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Real world analysis of the efficacy and safety of eribulin compared to utidelone in combination with capecitabine for the treatment of metastatic breast cancer

Cancer Cell International volume 24, Article number: 416 (2024) Cite this article

Abstract

Background

The objective of this study was to compare the efficacy and safety of subsequent chemotherapy with single eribulin or utidelone combined with a capecitabine regimen in patients with advanced breast cancer who had previously been treated with anthracyclines and paclitaxel.

Methods

This work was a retrospective analysis of 85 patients from July 2018 to July 2023. Forty-two and 43 patients were treated with the eribulin regimen and the utidelone/capecitabine regimen, respectively. The endpoints included progression-free survival, overall survival, the objective remission rate and safety. Survival analyses and multifactorial analyses were performed via the Kaplan‒Meier method, log-rank test and Cox regression models.

Results

As of 15 April 2024, the mPFS durations of the patients in the utidelone/capecitabine and eribulin treatment groups were 7.7 and 5.2 months, respectively, and the mOS durations were 22.0 and 18.2 months, respectively. Subgroup analyses revealed that in advanced first-line therapy, the mPFS durations of the utidelone/capecitabine group and the eribulin group were 11.8 and 7.0 months, respectively, and this difference was significant. In the eribulin treatment arm, the mPFS of first-line therapy was 7.0, whereas it was 3.3 months for posterior-line therapy, and this difference was significant. The most common adverse reactions were neurotoxicity, hand‒foot syndrome, hematological toxicity, gastrointestinal toxicity, and abnormalities in hepatic and renal functions.

Conclusions

In conclusion, either utidelone/capecitabine or eribulin chemotherapy may result in a survival benefit with a tolerable adverse effect profile and favorable safety profile in patients with metastatic breast cancer. The first-line use of eribulin resulted in better PFS and ORR than posterior-line use, and the combination of utidelone/capecitabine represents a more efficacious approach in the advanced first-line therapy of breast cancer.

Introduction

According to the global tumor data released by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) in 2020, the number of new cases of breast cancer was 2.26 million; therefore, breast cancer represents the most diagnosed type of tumor and has resulted in approximately 680,000 deaths. Moreover, the incidence and mortality rates for this cancer have surpassed those for lung cancer, which was previously considered the most common cancer [1].

Numerous clinical studies [2,3,4,5,6,7,8,9] have shown that the combination of anthracyclines and paclitaxel drugs can significantly improve the prognosis of breast cancer patients. However, an estimated 20–30% of patients with early-stage breast cancer will subsequently develop recurrent metastases. Metastatic breast cancer (MBC) is a disease with an incurable prognosis that has a 5-year survival rate of only 27% [10, 11]; the 10-year survival rate is 13%, with an overall median survival time of 2–3 years [12]. The objective of treatment is to prolong survival and to maintain or improve quality of life. Chemotherapy remains important for patients resistant to endocrine therapy and is the primary treatment for patients with triple-negative breast cancer (TNBC) [11, 13, 14]. Most MBC patients have already undergone treatment with anthracyclines and paclitaxel, both in the neoadjuvant and adjuvant stages. However, the reuse of these agents is also prone to problems such as multidrug resistance and accumulation toxicity in tumor cells [15], which greatly weakens patients' adherence and consequently affects their survival.

The NCCN Guidelines for 2023 and 2024 [16, 17] recommend systemic therapy for HER2-negative metastatic breast cancer without target mutations, for with the first choice of chemotherapy should be selected antimetabolites (capecitabine or gemcitabine), microtubule inhibitors (vincristine or eribulin), gosatuzumab, platinum (cisplatin or carboplatin), albumin‒paclitaxel, epoetin-type antitumour agents (ixabepilone), and other chemotherapy options. The latest ESMO Guidelines [18] suggest that capecitabine, vincristine, gemcitabine, platinum, eribulin and utidelone may be considered monotherapy or combination regimens in the first-line and subsequent palliative treatment of metastatic breast cancer [19]. CSCO Guidelines for 2024 [20] recommend that for HER2-negative advanced breast cancer for which paclitaxel-based therapy has failed, the first-line recommended chemotherapy is either eribulin, vincristine, gemcitabine, or capecitabine monotherapy or combination chemotherapy with NP (vincristine + platinum), GP (gemcitabine + platinum), UX(utidelone + capecitabine), or NX (vincristine + capecitabine). Furthermore, posterior-line treatment may be considered in conjunction with albumin paclitaxel, an anti-TROP-2-targeting agent (gosatuzumab), etoposide monotherapy, capecitabine in combination with bevacizumab, or albumin paclitaxel in combination with other chemotherapies. Nevertheless, research that compares late-stage first-line drugs is lacking, particularly head-to-head studies of eribulin and utidelone. Although numerous options exist for late-stage posterior line treatment, the methodology for identifying the relative advantages and disadvantages of these options has not been elucidated in any relevant studies.

Ebomycin B was first found to have inhibitory effects on tumor cells in 1995 [21] and has excellent antitumor properties and few adverse reactions [22]. Utidelone (UTD1) was the first approved epirubicin drug in China. Two open-label, uncontrolled Phase II clinical trials [23] involving UTD1 monotherapy and UTD1 + capecitabine combination therapy in MBC patients previously treated with anthracyclines and/or paclitaxel reported that the PFS and ORR of the combination group were longer than those of the monotherapy group. In this multicenter, randomized, open-label, Phase III study, BG01-1323L (NCT 02253459) [24], PFS (P < 0.00011) and OS (P = 0.0142) improved with the combination of utidelone and capecitabine compared with capecitabine alone. The ORR (P < 0.001) also significantly increased. In 2021, utidelone was officially approved for the treatment of metastatic breast cancer, breaking the stalemate of traditional breast cancer treatment and ending the lack of breakthroughs in chemotherapy drugs other than paclitaxel in China for nearly three decades.

Eribulin mesylate (hereinafter referred to as “Eribulin”) is a new type of nonpaclitaxel microtubule protein inhibitor [25, 26], and it is effective for patients who are resistant to paclitaxel [27]. Phase I/II clinical trials of eribulin in combination with everolimus, pembrolizumab, olaparib and gemcitabine have shown promising antitumour activity [28, 29]. A number of Phase II clinical studies [30, 31] have shown that eribulin has good efficacy and tolerable adverse reactions as well as good ORR and CBR in MBC patients previously treated with paclitaxel [32]. Eribulin was first developed in Japan and was launched in the United States on November 15, 2010. Eribulin was approved in China in 2019 for the treatment of advanced metastatic breast cancer previously treated with anthracyclines and paclitaxel. At present, eribulin can be used as the recommended chemotherapy drug for anti-human epidermal growth factor receptor 2 (HER-2)-negative breast cancer after the failure of anthracycline and paclitaxel treatment, and patients can also benefit from combination therapy [33, 34].

