ERCC1-Positive Circulating Tumor Cells in the Blood of Ovarian Cancer Patients as a Predictive Biomarker for Platinum Resistance

Abstract

BACKGROUND Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance. METHODS The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1. RESULTS At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1+CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1+CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis. CONCLUSIONS The presence of ERCC1+CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer.

Analysis of Circulating Tumor Cells in Ovarian Cancer and Their Clinical Value as a Biomarker

“…found the positive rate of CTCs in ovarian cancer patients was 60% in advanced stage disease using the CellSearch system targeting EpCAM+. Kuhlmann et al [38]. detected CTCs using immunomagnetic CTC enrichment targeting EpCAM and MUC1, followed by RT-PCR to detect EpCAM, MUC1, CA125, and ERCC1 positive cells.…”

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

“…A very interesting finding in this study was the association of ERCC1 + CTC with platinum resistance. The presence of ERCC1 + CTC at primary diagnosis independently predicted platinum resistance (p = 0.010), although the ICC analysis of ERCC1 expression in primary tumor tissue did not reveal any prognostic or predictive value [28]. In their very recently published study, they were able to show that the additional assessment of ERCC1-transcripts enhances overall CTC detection rate in ovarian cancer patients before surgery and after chemotherapy and defines an additional highly overlapping fraction of ERCC1-expressing CTCs, which is potentially selected by platinum-based chemotherapy.…”

Circulating tumor cells: hope to diagnose and treat metastatic cancer

“…Häfner et al [14] have isolated CTCs from metastatic cervical cancer patients and evaluated levels of HPV16-E6 mRNA by real-time PCR, as a more sensitive molecular marker than CK19 mRNA. At the same time, Kuhlmann et al [15] have shown that ERCC1+ CTCs can predict platinum resistance therapy in ovarian cancer. Overall, it seems that molecular profiling of CTCs is becoming a popular tool for diagnosis and therapies of solid tumor malignancies.…”