Our study showed that when CTC results are positive in breast cancer patients after surgery, a timely change of the treatment regimen compared with continuation of the original treatment regimen may improve CTC clearance and prolong DFS in patients. According to the CTC results, changing the treatment regimen at an earlier point may improve the prognosis of breast cancer patients. To date, our study is the only clinical study of changing the treatment regimen for patients based on CTC results after breast cancer surgery.
Studies have shown that CTC can be used to monitor the effect of comprehensive treatment of breast cancer, such as predicting chemosensitivity and drug resistance [8–11], monitoring the effects of targeted therapy [12–13], and assessing patient prognosis [14]. However, during postoperative follow-up, when CTC examination results were positive, imaging did not always identify tumor recurrence or metastasis, and it was unclear whether the treatment regimen should be changed based on CTC-positive results alone. Our study included patients with a high risk of recurrence. After their surgery and chemotherapy, 56.0% had positive CTC results during the follow-up period. The treatment regimen for some CTC-positive patients was changed innovatively. Specifically, for ER-positive or PR-positive patients, endocrine therapy was changed from AI to TAM, or TAM was changed to AI; for ER-negative and PR-negative patients, capecitabine was used. These changes in treatment regimens resulted in CTC clearance in 93.5% (29/31) of patients after breast cancer surgery, and CTC clearance was significantly increased compared with the unchanged treatment regimen.
Studies have confirmed that CTC may predict the prognosis of breast cancer patients [17–20] and shown that in patients with early or metastatic breast cancer, a positive CTC result can indicate a poor prognosis [18–20]. Cristofanilli et al. confirmed in a large sample clinical study that CTC monitoring results are an independent factor affecting DFS and OS in breast cancer patients [18]. Rack et al. examined CTC in 1767 breast cancer patients and showed that there was a correlation between CTC positivity and lymph node metastasis [19], while Lang et al. showed a correlation between CTC positivity and tumor metastasis and HER2 status of the primary tumor [20]. However, some scholars believe that CTC positivity is not a necessary condition for tumor metastasis or recurrence; even if CTCs are positive, the microenvironment of the target organ is not necessarily suitable for tumor metastasis [15–16]. Therefore, whether positive CTC results can be used as a basis for adjusting the treatment regimen, thereby resulting in a patient survival benefit, is unknown. Our study has demonstrated a significantly longer DFS in CTC-positive patients by changing the treatment regimen versus those who did not change. Specifically, improved CTC clearance may translate into a patient survival benefit. Adjusting the endocrine therapy regimen for hormone receptor-positive patients and treating hormone receptor-negative patients with capecitabine both improved CTC clearance and improved patient DFS. In addition, after changing the treatment regimen, the DFS of CTC-positive patients was not significantly different from that of CTC-negative patients. Therefore, we believe that positive CTC results can be used as a basis for adjusting the treatment regimen.
In ER-positive or PR-positive patients, drug resistance may occur during endocrine therapy. The 3-year drug resistance rate of advanced breast cancer is 31.4%, reaching 65.2% at 5 years. Activation of HER2, EGFR, FGFR, and other receptor tyrosine kinases promotes endocrine resistance [21]. Endocrine therapy resistance can only be indirectly inferred after tumor recurrence or metastasis based on previous follow-up protocols. The detection of CTCs makes it possible to detect drug resistance in advance, thereby changing to another class of drugs in a timely manner before tumor recurrence or metastasis. In the past, hormone receptor-negative patients, regardless of HER2 status, had no further treatment available when CTC-positive, and were required to wait for observation, resulting in distant tumor metastasis in some patients. In this study, by adjusting the drug, the CTC clearance rate was increased and the time to tumor recurrence was prolonged.
There is heterogeneity during tumor progression and metastasis [22–25], and the latter may manifest as changes in molecular typing during breast cancer progression and metastasis [23–25]. Helissey et al. studied 56 patients with metastatic breast cancer who received chemotherapy and found that patients with early CTC reduction had improved OS [22]. Guan et al. showed that some breast cancer patients with HER2-negative primary tumors, while some CTCs showed HER2-positive. The latter may play a key role in adjusting treatment regimens [26]. Although molecular typing of positive CTCs was not tested in this study, the change in treatment regimen was nonetheless based on molecular typing of the primary tumor. However, we believe that timely change of treatment regimen for CTC-positive patients is necessary, and its molecular basis requires further study.
Our study has some limitations. This study was a retrospective study. Also, the short follow-up time may not have allowed observation of benefits in OS, although follow-up of the studied patients is continuing. The change of treatment regimen was not randomized or controlled for, and the conclusions of this study should be verified by a multicenter, randomized controlled clinical study.