The mechanisms underlying the antitumor effect of fluoropyrimidines have been well-characterized [35], It promote genomic instability by inducing doublestrand DNA and single-strand DNA breaks, as well as by interfering with DNA synthesis, repair,and elongation. Capecitabine is the first oral fluoropyrimidine approved by the Food and Drug Administration for MBC after the use of an anthracyclines and paclitaxel regimen or in presence of contraindication to anthracycline therapy [36, 37]. Capecitabine is converted to 5-fluorouracil by an enzymatic reaction mediated by thymidine phosphorylase (TP). Andreetta et al. [38] evaluated the potential relationship between TP expression and benefit from capecitabine in patients with MBC. Study showed patients with TP-positive MBC and previously treated with a taxane-based therapy (also in combination or in sequence with anthracyclines) achieved a better clinical benefit and a significantly longer PFS than patients who did not receive these treatments before capecitabine.

Currently, the overall physical and mental recovery of breast cancer patients has garnered increasing attention, and advanced patients are no exception; additionally, highly effective and low-toxicity treatments are urgently needed. Although utidelone and eribulin have been approved for the treatment of metastatic breast cancer, their clinical application experience is insufficient, and head-to-head studies of the efficacy and safety of these two drugs in metastatic breast cancer are lacking. Therefore, we conducted a multicenter clinical trial to summarize the efficacy and safety of these two drugs in the treatment of advanced breast cancer in the real world. Subgroup analysis was also performed to compare the differences between the two groups in terms of first-line and later-line late-stage treatment to guide clinicians' drug selection.

Materials and methods

1. Clinical data: This retrospective study collected the clinical data of patients with metastatic breast cancer who had previously received anthracyclines and paclitaxel at designated specialized hospitals (Yunnan Cancer Hospital, Chuxiong Yi Autonomous Prefecture People's Hospital) and received utidelone combined with capecitabine and single eribulin from July 2018 to July 2023. The collected data included information on the patient's age, menstrual status, body mass index, tumor stage, molecular type, site of metastasis, whether the primary tumor was resected, and type of previous treatment received. A total of 85 patients with MBC were enrolled, with 42 patients in the eribulin chemotherapy group (hereinafter referred to as the “Eri group”), including 12 patients with advanced first-line therapy and 30 patients with advanced second-line or later therapy. The utidelone combined with capecitabine chemotherapy group (hereinafter referred to as the "UX group") consisted of 43 patients, including 11 patients with advanced first-line therapy and 32 patients with advanced second-line or later therapy (Fig. 1).

Fig. 1
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Flow chart of patient enrollment

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2. Patient diagnostic criteria: All patients with MBC underwent physical examination, blood biochemical examination, color Doppler ultrasound, CT or MRI examination and other imaging examinations at designated specialized hospitals. Tissue biopsy or lumpectomy was performed after assessment by a breast surgeon at a designated specialist hospital. Histopathological specimens were diagnosed as malignant tumors originating from the epithelium of the terminal ductal and lobular units of the breast by at least two doctors in the Department of Pathology of the designated specialist hospital. In addition, pathological immunohistochemistry results and FISH (fluorescence in situ hybridization) genetic test results were obtained directly from pathologists at the designated specialist hospitals for diagnosis or consultation for all patients. Progressive first-line treatment was defined as patients with prior anthracycline and paclitaxel use, a first diagnosis of metastatic breast cancer, and first-line therapy with utidelone in combination with capecitabine or eribulin.

3. The inclusion criteria for patients were as follows: (1) patients with postoperative recurrence and metastasis or newly diagnosed Stage IV breast cancer confirmed by histopathology; (2) patients treated with UX or Eri therapy who had progressed after prior neoadjuvant or adjuvant therapy with anthracyclines and paclitaxel; (3) patients with at least 1 measurable lesion according to response evaluation criteria in solid tumors (RECIST 1.1); (4) patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 2 points; (5) patients whose functions of important organs were normal and whose routine blood, liver and kidney function tests before chemotherapy were normal who lacked contraindications to treatment; (6) patients who were easy to follow up and sign the informed consent form.

4. The exclusion criteria were as follows: (1) patients with incomplete follow-up data and incomplete clinical data; (2) patients who received < 2 cycles of chemotherapy with UX or Eri; (3) male breast cancer patients; (4) patients with a combination of other primary second tumors; and (5) patients whose condition was complicated by important organ dysfunction and whose ability to tolerate chemotherapy was limited.

Study design and treatment

A total of 85 patients with MBC who met the inclusion criteria were enrolled. Clinical information, including age, menstrual status, BMI, tumor stage, molecular type, metastatic site, previous treatment received, and whether the primary tumor was removed, was collected. Forty-two patients in the Eri group, including 12 patients with advanced first-line therapy and 30 patients with advanced second-line or later therapy, received an eribulin-based antitumor treatment regimen. On Day 1 and Day 8 of each cycle, eribulin was intravenously infused over 60 min at a dose of 1.4 mg/m2 for 21 days as a cycle. Forty-three patients in the UX group, including 11 patients with advanced first-line therapy and 32 patients with advanced second-line or later therapy, were administered utidelone intravenously at a dosage of 30 mg/m2 once per day on Days 1–5 of each cycle, whereas capecitabine was administered orally (1000 mg/m2, twice per day) on Days 1–14 of each cycle, with 21 days as a cycle. Follow-up evaluations were conducted every 2 cycles, and treatment was continued if remission or stabilization of the disease occurred. After the completion of standard chemotherapy (6–8 courses), treatment was continued until progressive disease (PD), intolerable toxicity, or any other reason for discontinuation. Dose reductions during chemotherapy were allowed to control toxicity, and prophylactic administration of granulocyte colony-stimulating factor was allowed at the discretion of the physician.

