Neoadjuvant Docetaxel and Capecitabine (TX) versus Docetaxel and Epirubicin (TE) for Locally Advanced or Early HER2-Negative Breast Cancer: An Open-Label, Randomized, Multi-Center, Phase II Trial

doi:10.21203/rs.3.rs-1708642/v1

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Neoadjuvant Docetaxel and Capecitabine (TX) versus Docetaxel and Epirubicin (TE) for Locally Advanced or Early HER2-Negative Breast Cancer: An Open-Label, Randomized, Multi-Center, Phase II Trial

https://doi.org/10.21203/rs.3.rs-1708642/v1

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Purpose

The Combination of taxanes and anthracyclines is still the mainstay of chemotherapy for early breast cancer. Capecitabine is an active drug with a favorable toxicity profile, showing strong anti-tumor activity against metastatic breast cancer. This trial assessed the efficacy and safety of the TX regimen (docetaxel and capecitabine) and compared it with the TE (docetaxel and epirubicin) regimen in locally advanced or high risk early HER2-negative breast cancer.

Patients and Methods

This randomized clinical trial was conducted at five academic centers in China. Eligible female patients were randomly assigned (1:1) to the TX (docetaxel 75mg/m² d1 plus capecitabine 1000mg/m² twice d1–14, q3w) or TE (docetaxel 75mg/m² d1 plus epirubicin 75mg/m² d1, q3w) groups for four cycles. The primary endpoint was a pathological complete response in the breast (pCR). Secondary endpoints included pCR in the breast and axilla, invasive disease-free survival (iDFS), overall survival (OS), and safety.

Results

Between September 1, 2012, and December 31, 2018, 113 HER2-negative patients were randomly assigned to the study groups (TX: n = 54; TE: n = 59). In the primary endpoint analysis, 14 patients in the TX group achieved a pCR, and nine patients in the TE group achieved a pCR (25.9% vs. 15.3%), with a not significant difference of 10.6% (95% CI -6.0–27.3%; p = 0.241). In a subgroup with high Ki-67 score, TX increased the pCR rate by 24.2% (95% CI 2.2–46.1%; p = 0.029). At the end of the 69-month median follow-up period, both groups had equivalent invasive disease-free survival and overall survival rates. TX was associated with a higher incidence of hand-foot syndrome and less alopecia, with a manageable toxicity profile.

Conclusion

The anthracycline-free TX regimen yielded comparable pCR and long-term survival rates to the TE regimen. Thus, this anthracycline-free regimen could be considered in selected patients.

Trial Registration

ACTRN12613000206729 on 16/02/2013, retrospectively registered.

Breast neoplasms

Neoadjuvant therapy

Anthracycline

Taxane

Capecitabine

The introduction of taxanes and anthracyclines as modern chemotherapy has drastically improved the outcomes of patients with early breast cancer (EBC)[1, 2]. The combination of taxanes and anthracyclines has been recommended as the preferred regimen for patients with HER2-negative breast cancer, especially those with locally advanced breast cancer (LABC) or high risk early breast cancer, who were pursuing rapid tumor shrinkage through neoadjuvant chemotherapy[3].

However, anthracycline-containing chemotherapy causes quality of life-threatening, long-term side effects, such as heart failure and treatment-related leukemia[2]. As the number of long-term survivors, elderly patients, and patients with cardiac risk factors increases, the toxic profile becomes a more important discriminator in the neoadjuvant/adjuvant treatment decision-making framework, and the de-escalation of anthracycline-containing regimens is gaining popularity in neoadjuvant/adjuvant trials. The US Oncology 9735 trial demonstrated the superiority of four cycles of TC (docetaxel plus cyclophosphamide) to four cycles of AC (doxorubicin plus cyclophosphamide) [5], and the West German Study Group PlanB trial revealed the non-inferiority of six cycles of TC to a standard AC regimen followed by a taxane in clinically high-risk or genomically intermediate- to high-risk human epidermal growth factor receptor 2 (HER2)-negative patients[6]. The success of the TC regimen in the adjuvant setting increased the confidence to explore efficacy- and toxicity-balanced regimens in EBC.

