS than that of patients who had 0, 1+ and 2+ (p =0.028 and p = 0.015) in the high-grade serous subgroup. We also investigated the expression of CDH6 in 51 recurrent EOC; 38/51 (74.5%) recurrent tumors tested positive for CDH6 expression, and nine (23.7%), 17 (44.7%) and 12 (31.6%) received scores of 1+, 2+ and 3+, respectively. CDH6 expression from recurrent tumors was observed in 18/24 (75.0%) high-grade serous, 11/16 (68.8%) clear cell, 4/5 (80.0%) endometrioid and 5/6 (83.3%) other histotypes. Conclusions: CDH6 expression is frequently observed in primary and recurrent EOC of all histotypes, especially in high-grade serous carcinoma. The frequency of CDH6 expression is consistent between primary and recurrent tumors. CDH6 is a promising therapeutic target for the treatment of EOC.