Pathological interpretation standards

Tissue biopsy or lumpectomy specimens were diagnosed as malignant tumors originating from the epithelium of the terminal ductal and lobular units of the breast by two or more physicians in the Department of Pathology of the designated specialist hospital. The estrogen receptor (ER) and progesterone receptor (PR) status was categorized as follows: negative, percentage of tumor cells with positive nuclear staining < 1%; positive, percentage of tumor cells with positive nuclear staining ≥ 1% for any intensity of staining. The human epidermal growth factor receptor 2 (HER-2) status was categorized as follows: immunohistochemistry for HER-2(1 +) or HER-2(2 +) and fluorescence in situ hybridization (FISH) for HER-2/CEP17 < 2.0 were considered negative; HER-2(3 +) or HER-2(2 +) and FISH for HER-2/CEP17 ≥ 2.0 were considered positive. Ki-67 interpretation [39]: cells with nuclei stained yellowish to brownish yellow examined under a 400 × light microscope were considered positive. Ten fields of view were randomly selected, 500 cells were counted in each field of view, and the ratio of the number of Ki-67-positive cells to the total number of cells was calculated.

Observation indicators

1. Efficacy evaluation criteria: The primary endpoint of this study was patient progression-free survival (PFS). PFS was defined as the time interval between the initiation of treatment with Eri or UX and the 1st occurrence of disease progression or death from any cause, with the median PFS defined as the time to progression-free survival achieved by 50% of patients.

The secondary endpoints included overall survival (OS), the objective response rate (ORR), and safety. OS was defined as the time from the initiation of treatment with Eri or UX to the time until the patient's death or final follow-up visit, and the median OS was defined as the survival time in 50% of patients. All patients had baseline measurements before treatment of measurable lesions, and regular imaging and measurements were performed during treatment. According to the Response Evaluation Criteria in Solid Tumors version 1.1, a complete response (CR) was defined as the complete disappearance of all target lesions. A partial response (PR) was defined as a ≥ 30% reduction in the sum of all target lesions from baseline. Disease progression (PD) was defined as an increase of ≥ 20% in the sum of the diameters of all target lesions from the minimum value in the study and an absolute increase of at least 5 mm in the sum of diameters or the appearance of one or more new lesions. Stable disease (SD) was defined as a reduction in target lesions that did not reach a PR or an increase in target lesions that did not reach PD. The objective response rate (ORR) was the percentage of patients who achieved CR or PR. Additionally, this study analyzed the prognostic factors influencing the prognosis of patients with MBC.

2. Evaluation of adverse effects: Adverse reactions were collected from medical records during treatment, laboratory tests, and follow-up of patients' subjective feelings. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Routine hematological and blood biochemical tests were performed once on Days 2–3 and 7 of each treatment cycle until treatment was discontinued. In addition, the vital signs of the patients were regularly assessed during the treatment period, and ECG, echocardiography, and physical examination were performed to identify any abnormalities or significant changes from baseline. All assessments and examinations were performed at baseline and at the end of each treatment cycle during the treatment period.

3. The follow-up methods were as follows: 1. Telephone follow-up data, such as the start time of medication, course of treatment, subjective feelings about adverse reactions during medication, and time interval of death from any cause, were recorded; 2. Patient follow-up: Patients' laboratory and imaging findings at each outpatient follow-up visit were recorded, patients' vital signs were assessed, adverse reactions were evaluated, and the time to disease progression in patients was calculated. Follow-up began on July 1, 2018, and ended on April 15, 2024. All 85 patients enrolled in the study were followed up, with no patients lost to follow-up.

4. Statistical methods: IBM SPSS Statistics 22.0 and GraphPad Prism 10 were used for statistical analysis. A P < 0.05 was considered statistically significant. Categorical variables were analyzed via the chi-square test or Fisher's exact test and are presented as percentages. Efficacy and safety were summarized via descriptive statistics. The Clopper–Pearson method was used to calculate 95% confidence intervals for the ORR. The Kaplan‒Meier method and log-rank test were used for survival analysis. Univariate and multivariate Cox proportional hazards models were used to calculate hazard ratios (HRSs) and 95% confidence intervals. A univariate Cox model was used to test the prognostic factors of metastatic breast cancer, the clinical significance of the variables was considered, and a multivariate Cox model was used to identify the independent prognostic factors of metastatic breast cancer.

Results

1. Clinical characteristics of the study subjects: A total of 85 patients with MBC were enrolled (Table 1). The Eri group consisted of 42 patients, including 12 patients with advanced first-line therapy, 30 patients with advanced second-line or later therapy. The UX group consisted of 43 patients, including 11 patients with advanced first-line therapy and 32 patients with advanced second-line or later therapy. All patients were Chinese women aged between 32 and 70 years who had been previously treated with anthracyclines and paclitaxel-based drugs. P values were obtained via the Pearson chi-square test or Fisher's exact method. Age, menstrual status, body mass index (BMI), tumor size, molecular type, metastatic site, previous treatment received, or primary tumor resection did not significantly differ between the Eri group and UX group (P > 0.05). However, the P values of lymph node metastasis at initial diagnosis (P = 0.005) and distant metastasis at initial diagnosis (P < 0.001) were < 0.05. The subjects were divided into three subgroups (Table 2). The first subgroup received advanced first-line therapy with UX versus Eri. The second subgroup received advanced second-line or later therapy with UX versus Eri. The third subgroup received eribulin advanced first-line therapy versus eribulin advanced second-line or later therapy. These groups did not differ in age, menstrual status, body mass index (BMI), tumor size, lymph node metastasis at initial diagnosis, distant metastasis at initial diagnosis, molecular typing, metastatic site, previous treatment received, or whether the primary tumor was resected (P > 0.05).

Table 1 Study subject demographics
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Table 2 .Demographics of subgroup study participants
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2. Clinical efficacy and prognosis analysis: By April 15, 2024, a total of 28 events of progression-free survival had occurred in the Eri group, and 36 events of progression-free survival had occurred in the UX group. According to the researchers' assessment, the mPFS was 7.7 months in the UX group and 5.2 months in the Eri group; the mPFS of the UX group is better than that of the Eri group, but the difference was not statistically significant (log-rank P = 0.074, HR = 0.6073, 95% CI 0.3513–1.050) (Fig. 2A, Table 3).