Capecitabine is a nucleoside analog commonly used in patients with metastatic breast cancer[7, 8]. It is a prodrug of 5-fluorouracil (5-FU) activated by a complicated three-step conversion through three key enzyme activities. The final step of capecitabine conversion to 5-FU requires thymidine phosphorylase, which is highly expressed in breast cancer tissue [9]. Preclinical and clinical studies have shown that docetaxel upregulates thymidine phosphorylase in breast tumor tissue, indicating potential synergy between docetaxel and capecitabine (TX) [9, 10]. Several studies have demonstrated the highly effective anti-tumor activity of the TX regimen in metastatic breast cancer, even in anthracycline and taxane-pretreated tumors[11, 12]. However, little is known about the feasibility of translating this combination to the neoadjuvant/adjuvant setting.

Here, we performed a randomized phase II trial for locally advanced and high risk HER2-negative breast cancer to assess the efficacy and toxicity of the TX regimen using a combination of docetaxel and epirubicin (TE) as the standard comparator.

Study Design and Patients

This study was a randomized, open-label, phase II, multi-center clinical trial comparing TX with TE as neoadjuvant chemotherapy for stage II/III breast cancer conducted in Beijing, China. The study was approved by the Peking University Peoples’ Hospital Ethics Committee and Ethics Committees of all participating institutions and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each study subject prior to participating. This study was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12613000206729).

Eligible patients were women aged at least 18 years with clinical-stage cT1c–4/cN0-3/M0 (stage II-III) breast cancer. The histological diagnosis of the primary lesion was obtained at a local laboratory. Hormone receptor (estrogen receptor [ER] and progesterone receptor [PR] status), HER2, and Ki-67 status of the primary tumor had to be known. Participants were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants were also required to have adequate organ function based on laboratory assessment of absolute neutrophil count, platelet count, hemoglobin, serum creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total serum bilirubin, and serum alkaline phosphatase. Exclusion criteria included stage IV (metastatic) breast cancer, inflammatory breast cancer without in-breast tumor, a history of invasive breast cancer, and previous systemic therapy for the treatment or prevention of breast cancer. Patients were also excluded if they had HER2+ disease and neoadjuvant anti-HER2 targeted therapy would be prescribed.

Eligible patients were randomly assigned to receive either TX or TE (1:1). Patients were randomized with a permuted block randomization scheme using a telephone randomization system with no stratification factor.

Procedures

The TX group received intravenous docetaxel (75mg/m²) on day 1 plus oral capecitabine (1000mg/m²⁾ twice per day from day 1 to day 14 for every three-week cycle. The TE group received intravenous docetaxel (75mg/m²) and epirubicin (75mg/m²) on day 1 of every three-week cycle. Treatment was administered for four cycles before definitive surgery. Treatment was discontinued if progressive disease or unacceptable toxicity was noted. Pretreatment for docetaxel was performed in accordance with local regulations. Generally, 7.5 mg of oral dexamethasone was administered twice daily for a total of six doses, starting one day before each infusion. Dose reductions were permitted, and prophylactic granulocyte colony-stimulating factor administration was allowed.

Definitive surgery was performed two to four weeks after the last neoadjuvant chemotherapy treatment. The type of breast surgery (mastectomy or breast-conserving surgery) and axillary treatment (sentinel lymph node biopsy or axillary lymph node dissection) were determined by the treating surgeon. After surgery, adjuvant chemotherapy was given at the discretion of the physician. Radiotherapy and endocrine therapy were recommended according to international guidelines.

