Cancer Stem Cells, CD44, and Outcomes Following Chemoradiation in Locally Advanced Cervical Cancer: Results From a Prospective Study

Abstract

Purpose: Although cancer stem cells (CSCs) have been reported across solid tumors, there is a dearth of data regarding CSC and its impact on outcomes of cervical cancer.

Methods and materials: From October 2013 to December 2015, patients with squamous cancer of the cervix (stage IB2-IVA) were included. Pretreatment and posttreatment biopsy was obtained and immunohistochemistry was performed for SOX-2, OCT-4, Nanog, CD44, and Podoplanin. All patients received concurrent radiation and brachytherapy to an equivalent dose of 80 to 84 Gy to point A with concurrent weekly cisplatin. Correlation of CSC expression was performed with known prognostic factors. The effect of stem cell expression on disease outcomes was tested within multivariate analysis.

Results: One hundred fifty patients were included. The median dose to point A was 83 Gy (46-89 Gy) and a median of 4 cycles (range, 0-6 cycles) of chemotherapy was administered. At baseline, moderate to strong immunohistochemical expression of SOX-2, OCT-4, Nanog, CD44, and Podoplanin was observed in 12.8%, 4.8%, 24.4%, 15.5%, and 1.3% of patients, respectively. At median follow-up of 30 months (range, 3-51 months), locoregional and distant relapse was observed in 12.2% and 23.1% of patients, of whom 4.7% had both local and distant relapse. The 3-year disease-free survival rate was 87%. On multivariate analysis, moderate to high CSC expression and CD44 low status (hazard ratio [HR] = 8.8; 95% confidence interval [CI], 1.0-77.2; P < .04) independently predicted for locoregional relapse-free survival. International Federation of Gynecology and Obstetrics stage (HR = 2.6; 95% CI, 1.3-5.4; P = .004) and presence of residual tumor after external radiation (HR = 3.5; 95% CI, 1.8-6.5; P = .0001) predicted for a detriment in disease-free survival.

Conclusions: The presence of stem cell proteins and loss of CD44 independently predicts for reduced locoregional control in locally advanced cervical cancer. Further investigation into the interaction of stem cell and CD44 biology is warranted.