Fig. 2
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Kaplan–Meier survival estimates for PFS, OS. CI: confidence interval, UX (Utidelone plus Capecitabine), Eri(Eribulin). A Progression-Free-Survival in the UX therapy vs Eri therapy population. The mPFS was 7.7 months and 5.2 months separately(log-rank P = 0.074, HR = 0.6073, 95%CI 0.3513–1.050). B Progression-Free-Survival in the UX first-line therapy vs Eri first-line therapy population. The mPFS was 11.8 months and 7.0 months separately (log-rank P = 0.017, HR = 0.2323, 95%CI 0.07007–0.7702). C Progression-Free-Survival in the UX second-line or above therapy vs Eri second-line or above therapy population. The mPFS was 5.1 months and 3.3 months separately(log-rank P = 0.2676, HR = 0.7011, 95%CI 0.3742–1.314). D Progression-Free-Survival in the Eri first-line therapy vs Eri second-line or above therapy population. The mPFS was 7.0 months and 3.3 months separately(log-rank P = 0.0221, HR = 0.5936, 95%CI 0.2755–1.279). E Overall survival in the UX therapy vs Eri therapy population. The mOS was 22.0 months and 18.2 months separately(log-rank P = 0.9569, HR = 1.021, 95%CI 0.4808–2.168). F Overall survival in the UX second-line or above therapy vs Eri second-line or above therapy population. The mOS was 18.8 months and 13.5 months separately (log-rank P = 0.4194, HR = 1.418, 95%CI 0.6073–3.313)

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Table 3 .Summary of survival analysis results
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Subgroup analysis revealed 8 progression-free survival events in the Eri first-line therapy group, 20 progression-free survival events in the Eri second-line or later therapy group, 7 progression-free survival events in the UX first-line therapy group, and 29 progression-free survival events in the UX second-line or later therapy group. The mPFS was 11.8 months in the UX first-line therapy group and 7.0 months in the Eri first-line therapy group. The mPFS in the UX first-line therapy group was longer than that in the Eri first-line therapy group, and the difference was statistically significant (log-rank P = 0.017, HR = 0.2323, 95% CI 0.07007–0.7702) (Fig. 2B, Table 3). The mPFS was 5.1 months in the UX second-line or later therapy group and 3.3 months in the Eri second-line or later therapy group. The mPFS of the UX second-line or later therapy group was better than that of the Eri second-line or later therapy group, but the difference was not statistically significant (log-rank P = 0.2676, HR = 0.7011, 95% CI 0.3742–1.314) (Fig. 2C, Table 3). The mPFS was 7.0 months in the Eri first-line therapy group and 3.3 months in the Eri second-line or later therapy group; the mPFS of the Eri first-line therapy group was better than that of the Eri second-line or later therapy group, and the difference was statistically significant (log-rank P = 0.0221, HR = 0.5936, 95% CI 0.2755–1.279) (Fig. 2D, Table 3).

In the final OS analysis at the cutoff date, 11 deaths had occurred in the Eri group, and 22 deaths had occurred in the UX group, with mortality rates of 26.19% and 51.16%, respectively (the Eri group had a shorter follow-up time than the UX group). The mOS was 22.0 months in the UX group and 18.2 months in the Eri group; the mOS of the UX group was longer than that of the Eri group, but the difference was not statistically significant (log-rank P = 0.9569, HR = 1.021, 95% CI 0.4808–2.168) (Fig. 2E, Table 3).

Subgroup analyses revealed a total of 4 deaths in the Eri first-line therapy group, 7 deaths in the Eri second-line or later therapy group, 2 deaths in the UX first-line therapy group, and 20 deaths in the UX second-line or later therapy group. The mortality rates were 33.3%, 18.9%, 18.18% and 62.5%, respectively (the Eri group had a shorter follow-up than the UX group). mOS data were not obtained in the Eri first-line group or the UX first-line group. The mOS was 18.8 months in the UX second-line or later therapy group and 13.5 months in the Eri second-line or later therapy group. The mOS of the UX second-line or later therapy group was longer than that of the Eri second-line or later therapy group, but the difference was not statistically significant (log-rank P = 0.4194, hazard ratio (HR) = 1.418, 95% confidence interval (CI) = 0.6073–3.313) (Fig. 2F, Table 3).

In the efficacy evaluation section, 43 patients in the UX group were evaluated for response, and 3 were not evaluated (1 patient did not undergo enhanced CT or MRI because of severe fever due to COVID-19; the other 2 patients did not receive enhanced CT or MRI after the completion of 2 cycles of chemotherapy for physical or financial reasons). Among the 42 patients in the Eri group, 39 patients were evaluated, and 3 patients were not evaluated (1 patient continued to be treated at another hospital after 2 cycles of chemotherapy, and the relevant follow-up data after 2 cycles could not be found; the other 2 patients did not receive enhanced CT or MRI after the completion of 2 cycles of chemotherapy for physical or financial reasons). At the end of the study, 1 case of complete response (CR), 7 cases of partial response (PR), 10 cases of stable disease (SD) and 22 cases of progressive disease (PD) were observed in the UX group, with an ORR of 18.6% (95% CI 0.084–0.334). A total of 0 CR, 9 PR, 14 SD and 16 PD cases were observed in the Eri group, with an ORR of 21.43% (95% CI 0.103–0.368). The difference in ORR between the two groups was not statistically significant (P = 0.745) (Fig. 3A, Table 4).

Fig. 3
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ORR, CR, PR, SD, PD ratio of the different treatment groups. CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: objective response rate. UX (Utidelone plus Capecitabine), Eri (Eribulin). A ORR, CR, PR, SD, PD ratio of the UX vs Eri therapy. a total of 1 CR, 7 PR, 10 SD and 22 PD were observed in the UX group, with an ORR of 18.6%(95%CI 0.084–0.334); a total of 0 CR, 9 PR, 14 SD and 16 PD were observed in the Eri group, with an ORR of 21.43%(95%CI 0.103–0.368). B ORR, CR, PR, SD, PD ratio of the UX first-line vs Eri first-line therapy.a total of 1 CR, 2 PR, 3 SD and 3 PD were observed in the UX advanced first-line group, with an ORR of 27.27%(95%CI 0.060–0.610); 0 CR, 3 PR, 6 SD and 2 PD were observed in the Eri advanced first-line group, with an ORR of 25% (95% CI 0.055–0.572). C ORR, CR, PR, SD,P D ratio of the UX second-line or above vs Eri second-line or above therapy.a total of 0 CR, 5 PR, 7 SD and 19 PD were observed in the UX advanced second-line and above group, with an ORR of 15.63%(95%CI 0.053–0.328); 0 CR, 6 PR, 8 SD and 14 PD were observed in the Eri advanced second-line and above group, with an ORR of 20%(95%CI 0.077–0.386). D ORR, CR, PR, SD, PD ratio of the Eri first-line vs second-line or above therapy.a total of 0 CR, 3 PR, 6 SD and 2 PD were observed in the Eri advanced first-line group, with an ORR of 25%(95%CI 0.055–0.5); a total of 0 CR, 6 PR, 8 SD and 14 PD were observed in the Eri advanced second-line and above group, with an ORR of 20%(95%CI 0.077–0.38)