Statistical Analysis

The pCR rate, defined as the absence of invasive tumor cells in the breast (ypT0/is), was measured as the primary endpoint. Secondary endpoints included pCR in the breast and axilla (ypT0/isN0), clinical response assessed using Response Evaluation Criteria in Solid Tumors (RECIST ver1.1), clinical and pathologic stage (CPS) and estrogen receptor status and histologic grade (EG) (CPS&EG) score, invasive disease-free survival (iDFS), and overall survival (OS). Treatment-related toxicities were also examined using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) system.

The sample size was estimated by assuming that the pCR rate of the TX group would be non-inferior to that of the TE group by 3%. The type I error was set at 5% using two-sided significance tests. With a sample size of 440 patients, there was an 80% probability of rejecting the null hypothesis. The trial was terminated in December 2018 for slow enrollment after 166 patients had been screened. Because the confirmatory analysis was deemed underpowered, we carried out an exploratory analysis to determine the feasibility and safety of the TX regimen in the neoadjuvant setting.

Patients who received the assigned chemotherapy were included in the efficacy analysis. Those who received at least one dose of either regimen were included in the safety analysis. The pCR rates were compared between the two groups using the χ2 or Fisher’s exact test. Differences and 95% confidence intervals (CIs) were calculated. The pCR rates of the groups were compared for different Ki-67 levels and various molecular subtypes. The subtype definition was in accordance with current guidelines, while the Ki-67 score were categorized into high and low with a threshold of 20%. Clinical response was assessed using RECIST criteria v1.1. The CPS&EG score was developed to evaluate the response to neoadjuvant therapy after incorporating clinical stage, pathological stage, ER, and grade and validated to predict long-term survival. The CPS&EG scores were compared between the groups using the χ2 test. iDFS and OS were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Safety profiles were compared using the χ2 or Fisher's exact test.

The final date of data acquisition for this study was December 28, 2021. Data were analyzed with R (http://r-project.org).

Patient and Tumor Characteristics

Between September 1, 2012, and December 31, 2018, 139 patients from five participating centers in China were randomly assigned to the treatment groups (TX: n = 65; TE: n = 74). Because anti-HER2 targeted therapy was not widely used in China for medical resource reasons at the time of the trial design, we included patients who would not have received trastuzumab in the neoadjuvant phase at the start of the study. With improvements in the Chinese public medical insurance reimbursement policy for anti-HER2 therapy, we stopped recruiting HER2+ patients in 2016. Finally, we excluded the 26 HER2+ patients from the final analysis dataset for confounding concerns. Thus, 113 patients were evaluated for the primary endpoint (TX: n = 54; TE n=59). Figure 1 shows the CONSORT study flowchart. The demographic characteristics of the 113 subjects who received the assigned treatments are presented in Table 1. Patient and treatment features were balanced between the two groups. The median age of the overall population was 52 (22–79 years). TX group included more old patients (>50: 61.1% vs 42.2%) than TE group, with a marginal significance (p = 0.072). T2-4 tumors were found in 78.8% of the study patients, and 89.4% of the axillary lymph nodes were positive. The proportions of breast-conserving surgery in the two groups were 20.4% and 18.6%, respectively (p = 1.000). A total of 84.1% of study patients (TX: 92.6%; TE: 83.1%) received response-guided adjuvant therapy at the discretion of the treating physician. The most common adjuvant chemotherapy for TX group were additional two to four cycles of TX and an additional AC regimen. Most patients in TE group were given additional two to four cycles of TE to complete a full course of TE.

Pathological and Clinical Response

In the primary endpoint analysis, a pCR was achieved by 14 patients in the TX group (25.9%, 95% CI 16.1%–38.9%) and nine patients in the TE group (15.3%, 95% CI 8.2%–26.5%); the difference between the groups was not significant (10.7%, 95% CI -4.2%–25.5%, p = 0.241) (Figure 2A). There was also no significant difference between the groups for the pCR rate in both breast and axilla (Figure 2B).

