Circulating tumor cells help differentiate benign ovarian lesions from cancer before surgery: A literature review and proof of concept study using flow cytometry with fluorescence imaging

Abstract

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Keywords: circulating tumor cells; dynamic changes; liquid biopsy; ovarian cancer; prognosis; survival.

Figure 1.

Study flowchart. CTC, circulating tumor cell.

Figure 2.

ROC curve and cutoff of CTCs to differentiate between malignant and benign lesions. The (A) ROC curve demonstrates the accuracy of CTC measurements in differentiating between ovarian cancer and benign ovarian lesions, with (B) an area under the curve of 0.900 and P<0.0001. (C) Cutoff value was defined as 4.75 cells/ml with a sensitivity of 76.9% and a specificity of 97.4%, which were calculated using the Youden index. ROC, receiver operating characteristic; CTC, circulating tumor cells; Std., standard.

Figure 3.

Differences in survival between groups by baseline and changes in CTCs. Patients with lower baseline CTC counts had (A) a longer PFS and (B) significantly longer OS. The decline of CTC numbers after therapy may predict (C) significantly longer PFS and (D) markedly longer. The red box in C highlights the optimal cutoff value determined through the Youden index method. CTC, circulating tumor cell; PFS, progression-free survival; OS, overall survival.