Discoidin Domain Receptor 2 (Ddr2) Expression In Combination With Mutation Status Is Predictive Of Survival In Patients With Ovarian Cancer

Objectives: Dicoidin Domain Receptor 2 (DDR2) is a tyrosine kinase receptor which binds the most common extracellular matrix protein, fibrillar collagen type 1. Expression of DDR2 is critical for invasion and migration of ovarian cancer tumor cells. Clinically, high DDR2 expression has been shown to be associated with advanced stage disease and decreased survival. It is not known how BRCA mutation status, a known marker for treatment sensitivity, impacts this relationship between DDR2 expression and survival. This study aimed to determine whether DDR2 expression was correlated with BRCA mutation status and to quantify the effects of this relationship on survival. Methods: Immunohistochemical (IHC) analysis of DDR2 expression in two ovarian cancer tissue microarrays (TMA) was performed. DDR2 staining on the membrane of tumor cells was scored microscopically according to the intensity and percentage of cells positive for DDR2 expression compared to controls. High DDR2 staining was defined as >70% and low staining <69%. Clinical information, including germline mutational status and survival data, was abstracted from the electronic medical record. Statistical analysis was performed using descriptive statistics and unpaired t-tests. Survival analysis was performed using the Kaplan-Meier method with statistical significance determined using the log-rank test. Results: The cohort included 164 patients diagnosed between 2/1994 and 1/2017. The majority had advanced stage disease (79%) and high-grade serous histology (76%). Germline mutation status was known in 93 patients (57%). BRCA1 was the most common mutation in 38 patients (64%) followed by BRCA2 in 20 patients (34%). 34 patients had negative germline testing. DDR2 expression was significantly associated with mutational status. Patients without a germline mutation had significantly higher DDR2 expression (64%) compared to BRCA1 (37%) (p=0.002) and BRCA2 had significantly higher DDR2 expression (55%) compared to BRCA1 (37%) (p=0.03). DDR2 expression did not vary by stage, grade or platinum sensitive status. In survival analysis, patients with high DDR2 expression had significantly lower overall survival (33mo vs 83mo, HR 1.94, p=0.002) and progression free survival (17mo vs 34mo, HR 1.668, p=0.04) compared to patients with low DDR2 expression. When survival analysis was stratified by mutation status and DDR2 expression, survival differences were seen. In patients without a germline mutation, high DDR2 expression was associated with worse overall survival (42mo vs 147mo, HR=2.818, p=0.04) compared to low DDR2 expression. Conclusions: Tumor DDR2 expression is correlated with mutation status and when combined, provides useful prognostic information. Studies are ongoing to identify additional BRCA deficient tumors for further survival analysis. Dicoidin Domain Receptor 2 (DDR2) is a tyrosine kinase receptor which binds the most common extracellular matrix protein, fibrillar collagen type 1. Expression of DDR2 is critical for invasion and migration of ovarian cancer tumor cells. Clinically, high DDR2 expression has been shown to be associated with advanced stage disease and decreased survival. It is not known how BRCA mutation status, a known marker for treatment sensitivity, impacts this relationship between DDR2 expression and survival. This study aimed to determine whether DDR2 expression was correlated with BRCA mutation status and to quantify the effects of this relationship on survival. Immunohistochemical (IHC) analysis of DDR2 expression in two ovarian cancer tissue microarrays (TMA) was performed. DDR2 staining on the membrane of tumor cells was scored microscopically according to the intensity and percentage of cells positive for DDR2 expression compared to controls. High DDR2 staining was defined as >70% and low staining <69%. Clinical information, including germline mutational status and survival data, was abstracted from the electronic medical record. Statistical analysis was performed using descriptive statistics and unpaired t-tests. Survival analysis was performed using the Kaplan-Meier method with statistical significance determined using the log-rank test. The cohort included 164 patients diagnosed between 2/1994 and 1/2017. The majority had advanced stage disease (79%) and high-grade serous histology (76%). Germline mutation status was known in 93 patients (57%). BRCA1 was the most common mutation in 38 patients (64%) followed by BRCA2 in 20 patients (34%). 34 patients had negative germline testing. DDR2 expression was significantly associated with mutational status. Patients without a germline mutation had significantly higher DDR2 expression (64%) compared to BRCA1 (37%) (p=0.002) and BRCA2 had significantly higher DDR2 expression (55%) compared to BRCA1 (37%) (p=0.03). DDR2 expression did not vary by stage, grade or platinum sensitive status. In survival analysis, patients with high DDR2 expression had significantly lower overall survival (33mo vs 83mo, HR 1.94, p=0.002) and progression free survival (17mo vs 34mo, HR 1.668, p=0.04) compared to patients with low DDR2 expression. When survival analysis was stratified by mutation status and DDR2 expression, survival differences were seen. In patients without a germline mutation, high DDR2 expression was associated with worse overall survival (42mo vs 147mo, HR=2.818, p=0.04) compared to low DDR2 expression. Tumor DDR2 expression is correlated with mutation status and when combined, provides useful prognostic information. Studies are ongoing to identify additional BRCA deficient tumors for further survival analysis.