An exploratory molecular subgroup analysis was performed to find the potential benefit of TX. The pCR rates were 36.4% (12/33) and 12.8% (5/39) in the Ki-67 high subgroups of the TX and TE groups, respectively (95% CI 3.7%–42%; p = 0.026). We further analyzed the other molecular subtype subgroups and found very low pCR rates in the luminal A and luminal B PR negative subtypes. In the luminal B Ki-67 high and triple-negative breast cancer (TNBC) subtypes, TX provided a higher pCR rate; however, statistical significance was only achieved with the luminal B Ki-67 high group. These data are presented in Figure 2C–F. Additional exploratory subgroup analyses are shown in Figure 3 as a forest plot. The pCR rate difference in different histological types, initial cT stage, initial cN stage, or HR status subgroups were not significant. For age subgroups, pCR rate favored TX in age > 50 subgroup, which was inconsistent with the slightly un-balanced age distribution of the study population. For molecular subtypes, pCR rate favored TX for Ki-67 high group and luminal B Ki-67 high group as abovementioned.

We also analyzed the clinical response using RECIST and CPS&EG. There was no progressive disease in either group. There were no statistically significant differences in the clinical responses or CPS&EG scores between the two treatment groups (Supplemental Table 1).

Survival Analysis

At the end of the 69-month median follow-up period, iDFS and OS was similar between the two groups. The five-year iDFS rate was 87% (95% CI 78.5–96.5%) for TX and 84.2% (95% CI 74.6–95%) for TE (p = 0.93) (Figure 4A). The five-year OS rates were 88.8% (95% CI 80.7–97.7%) for treated with TX compared with 96.4% (95% CI 91.5–100%) when treated with TE (p = 0.64) (Figure 4B). The survival differences between the different regimens were not significant for the Ki-67 high and luminal B Ki-67 high subgroups (Figure 4C–F).

Toxic Effects

Both regimens caused a relatively high incidence of neutropenia (TX: 64.6%; TE: 78.4%). The capecitabine-containing regimen increased the incidence of hand-foot syndrome (any grade: 64.6%; grade 3: 20%). The incidence of alopecia was lower in the TX group (18.5% vs. 70.3% for grades 3 and 4). No symptomatic cardiac events were documented for either group during the follow-up period. There was one occurrence of acute lymphocyte leukemia in the TE group. The incidences of other adverse events were comparable between the two groups (Table 2).

The present study was a multi-center prospective randomized controlled study to assess the efficacy and toxicity of four cycles of TX compared to the traditional TE regimen. For HER2-negative patients, the pCR rates of the two regimens were comparable (pCR in the breast: 25.9% vs. 15.3%, p = 0.241), with similar results for pCR in both breast and axilla. In a subgroup of patients with a high Ki-67 index, the pCR rate of TX was significantly higher than that of TE (pCR in the breast: 38.4% vs. 12.8%, p = 0.029). At the median of the 69-month follow-up, the iDFS and OS were similar between the two groups. Our study supports the results of previous studies that TX is a highly active anthracycline-free regimen for breast cancer without compromising long-term survival. It revealed that TX could be a potential choice for patients eligible for neoadjuvant chemotherapy but ineligible for the anthracycline-containing regimen.