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Table 4 .Study subject end of treatment objective response rates
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Subgroup analyses revealed that of the 11 patients in the UX advanced first-line group, 9 were evaluated for efficacy and 2 were not evaluated (2 patients did not undergo enhanced CT or MRI after completing 2 cycles of chemotherapy for physical or financial reasons). Of the 32 patients in the UX advanced second-line or later therapy group, 31 were evaluated for efficacy and 1 patient was not evaluated (no enhanced CT or MRI examination due to severe fever due to COVID-19 infection). Of the 12 patients in the Eri advanced first-line group, 11 were evaluated for efficacy and 1 was not evaluated (did not undergo enhanced CT or MRI after completing 2 cycles of chemotherapy for financial reasons). Of the 30 patients in the Eri advanced second-line or later therapy group, 28 were evaluated for efficacy and 2 were not evaluated (1 patient continued treatment in an outside hospital after completing 2 cycles of chemotherapy, the relevant review data after 2 cycles could not be found; 1 patient did not receive enhanced CT or MRI examination after completing 2 cycles of chemotherapy for physical reasons). At the end of the study, a total of 1 CR, 2 PR, 3 SD and 3 PD cases were observed in the UX advanced first-line group, with an ORR of 27.27% (95% CI 0.060–0.610); in the Eri advanced first-line group, 0 CR, 3 PR, 6 SD and 2 PD cases were observed with an ORR of 25% (95% CI 0.055–0.572) (Fig. 3B). The ORR did not significantly differ between the two groups (27.27% vs. 25%, P > 0.999) (Table 5). A total of 0 CR, 5 PR, 7 SD and 19 PD cases were observed in the UX advanced second-line or later group, with an ORR of 15.63% (95% CI 0.053–0.328); in the Eri advanced second-line or later group, 0 CR, 6 PR, 8 SD and 14 PD cases were observed with an ORR of 20% (95% CI 0.077–0.386) (Fig. 3C). The ORR did not significantly differ between the two groups (15.63% vs. 20%, P = 0.652) (Table 5). Moreover, the ORR did not significantly differ between the Eri advanced first-line group and the Eri second-line or later group 25% vs. 20%, P = 0.699) (Fig. 3D) (Table 5).

Table 5 .subgroup study subject end of treatment objective response rates
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According to the distribution graph of the results of the investigator's efficacy evaluation, none of the patients in the Eri group achieved CR, but compared with the UX group, the ORR was higher, the proportion of patients who achieved PR and SD was greater, and the proportion of patients with PD was lower. The same distribution of efficacy was also observed in the two subgroups of patients who received advanced first-line therapy with Eri or UX and advanced second-line or later therapy with Eri or UX. In the subgroup analysis of Eri advanced first-line therapy versus second-line or later therapy, the Eri first-line therapy group had higher ORR, PR and SD values, as well as lower PD rates.

This study further analyzed any differences in the proportions of patients who achieved CR/PR and SD/PD in the response evaluation of advanced breast cancer patients receiving different treatments. The chi-square test and Fisher's exact test were used to analyze differences between the number of patients who achieved CR/PR and SD/PD in the UX group and the Eri group, respectively (Table 6), but none of the differences were significant (P > 0.05). Further analysis of the 3 subgroups revealed similar statistical results (Table 7). The clinical efficacy, as indicated by CR/PR or SD/PD, did not significantly differ between the UX therapy group and the Eri therapy group, between the UX advanced first-line group and the Eri advanced first-line group, between the UX advanced second-line and later group and the Eri advanced second-line and later group, or between the Eri advanced first-line group and the Eri advanced second-line or later group.

Table 6 Comparison of CR/PR and SD/PD efficacy in different treatment groups
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Table 7 Comparison of CR/PR and SD/PD efficacy in subgroups
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The efficacy of different treatments for different breast cancer subtypes was also analyzed. The results revealed that for the four subtypes of advanced breast cancer—the HER2 + subtype, HER2- subtype, HER2-ER-PR- subtype, and HER2-ER + PR + subtype—clinical efficacy did not significantly differ by treatment type (UX or Eri treatment, Table 8) or treatment line (Table 9) (P > 0.05). These results must be interpreted with caution due to the limited sample size of the study.

Table 8 .The efficacy of UX therapy and Eri therapy based on the subtypes of breast cancer
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Table 9 The efficacy of subgroups based on the subtypes of breast cancer
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Factors that influence the prognosis of patients with MBC were also explored in this study. First, we applied univariate Cox regression analysis to screen for numerous known variables, including age, menstrual status, BMI, molecular type, and type of previous treatment received. Among the variables considered, ER (P = 0.012), PR (P = 0.001), and the number of metastatic sites (P = 0.035) were significantly associated with the prognosis of patients with MBC (Fig. 4A). Moreover, the clinical significance of each variable was considered comprehensively, and variables with P < 0.2 were included in the Cox multifactorial regression analysis to exclude the influence of confounding factors and comprehensively analyze the influence of multifactorial interactions on the prognosis of patients with MBC. The results of multivariate Cox regression analysis revealed that the presence of distant metastases at the initial diagnosis (P = 0.008, − 10.145), PR status (P = 0.017, HR = 5.288, 95% CI 1.346–20.776), and more than 2 sites of distant metastasis prior to the application of the Eri or UX regimen for rescue chemotherapy (P = 0.022, HR = 0.42, 95% CI 0.2–0.884) significantly affected the prognosis or patients with breast cancer (P < 0.05) (Fig. 4B).

