Background: Circulating tumor cells (CTCs) are the precursors of metastatic cancer because they originate from primary tumor sites into the vascular system. The prognostic information of CTCs was well established in breast cancer treatment while the predictive value was still unclear. The aim of this study was to analyze the predictive value of CTCs count during treatment. Materials and Methods: A prospective study was conducted from 2019 to 2021, and 31 female breast cancer patients were enrolled, and 54 blood samples were collected at Linkou Chang Gung Memorial Hospital. The median age was 47 years old. We used LIPO platform for CTC isolation with anti-EpCAM antibody. To achieve maximum cellular viability, the LIPO platform was further optimized by using liposomes-lipid bilayers instead of lipid bilayers as the underneath surface coating to facilitate the detachment of bound cells from the surface and maintain cellular viability. Results: Fourteen patients were Stage II or stage III (non-metastasis) and 17 metastatic patients were included. Eleven patients (35.5%) were ER-positive HER2-negative while 10 patients (32.6%) were ER-positive HER2-positive. Three patients (9.7%) were HER2 enriched subtypes, and 7 patients (22.6%) were triple negative breast cancer. Blood samples from a total of 28 patients can be analyzed. At least one CTC was detected in 44/49 (89.8%) blood samples, CTC can’t be identified in 2/5 (40%) post-treatment with good response. The average single CTC count per 2 ml was 34.40 in non-metastatic patients versus 110.43 in metastatic patients (p = 0.3895). The average clustered CTC count per 2 ml was 13.44 in non-metastatic patients versus 40.16 in metastatic patients (p = 0.424). The total single and clustered CTC count per 2 ml was 47.84 non-metastatic patients versus 150.59 in metastatic patients (p = 0.3977). In 10 patients with clinically partial response, the average single CTC count per 2 ml was 61.9 before treatment and 11.81 after treatment (p = 0.0716), and the average clustered CTC per 2 ml was 15.83 before treatment and 5.28 after treatment (p = 0.8806). In 4 patients with clinical progression, the average single CTC count per 2 ml was 22.694 before treatment and 26.125 after treatment (p = 0.0257), and the average clustered CTC per 2 ml was 7.69 before treatment and 16.61 after treatment (p = 0.3798). Conclusions: Our findings concluded that the decline of circulating tumor cell clusters count can predict the treatment response in breast cancer patients.