For years, the introduction of capecitabine into the adjuvant/neoadjuvant phase of treatment has been proposed for its non-cross-resistant mechanism compared with anthracyclines and taxanes and its outstanding clinical performance in metastatic settings [13]. At least 14 trials have explored the addition of capecitabine to the standard anthracycline and taxane regimen. Several meta-analyses generated similar results[14, 15]: in unselected patients, the addition of capecitabine did not improve DFS or OS, but survival was significantly increased in the TNBC subgroup. The addition of capecitabine caused more adverse effects, such as diarrhea and hand-foot syndrome, resulting in more treatment discontinuation. The data indicate that the introduction of capecitabine should be tailored according to the disease risk and chemo-sensitivity. Several strategies were employed to maximize the benefit-cost ratio: 1) CREATE-X used a neoadjuvant platform to select high-risk non-PCR patients to escalate treatment [16]; 2) CBCSG10 restricted its usage in the TNBC subtype [17]; 3) SYUCC001 adopted a novel lower dosage but longer duration[18]. Besides those strategies, a Korean group proposed substituting anthracycline with capecitabine to balance the benefit and adverse effects [19]. This group tested the TX regimen in the neoadjuvant phase and compared it with AC. A total of 209 stage II–III patients were randomized into four cycles of TX or AC. Compared with AC, TX increased the pCR in the primary tumors (21% vs. 10%, respectively, P = 0.024) and clinical response (84% vs. 65%, P = 0.003). TX was associated with less nausea and vomiting but more stomatitis, diarrhea, myalgia, and skin/nail changes than AC. The result suggested that TX in neoadjuvant chemotherapy is feasible and might be an active alternative to standard regimens[19]. However, AC was considered a weak regimen for high-risk breast cancer selected for neoadjuvant chemotherapy in the control group. Our study adopted concurrent taxane and anthracycline as a control to explore the real neoadjuvant performance of the TX regimen. Despite underpowered statistical analysis caused by the early termination of the trial, we found that the pCR rate, clinical response, and long-term survival were comparable between the two groups. These results indicated that TX could be an active choice for patients with LABC or high risk EBC.

We found that the Ki-67 index is a predictive marker for selecting TX. Ki-67 is an immune-histochemical marker for assessing a nuclear antigen expressed in all cell cycle phases except G0, suggesting it is an ideal marker for cell proliferation. Studies have shown a high correlation between the Ki-67 index and histological grade[20]. High pretreatment Ki-67 levels are associated with poor prognosis and predictive of better preoperative chemotherapy response[21–25]. There is little data on the predictive value of Ki-67 for chemotherapy agent selection because most previous studies focused on the anthracyclines and taxanes. Ohno et al.[26] performed an exploratory analysis of a neoadjuvant trial, evaluating docetaxel with and without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC). There were no significant differences in the pCR rates (TX: 23%; docetaxel 24%; p = 0.748), DFS, or OS. However, patients with mid-range Ki67 staining (10–20%) showed a trend towards an improved pCR rate for the TX patients compared to docetaxel alone. This finding is consistent with our results. The mechanism of high capecitabine sensitivity for tumors with a high proliferation rate is still unclear. However, the Ki-67 index is associated with thymidine phosphorylase expression in colorectal cancer [27]. This enzyme is a key activation enzyme for capecitabine and is considered predictive of a capecitabine benefit in breast cancer[28]. Furthermore, capecitabine has a lower impact on the bone marrow-derived immune system and might be an immune modulator [29]. This feature could explain its lower hematological toxicity and the feasibility of two-week continuous administration. We hypothesized that these characteristics allow capecitabine to continuously suppress tumor cells and act as an immune modulator in the tumor microenvironment essential for highly proliferating tumors. However, more data is needed to support these findings and our hypothesis.

In the current study, we found the main benefit of TX was for luminal B Ki-67 high patients. Locally advanced tumors with luminal subtypes are traditionally challenging for the worst chemotherapy efficacy, having a pCR rate of around 6–11%, with a disparity with other subtypes (pCR rate 20%-30% in HER2 + and TNBC) [30]. CDK4/6i was recently combined with endocrine therapy as a novel neoadjuvant therapy against these HR-positive tumors. Although the response rate was significantly increased compared to endocrine therapy alone, the pCR rate was not substantially improved to a ideal level compared to standard chemotherapy[31]. In our study, the pCR rate was 38.4% in patients with luminal B Ki-67 > 20% receiving the neoadjuvant TX regimen, suggesting that TX could be a promising treatment for this subgroup.

