Human epididymis protein 4 and Lewis y enhance chemotherapeutic resistance in epithelial ovarian cancer through the p38MAPK pathway

Background Ovarian cancer has a high mortality rate due to difficulties in early detection and chemotherapy resistance. Human epididymal protein 4 (HE4) has been adopted as a novel serum biomarker for early ovarian cancer diagnosis, we have previously detected the presence of Lewis y antigen modifications on HE4 in ovarian cancer cell lines. In this study, we aimed to analyze the expression of HE4 and Lewis y antigen in human ovarian cancer in order to analyze their correlation with each other, as well as with the clinical pathological parameters of ovarian cancer patients. Methods We first used immunohistochemistry to detect the respective expressions of these compounds in two patient groups (chemotherapy-resistant and -sensitive) containing a total of 95 patients. Then, we adopted a bioinformatic approach and used online large-sample databases (TCGA, CCLE and GTEx; Metascape, Cytoscape) to explore the potential mechanisms of action of these compounds. Results Our results demonstrate that high HE4 and Lewis y expressions could be used as markers for chemotherapy-resistance and poor prognosis in ovarian cancer patients. These two expressions were widely correlated in various cancer tissues and are thought to act by activating the p38 MAPK pathway and inducing VEGFA, PTGS2,EGR1,andHIFI1A, thereby promoting malignant biological behavior and resistance in ovarian cancer. Conclusions This finding not only reveals the possible mechanism by which HE4 and Lewis y antigen affect ovarian cancer, but also identifies a four-gene signature that could be very useful in ovarian cancer detection and/or the development of new targeted therapies.

Phase II Trial of Humanized Anti-Lewis Y Monoclonal Antibody for Advanced Hormone Receptor-positive Breast Cancer That Progressed on Previous Endocrine Therapy

Purpose: Lewis Y antigen is expressed in 44 to 90% of breast cancer. The expression of the antigen in carcinoma tissue is different from what occurs in normal tissue. The objective of the present study was to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive breast cancer, after progression on endocrine therapy.Methods: A single-arm phase II study was conducted in 7 centers. Patients with advanced hormone receptor-positive breast cancer who had failed previous first-line endocrine therapy were included. All patients were required to present tumoral expression of Lewis Y antigen by immunohistochemistry. Treatment consisted of hu3S193 antibody at intravenous doses of 20 mg/m2 weekly given at 8-week cycles. The primary endpoint was clinical benefit rate. Results: The study stopped accrual after an unplanned interim analysis since the hu3S193 antibody lacked sufficient activity to justify the study continuation. Twenty-two patients were enrolled; 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting stable disease confirmed after 24 weeks. One patient received the medication for more than 2 years, with prolonged stable disease. No partial or complete responses were observed. Median time to progression and overall survival were 5.4 and 37.5 months, respectively. Conclusions: The humanized anti-Lewis Y monoclonal antibody, hu3S193, showed insufficient activity in this cohort. However, we cannot rule out the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression.Trial registration: Clinicaltrials.gov, NCT01370239. Registered 9 June 2011, https://clinicaltrials.gov/ct2/show/NCT01370239