Fig. 4
figure 4

Univariate and multivariate COX analysis of prognostic factors in metastatic breast cancer. BMI: body mass index; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor type 2. A Univariate Cox model analysis for OS. B Multivariate Cox model analysis for OS

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3. Security Analysis. All 85 patients included in the study received at least 2 cycles of treatment, during which they underwent physical examination; regular assessment of vital signs; and imaging tests, such as electrocardiogram and echocardiogram; and color ultrasound, CT, or MRI examinations at designated specialist hospitals. Routine blood and biochemical tests were performed once on Days 2–3 and once on Day 7 of each treatment cycle until treatment was discontinued. Among the 43 patients in the UX group, 1 (2.33%) had no chemotherapy-related adverse events of any grade, 31 (72.09%) had Grade 1–2 adverse events, and 11 (25.58%) had Grade 3 or higher adverse events (Fig. 5A). Among the 42 patients in the Eri group, 3 (7.14%) had no chemotherapy-related adverse events of any grade, 23 (54.76%) had Grade 1–2 adverse events, and 16 (38.10%) had Grade 3 or higher adverse events (Fig. 5B). Deaths due to drug-related adverse effects did not occur in either group.

Fig. 5
figure 5

Treatment related adverse events. UX (Utidelone plus Capecitabine); Eri (Eribulin). A Distribution of adverse reactions at any level in the UX group. B Distribution of adverse reactions at any level in the Eri group. C Classification of toxic and side effects in the UX group. D Classification of toxic and side effects in the Eri group

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In terms of the classification and grading of adverse reactions, in the UX advanced first-line therapy group (11 cases), Grade 1–2 neurotoxicity occurred in 6 patients (54.55%), and no Grade 3 or above neurotoxicity occurred; Grade 1‒2 hand‒foot syndrome occurred in 4 patients (36.36%), and Grade 3 or above neurotoxicity occurred in 1 patient (9.09%); Grade 1‒2 gastrointestinal reactions occurred in 3 patients (27.27%), and Grade 3 or above neurotoxicity occurred in 1 patient (9.09%); Grade 1‒2 hematological toxicity occurred in 3 patient (27.27%); Grade 3 and above neurotoxicity occurred in 1 patient (9.09%); Grade 1‒2 hepatic and renal impairment occurred in 1 patient (9.09%); and Grade 3 and above hepatic and renal impairment did not occur. In the UX advanced second-line therapy group (32 patients), Grade 1–2 neurotoxicity occurred in 28 patients (87.5%), Grade 3 neurotoxicity and above in 3 patients (9.38%), Grade 1–2 hand‒foot syndrome occurred in 18 patients (56.25%), Grade 3 neurotoxicity and above in 1 patient (3.13%), Grade 1–2 gastrointestinal reactions occurred in 18 patients (56.25%), Grade 3 neurotoxicity and above in 5 patients (15.63%), Grade 1–2 hematological toxicity occurred in 7 patients (21.88%), and no Grade 3 or above hematological toxicity occurred; Grade 1–2 hepatic and renal impairment occurred in 12 patients (37.50%), and Grade 3 or above hepatic and renal impairment occurred in 2 patients (6.25%) (Fig. 5C).

In the Eri advanced first-line therapy group (12 patients), Grade 1–2 neurotoxicity occurred in 6 patients (50%), Grade 3 neurotoxicity and above occurred in 1 patient (8.33%), Grade 1–2 hand‒foot syndrome occurred in 3 patients (25%), and Grade 3 neurotoxicity and above hand‒foot syndrome did not occur. Grade 1–2 gastrointestinal reactions occurred in 7 patients (58.33%), and Grade 3 and above gastrointestinal reactions did not occur. Grade 1–2 hematological toxicity occurred in 7 patients (58.33%), Grade 3 and above hematological toxicity occurred in 2 patients (16.67%); Grade 1–2 hepatic and renal impairment occurred in 3 patients (25%), and Grade 3 and above hepatic and renal impairment did not occur. In the Eri advanced second-line therapy group (30 patients), Grade 1–2 neurotoxicity occurred in 13 patients (42.33%), and no Grade 3 or above neurotoxicity occurred; Grade 1–2 hand‒foot syndrome occurred in 13 patients (42.33%), and no Grade 3 or above hand‒foot syndrome occurred; Grade 1–2 gastrointestinal reactions occurred in 12 patients (40%); Grade 3 or above neurotoxicity occurred in 2 patients (26.67%); grade 1–2 hematological toxicity occurred in 13 patients (43.33%); Grade 3 and above neurotoxicity occurred in 13 patients (43.33%); Grade 1–2 hepatic and renal function impairment occurred in 12 patients (40%), and Grade 3 and above hepatic and renal function impairment did not occur (Fig. 5D).

Notably, as the number of therapy lines increased, the incidence and severity of neurotoxicity, gastrointestinal dysfunction, hand-foot syndrome and hepatic and renal impairment tended to increase in the UX group, and the incidence and severity of gastrointestinal dysfunction, hematological toxicity, and hepatic and renal impairment tended to increase in the Eri group. However, no deaths due to adverse effects were observed. These results must be interpreted with caution due to the limited sample size of the study. Based on the results of this study, clinicians should closely monitor neurotoxicity, hand-foot syndrome, and gastrointestinal dysfunction in patients treated with UX chemotherapy, and pay more attention to hematologic toxicity and gastrointestinal dysfunction in patients treated with Eri chemotherapy in clinical practice. The incidence of hepatic and renal impairment was not high in both groups, and the overall adverse reactions were controllable.

Based on these findings, clinicians may be more inclined to choose UX therapy in clinical practice if MBC patients meet the inclusion and exclusion criteria of this study. Earlier use of Eri may be more beneficial to patients if utidelone is not available in some areas. In conclusion, either UX or Eri chemotherapy may result in a survival benefit with a tolerable adverse effect profile and favorable safety profile in patients with MBC who have received prior neoadjuvant and adjuvant therapy with anthracyclines and paclitaxel.

Discussion

The significance of this study is that it reports, for the first time, the clinical efficacy and safety of utidelone in combination with capecitabine compared with those of single eribulin in the treatment of MBC. Capecitabine, vincristine, gemcitabine, platinum, eribulin, and utidelone may be considered monotherapy or combination regimens in the first-line and subsequent palliative treatment of MBC [14, 18, 19, 40]. However, comparative studies on the efficacy and safety of various available drugs for MBC are rare, and comparative studies on various lines of drug therapy in advanced stages are lacking, especially reports that compare UX with Eri in the treatment of MBC. The innovation of this study is based on the clinical efficacy and safety analyses of UX versus Eri in the treatment of advanced breast cancer. Further subgroup analyses of UX versus Eri were performed in patients who received first-line therapy in advanced stages and patients who received second-line or later therapy, and subgroup analyses of the differences in efficacy between the first-line or second-line application of eribulin were also performed.