Patients with TNBC have a poor prognosis due to its aggressive nature and the lack of endocrine and traditional anti-HER2-targeted therapy[32]. Recently, great progress has been made in the neoadjuvant treatment of TNBC. The incorporation of platinum has increased the pCR rate by at least 10%. In the recent survival analysis of the phase III BrighTNess trial[33], long-term survival was improved by adding carboplatin. Immune checkpoint inhibitors, such as the PD-1/PD-L1 inhibitor, could further increase the pCR of TNBC up to 60% [34]. It is foreseeable that anthracyclines, taxanes, platinum, immunotherapy, and poly (ADP-ribose) polymerase inhibitors (PARPi)[35] could be the mainstay for neoadjuvant therapy against TNBC. However, these new treatments are associated with specific short-term and long-term adverse effects, suggesting tolerance could be a problem for future decision-making. Adjuvant capecitabine has been proven effective against non-PCR TNBC patients[16, 36] and early TNBC patients also benefit from lower-dose adjuvant therapy [18]. These results suggest that capecitabine is efficacious against this subtype. Despite of the small sample size, our study showed that the pCR rate of TX for TNBC was 35.3%, a meaningful response for this subtype. Thus, TX might be a neoadjuvant option for select TNBC patients.

It is not surprising that TX caused a higher incidence of hand-foot syndrome (20%), which was consistent with a previous trial on metastatic disease[11]. Interestingly, grade 3–4 neutropenia was as frequently observed in the TX group as in the TE group. It was speculated that the physicians’ reluctance to administer prophylactic granulocyte colony-stimulating factor in the TX group due to the continuous use of capecitabine may be the main reason for the difference between the two groups, since the severe neutropenia rate for TX was comparable to another study carried out in 2002[11]. This brings us to an important point, more attention should be devoted to the hematologic toxicity management in chemotherapy with TX regimen. The advantage of TX is expected to be less likely to cause rare severe long-term adverse effects, such as heart failure and secondary cancer, that may be observed in larger cohorts. We did not detect any symptomatic cardiac events in either group in the current study. However, one patient in the TE group was diagnosed with acute leukemia during follow-up. In the Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741 trials, 7290 patients received anthracyclines, and 47 patients developed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) [30 AML (0.3%), 17 MDS (0.2%)] [37]. In adjusted analyses, older age and anthracycline treatment were significantly associated with AML/MDS, which indicates that long-term toxicity should be considered in the decision-making for EBC. Compared to another anthracycline-free regimen used in an adjuvant setting (TC), TX showed a higher incidence of hand-foot syndrome, similar hematological adverse effects, and slightly more severe gastrointestinal toxicity[5].

There were several limitations to our study. Because of an imbalance in the medical resource distribution in China, local guidelines recommended concurrent usage of anthracyclines and taxanes as the preferred regimen for neoadjuvant chemotherapy until 2017. Thus, we adopted the concurrent use of anthracycline and taxane as the positive control during the trial design, which as substituted by sequential usage and a dose-dense schedule in international guidelines. For the same reason, we used TE according to local guidelines rather than TAC (TA [taxanes and anthracyclines] and cyclophosphamide) as the comparator. There are few studies assessing the efficacy of the TE regimen with or without cyclophosphamide. Recently, a Chinese group reported a randomized trial involving 640 node-positive patients that compared TA versus TAC. Their results showed that the two regimens produced similar DFS and OS. In contrast, TA was associated with less severe adverse events, lower economic burden, and better quality of life than TAC. Finally, due to the early termination of the trial, the statistical analysis was underpowered. However, the results for specific subtypes were still attractive and warrant further study.

Despite its limitations, our study was the first randomized, positive-controlled study to validate the feasibility of using TX as an anthracycline-free regimen against LABC and high risk early HER2-negative breast cancer. This regimen could be an active option for select patients. These findings must be confirmed in a definitive trial with a larger sample size.

