Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062)

Abstract

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Trial registration: ClinicalTrials.gov NCT00803062.

Conflict of interest statement

Conflicts of Interest/Disclosure:

Dr(s) Tewari, Monk, Penson, and Birrer disclose that they have attended Advisory Boards held by Genentech/Roche.

©2020 American Association for Cancer Research.

Figures

Figure 1:

CONSORT Diagram indicating sample collection according to the schema of Gynecologic Oncology Group protocol 240.

Figure 2:. Circulating tumor cell (CTC) is indicated by the arrow.

Pan-cytokeratin positive (panel A), CD45 (leukocyte common antigen) negative (panel B) were counted as CTC. Panel C merges panels A and B. Cells were stained with DAPI (panel D) to assess fluorescence excitation/emission. The bright field image is also depicted (panel E). Images kindly provided by M. Takakura from Kanazawa Medical University, Uchinada, Japan.

Figure 3:

Kaplan-Meier curves demonstrating overall survival [HR 0.57; 95% CI, 0.32–1.03] (panel A) and progression-free survival [HR 0.59; 95% CI, 0.36–0.96] (panel B) among patients with high vs low levels of pre-Cycle 1 circulating tumor cells stratified by treatment with and without bevacizumab. The effect of bevacizumab administration on progression-free survival has its greatest impact among women treated with the cisplatin-paclitaxel chemotherapy backbone [HR 0.26; 95% CI, 0.12–0.55] (panel C). The green arrows that appear in each panel suggest that high levels of pre-treatment CTCs may represent a predictive biomarker as treatment with bevacizumab shifts the survival curve to the right.