Our study revealed that rescue chemotherapy with UX prolonged the mPFS and mOS of patients compared with the use of Eri, but the difference was not statistically significant. We were also pleasantly surprised to find that late first-line application of UX significantly prolonged patients' mPFS compared with Eri treatment. Moreover, mPFS and mOS were prolonged in the UX second-line or later therapy group compared with the Eri second-line or later therapy group, but the difference was not statistically significant. Compared with the second-line or later therapy group, the early first-line therapy group had a significantly longer mPF. For breast cancer patients who previously received anthracycline and paclitaxel neoadjuvant and adjuvant therapy, salvage chemotherapy with either UX or Eri can benefit patients and is generally well tolerated, and side effects are manageable. However, further subgroup analysis revealed that the first-line application of UX was better than that of Eri; for patients who received eribulin rescue chemotherapy, advanced first-line application was better than posterior line application. Based on the results of this study, clinicians may be more inclined to choose UX therapy in clinical practice if MBC patients meet the inclusion and exclusion criteria of this study. Earlier use of Eri may be more beneficial to patients if utidelone is not available in some areas. Either UX or Eri chemotherapy may result in a survival benefit with a tolerable adverse effect profile and favorable safety profile in patients with MBC who have received prior neoadjuvant and adjuvant therapy with anthracyclines and paclitaxel., which has certain guiding significance for clinical application.

The previous BG01-1323L (NCT 02253459) [24] multicenter, randomized, open-label Phase III clinical study demonstrated the advantages of balancing efficacy and safety in the treatment of breast malignancies and revealed that utidelone in combination with capecitabine prolonged PFS compared with capecitabine alone [HR = 0.47, 95% CI (0.37–0.59), P < 0.00011], with median PFS values of 8.4 months [95% CI (7.89–9.49)] and 4.1 months [95% CI (3.09–5.09)], respectively; OS was also prolonged [HR = 0.75, 95% CI (0.59–0.94), P = 0.0142], with median OS values of 19.8 months [95% CI (17.02–21.59)] and 16.0 months [95% CI (14.26–18.53)], respectively; the ORR values were 45.6% and 23.7%, respectively (P < 0.001). In our study, the mPFS in the UX group was 7.7 months, and the mOS was 22.0 months. We further performed subgroup analyses, and the mPFS in the UX first-line therapy group was 11.8 months, but mOS data were not available for this group. However, the mPFS in the UX second-line or later therapy group was 5.1 months, and the mOS was 18.8 months. The results were generally consistent with those of the BG01-1323L trial (NCT 02253459).

Zhang P et al. reported that the ORR of patients treated with UX therapy was 42.4% [23]. In contrast, the ORR in the UX group in our study was 18.6% (95% CI 0.084–0.334). The ORR in our study was lower than that in the study by Zhang P et al., both in the advanced first-line and second-line or or later therapy of the UX regimen. Zhang P et al.'s study included patients with MBC who had not previously received more than three chemotherapy regimens. In our study, some of the patients who had received multiline chemotherapy were considered to have greater drug resistance, which may have led to a lower ORR. In the study by Zhang P et al., the ORR in the UX group of patients with ≤ 2 metastatic sites and the proportion of primary tumors resected were greater than the respective values in our study (60.6% vs. 48.8% and 97% vs. 72%, respectively) because the patients enrolled in our study appeared to have more advanced disease. In addition, our study is a retrospective study, whereas the study by Zhang P et al. was conducted in two stages. First, a dose escalation study was conducted at one clinical study site. Based on the safety and efficacy results obtained from the three dose groups, the second stage of the study included three clinical study sites with an MTD (30 mg/m2/day) of utidelone. Eligible patients were continually enrolled in the study until the total number of study subjects reached the planned sample size. These factors are potential biases that could lead to a higher ORR in the study by Zhang P et al.

Ge et al. [41] reported the case of a breast cancer patient with multiple metastases who achieved a good response and tolerance to the combination treatment of UX therapy. After being treated with 10 cycles of combined treatment, the patient is now in a good general condition with a PFS of 10 months. This combined treatment offers a new option for patients with multi-drug resistant breast cancer. Bi et al. [42] reported that the median PFS reached 11.70 months (95% CI 0.093–0.141) in UX group in the advanced first-line therapy, compared to 5.60 months (95% CI 0.025–0.079) in the second-line or above therapy [HR 0.42, (95% CI 0.226–0.787), P = 0.0077]. In UX therapy, the median OS in the second-line or above therapy was 19.50 months (95% CI 0.083–0.307), with a mean overall survival of 16.89 months (95% CI 0.136–0.202) [HR 0.26, (95% CI 0.098–0.678), P = 0.0495]. The results are consistent with those reported in this study.

Previous researchers conducted a secondary systematic review of 34 studies on the efficacy of eribulin in patients with locally advanced breast cancer and reported that the mPFS was 2.3–14.7 months [43], indicating good clinical efficacy of eribulin in the treatment of MBC. The mPFS in the Eri group in our study was 5.2 months, which is in accordance with the above findings. Another study [44] retrospectively analyzed the efficacy of eribulin in clinical application and reported an mPFS of 5.3 months in triple-negative breast cancer (TNBC) patients with third-line or later treatment; in HR + /HER2- patients who were previously treated with a CDK4/6 inhibitor, the mPFS of those treated with eribulin in the 3rd line or later was 2.7–3.6 months. In the subgroup analysis of our study, the mPFS of the enrolled patients was 7.0 months in the Eri first-line therapy group and 3.3 months in the Eri second-line or later therapy group, which was also consistent with the results of previous studies [34, 45, 46].

A Phase III study of eribulin versus vincristine in the treatment of locally recurrent/metastatic breast cancer in China led by Professor Binghe Xu [47] revealed that the ORR of eribulin versus vincristine in 2 or more lines for the treatment of advanced breast cancer was 30.7% (95% CI 25.2–36.6%) versus 16.9% (95% CI 12.6–22.0%), respectively. We also performed a subgroup analysis of the Eri advanced second-line or later therapy group, with an ORR of 20% (95% CI 0.077–0.386), which was lower than that of the above studies but also higher than the ORR of the vincristine control group. An analysis of 11 previous retrospective studies [48] revealed that the ORR of eribulin in clinical practice was 20.1%, which was similar to the ORR of 21.43% (95% CI 0.103–0.368) reported in our study. However, the PERUSE single-arm, Phase II study [49] revealed that the ORR of eribulin combined with trastuzumab and patuximab for first-line therapy for HER-2-positive metastatic breast cancer was as high as 80%, with a median PFS time of 23.1 months, which was superior to that of the current standard of care (docetaxel combined with trastuzumab and patuximab), suggesting that the combination of eribulin and targeted therapy might lead to new treatment options for HER-2-positive metastatic breast cancer patients.