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Houpu Yang, Ling Xu, Shan Guan, Xiaopeng Hao, Zhicheng Ge, Shu Wang. The first draft of the manuscript was written by Houpu Yang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The datasets generated during and/or analysed during the current study are not publicly available due to ethics requirements but are available from the corresponding author on reasonable request.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Peking University People’s Hospital.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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Table 1. Patient and Tumor Characteristics

	Total (n = 113) N (%)	TX (n = 54) N (%)	TE (n = 59) N (%)	p
Age
> 50	58 (51.3)	33 (61.1)	25 (42.4)	0.072
≤ 50	55 (48.7)	21 (38.9)	34 (57.6)
Histological Type
No special type	99 (87.6)	47 (87.0)	52 (88.1)
Invasive lobular	7 (6.2)	4 (7.4)	3 (5.1)	0.853
Mixed	7 (6.2)	3 (5.6)	4 (6.8)
Initial cT Stage
cT0	1 (0.9)	0 (0.0)	1 (1.7)	0.704
cT1	23 (20.4)	9 (16.6)	14 (23.7)
cT2	70 (61.9)	36 (66.7)	34 (57.6)
cT3	9 (8.0)	5 (9.3)	4 (6.8)
cT4	10 (8.8)	4 (7.4)	6(10.0)
Initial cN Stage
N0	12 (10.6)	7 (13.0)	5 (8.5)	0.730
N1	46 (40.7)	23 (42.6)	23 (39.0)
N2	44 (38.9)	20 (37.0)	24 (40.7)
N3	11 (9.7)	4 (7.4)	7 (11.9)
Hormone Receptor
Negative	35 (31.0)	15 (27.8)	20 (33.9)	0.618
Positive	78 (69.0)	39 (72.2)	39 (66.1)
Ki-67
> 20%	72 (63.7)	33 (61.1)	39 (66.1)	0.722
≤20%	41 (36.3)	21 (38.9)	20 (33.9)
Surgery
Breast conservation	22 (19.5)	11 (20.4)	11 (18.6)	1.000
Mastectomy	91 (80.5)	43 (79.6)	48 (81.4)
Adjuvant Chemotherapy	95 (84.1)	48 (92.6)	47 (83.1)	0.181
Original neoadjuvant regimen	64 (64.5)	23 (47.9)	41 (87.2)
Non-cross resistant regimen
Anthracycline + CTX	17 (17.1)	17 (35.4)	0 (0)
Capecitabine alone	6 (6.1)	1 (2.1)	5 (10.6)
Others	8 (8.1)	7 (14.6)	1 (2.1)

Table 2. Adverse Effects

	TX (n = 65)		TE (n = 74)
	Any Grade (%)	Grade 3–4 (%)	Any Grade (%)	Grade 3–4 (%)
Neutropenia	42(64.6)	18(47.6)	58(78.4)	25(33.8)
Anemia	15(23.1)	1(1.5)	18(24.3)	3(4.1)
Hand-foot syndrome	42(64.6)	13(20)	6(8.1)	0
Sensory neuropathy	27(41.6)	2(3.1)	34(45.9)	1(1.4)
Symptomatic heart failure	0	0	0	0
ALT/AST increased	12(18.5)	5(7.7)	20(27)	9(12.2)
Vomiting	18(27.7)	4(6.2)	22(29.7)	5(6.8)
Nausea	33(50.7)	3(4.6)	38(51.4)	5(6.8)
Diarrhea	12(18.5)	5(7.7)	10(13.5)	3(4.1)
Alopecia	50(76.9)	NA	68(91.9)	NA
Wound infection	3(4.6)	1(1.5)	2(2.7)	0
Leukemia	0	0	1	1(1.4)）

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Neoadjuvant Docetaxel and Capecitabine (TX) versus Docetaxel and Epirubicin (TE) for Locally Advanced or Early HER2-Negative Breast Cancer: An Open-Label, Randomized, Multi-Center, Phase II Trial

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