Patients with Cervical Cancer and CTCs Treated With Bevacizumab Show Improved OS

Krishnansu S. Tewari, MD

Circulating tumor cells (CTCs) have previously been reported to be prognostic in other solid tumors: can they become a prognostic biomarker in cervical cancer? A newly reported exploratory analysis of the presence of CTCs in advanced cervical cancer patients enrolled in the Gynecologic Oncology Group (GOG) 240.2 trial found that CTCs can be identified in women with recurrent and metastatic cervical cancer. Further, the study reported that the median pre-cycle 1 CTC count dropped from 7 CTCs/8.5 mL whole blood (range, 0-18) to 4 CTCs (range, 0-17) at 36 days posttreatment. Patients receiving the cisplatin-paclitaxel-bevacizumab regimen had a posttreatment hazard ratio (HR) for death of 0.9 at a 95% confidence interval (CI) of 0.81-0.99. Patients receiving CDDP-paclitaxel with or without bevacizumab had a post-treatment HR for death of 1.12 (95% CI 1.018-1.224).

The data were presented March 29, 2015 at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

In the GOG 240.2 trial, the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic cervical cancer (n=452) was associated with an improvement of 3.7 months in median overall survival. In August 2014, the US Food and Drug Administration approved bevacizumab for the treatment of recurrent, persistent or metastatic cervical cancer as a result of GOG 240.2. Approval in the UK, Switzerland and several Latin American countries followed, with others pending.

According to the lead author of the new analysis, Krishnansu S. Tewari, MD, the primary translational objective of GOG 240.9 was to determine whether CTCs can be isolated from patients with recurrent, persistent, or metastatic cervical cancer. Secondary translational objectives were to determine the association of CTCs and survival, to determine whether CTCs increase or decrease following intervening therapy, and to determine the impact of clearance of CTCs and survival.

The methodology was to draw 8.5 mL blood specimens on pre-cycle day 1 and 36 days post-cycle 1. Immunomagnetic separation using a microfluidic-based CTC chip was performed. Each CTC chip contained 78,000 EpCAM-coated microposts. The captured CTCs were stained for DNA content, epithelial cells, and non-specifically bound leukocytes. The study team used logistic regression and survival analysis to estimate HR for death and disease progression. The exploratory analysis estimated the impact of pre-treatment and 36-day post-treatment CTC counts on survival.

“CTCs are minimally invasive ‘liquid biopsies’ that may allow for phenotypic evaluation of the biologic parameters that govern the spatial and temporal dynamics of advanced cervical cancer,” Tewari said. “The improved overall survival associated with high pre-treatment CTC counts and treatment with bevacizumab may reflect increased tumor vascularization and concomitant vulnerability to antiangiogenesis therapies.” Tewari, an associate professor of gynecologic oncology at the University of California, Irvine, was also lead author on the GOG 240.2 trial.

The study team agrees that prospective validation is necessary. Future work can focus on CTCs and tumor-free DNA. Additionally, the phenomenon of CTCs’ ability to transform from an epithelial to a mesenchymal phenotype may govern metastatic potential and should be explored.

In providing the distillation for a plenary session that focused on biomarkers, Elise Kohn, MD, of the National Cancer Institute began by categorizing biomarkers into types: descriptive or biologic, surrogate, pharmacodynamics, prognostic and predictive. After characterizing it as "very provocative," Kohn categorized the GOG 240.9 work as surrogate, prognostic and, possibly, predictive in nature. At the end of her talk, she concluded, "Our focus should now be on predictive biomarkers to move us into the future. That requires different correlative science designs and focus."

Tewari KS, Sill M, Monk BJ, et al. Impact of circulating tumor cells (CTCs) on overall survival among patients treated with chemotherapy plus bevacizumab for advanced cervical cancer: an NRG Oncology/Gynecologic Oncology Group study. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Abstract Number: 24.