Circulating Tumor Cells as a Tool of Minimal Residual Disease Can Predict Lung Cancer Recurrence: A longitudinal, Prospective Trial

Ching-Yang Wu, Chia-Lin Lee, Ching-Feng Wu, Jui-Ying Fu, Cheng-Ta Yang, Chi-Tsung Wen, Yun-Hen Liu, Hui-Ping Liu, Jason Chia-Hsun Hsieh, Ching-Yang Wu, Chia-Lin Lee, Ching-Feng Wu, Jui-Ying Fu, Cheng-Ta Yang, Chi-Tsung Wen, Yun-Hen Liu, Hui-Ping Liu, Jason Chia-Hsun Hsieh

Abstract

Background: The role of circulating tumor cells (CTCs) for predicting the recurrence of cancer in lung cancer patients after surgery remains unclear.

Methods: A negatively selected protocol of CTC identification was applied. For all the enrolled patients, CTC testing was performed before and after surgery on the operation day (day 0), postoperative day 1, and day 3. The daily decline and trend of CTCs were analyzed to correlate with cancer relapse. The mixed model repeated measures (MMRM) adjusted by cancer characteristics was applied for statistical significance.

Results: Fifty patients with lung mass undergoing surgery were enrolled. Among 41 primary lung cancers, 26 (63.4%) were pathological stage Tis and I. A total of 200 CTC tests were performed. MMRM analysis indicated that surgery could contribute to a CTC decline after surgery in all patients with statistical significance (p = 0.0005). The daily decrease of CTCs was statistically different between patients with and without recurrence (p = 0.0068). An early rebound of CTC counts on postoperative days 1 and 3 was associated with recurrence months later.

Conclusion: CTC testing can potentially serve as a tool for minimal residual disease detection in early-staged lung cancer after curative surgery.

Keywords: circulating tumor cells; early detection; early-stage; minimal residual disease’ mixed model repeated measures; non-small cell lung cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The study flow of the prospective design. (CTC, circulating tumor cell; POD1, postoperative day 1; POD3, postoperative day 3).
Figure 2
Figure 2
The positivity of circulating tumor cells (CTCs) in different clinical scenarios. The CTC positivity is not different among four subgroups before curative surgery and is statistically different immediately after the surgery (postoperative day 0, p = 0.04). A possible false positivity of 25.0% can be observed in the benign group (n = 4), but it goes down to zero after surgery. On the other hand, the CTC positivity of the oligometastasis group (n = 6) remains 40.0–80.0% though the operation has removed even the visible tumor(s).
Figure 3
Figure 3
The rebound of circulating tumor cell counts correlates to minimal residual disease. In this figure, a rebound of mean CTC number was observed on day three after surgery in both oligometastasis group (red) and primary lung cancer with recurrence group (green), indicating possible minimal residual tumor signals in blood after surgery.
Figure 4
Figure 4
Boxplots of circulating tumor cells within 3 days of surgery.

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