Zhao et al.'s network meta-analysis [50] compared the efficacy and safety of Eri versus other chemotherapies in locally advanced breast cancer or metastatic breast cancer patients. Comparators included: capecitabine (CAP), gemcitabine (GEM), ixabepilone (IXA), utidelone (UTI), treatment by physician’s choice (TPC), and vinorelbine (VIN). Results showed that second- or later-line patients treated with Eri had statistically longer overall survival versus TPC (HR: 0.81; CrI: 0.66–0.99) or GEM + VIN (0.62; 0.42–0.90) and statistically longer progression-free survival versus TPC (0.76; 0.64–0.90), but statistically shorter progression-free survival versus CAP + IXA (1.40; 1.17–1.67) and CAP + UTI (1.61; 1.23–2.12).

In terms of safety, the most common drug-related adverse events in the UX and Eri therapy groups were peripheral neuropathy, hand‒foot syndrome, hematologic toxicity, gastrointestinal toxicity, and hepatorenal toxicity, which were similar to the adverse events reported in previous studies [51]. Most of the adverse reactions in our study were Grade 1–2; the incidence of Grade ≥ 3 adverse reactions was 38.1% in the Eri group, which was greater than the 25.58% rate in the UX group. In both the UX and Eri groups, the incidence of adverse events tended to increase as the number of treatment lines increased, with the Eri group having a higher incidence of hematological toxicity than the UX group in both the first- and later-line therapy groups for advanced disease. However, the rates of hand‒foot syndrome and neurotoxicity were lower in the Eri group than UX group. This finding is consistent with the results of previous studies [52,53,54]. Multiple Phase III clinical studies have shown that eribulin has combined efficacy and safety benefits in the treatment of breast cancer [47, 55,56,57]. The drug-related adverse reactions in our study were usually alleviated by symptomatic and supportive treatment (granulocyte colony-stimulating factor, ondansetron, vitamins, etc.), delayed administration or dose reduction. Deaths due to drug-related adverse reactions did not occur, and the overall safety was controllable and well tolerated.

Based on our study, we can conclude either UX or Eri salvage chemotherapy can benefit patients with MBC who have previously received neoadjuvant and adjuvant therapy with anthracyclines and paclitaxel, with good tolerability and manageable adverse effects. However, the first-line application of UX is preferable to that of Eri, and advanced first-line application is better than late-line application of eribulin as a rescue chemotherapy.

The essence of scientific research lies in the exploration and discovery, and it is difficult to achieve perfection. As both eribulin and utidelone are recommended drugs for the backline treatment of breast cancer, and have not been approved for a long time in China, this study only collected 85 patients who met the criteria from 2 research centers, which is a small sample size, and therefore, the credibility and universality of the results of our study will be reduced. In general, this study has a small sample size and is retrospective, and bias is difficult to avoid. In addition, most patients with advanced breast cancer have experienced long-term comprehensive treatment, and the combination regimens are diverse and complex, which makes homogeneous comparisons difficult. The results of the present study can guide the clinical decision-making to a certain extent. In the future, we will also increase the sample size by carrying out joint studies with more centers and extending the follow-up time. Further randomized, double-blind, controlled studies are needed to further investigate the efficacy and safety of combinations of utidelone and eribulin with different chemotherapies, targeted therapies, endocrine therapies, and immunotherapy regimens for different molecular phenotypes and clinical stages of breast cancer to provide better guidance in clinical practice.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (Grant No. 81960542, 82360614 and 81960517), Yunnan Province “14th Five-Year Plan” Provincial Key Clinical Specialty General Surgery Construction Project, Science and Technology Project of Yunnan Provincial Science and Technology Department (Grant No. 202201AY070001-169), Yunnan Health Training Project of High Level Talents (Grant No. H-2019075), Beijing Science and Technology Innovation Medical Development Foundation (Grant No. KC2021-JK-0044-6) and Wu Jieping Medical Foundation (Grant No. 320.6750.2022-19-58).

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Author notes

  1. Mengya Feng, Pingping Bi and Yihua Kang have contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Surgery, The People’s Hospital of Chuxiong Yi Autonomous Prefecture, No. 318 Lucheng South Road, Chuxiong, 675000, Yunnan, China

    Mengya Feng, Xianping Lu, Guojian Xie, Hai Lei & Dan Mo

  2. Department of Oncology, The People’s Hospital of Lincang, No.116 Nantang Street, Linxiang District, Lincang, 677000, Yunnan, China

    Pingping Bi

  3. Department II of General Surgery, The People’s Hospital of Chuxiong Yi Autonomous Prefecture, No. 318 Lucheng South Road, Chuxiong, 675000, Yunnan, China

    Yihua Kang

  4. Department of Breast Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, No. 519 Kunzhou Road, Xishan District, Kunming, 650100, Yunnan, China

    Dechun Yang & Shengnan Ren

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Contributions

HL, DM confirmed the authenticity of all the raw data, and gave administrative supportand, gave provision of study materials or patients; DM conceptualized and designed the study; MF performed the statistical analysis and prepared the manuscript; MF, PB, YK responsible for data collection and assembly and data analysis and interpretation; All authors reviewed the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hai Lei or Dan Mo.

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The author is responsible for all aspects of the work to ensure that issues related to the accuracy and completeness of any part of the work are properly investigated and resolved. Subjects have given their written informed consent and that the study protocol was approved by the in stitute's committee on human research. Study approval statement: This study complies with the Declaration of Helsinki (revised in 2013) and was approved by the ethics committee.Written informed consent was obtained from participants to participate in the study.

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Feng, M., Bi, P., Kang, Y. et al. Real world analysis of the efficacy and safety of eribulin compared to utidelone in combination with capecitabine for the treatment of metastatic breast cancer. Cancer Cell Int 24, 416 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-024-03608-7

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Cancer Cell International

ISSN: 1475-2867

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