Abstract

Background: To evaluate the activity and safety of nonanthracycline-containing weekly PCb [paclitaxel (Taxol) plus carboplatin] regimen in neoadjuvant treatment of breast cancer.

Patients and methods: Eligible patients were assigned to receive four cycles of PCb with dose of paclitaxel 80 mg/m2 and carboplatin at an area under the curve of 2 mg × min/ml, given day 1, day 8 and day 15 of every 4 weeks. Pathological complete remission (pCR) was defined as no invasive cancer in breast and axillary samples.

Results: Overall, 107 consecutive patients received weekly PCb treatment from December 2007 to December 2008, and one was diagnosed with bilateral breast cancer. A total of 85.2% of patients were initially diagnosed with stage III diseases. Clinical response rate was 86.1% with complete remission rate 32.4%. Twenty-one patients achieved pCR after neoadjuvant treatment, with pCR rate 19.4%. The incidence of grade 3–4 neutropenia was 40.2% and only one patient was reported with febrile neutropenia. Severe anemia and thrombocytopenia occurred in 4.7% and 0.9%, respectively, of patients. Peripheral neuropathy was frequent but never severe. Patients with estrogen receptor-negative, progesterone receptor-negative, triple-negative or human epidermal growth factor receptor 2 (Her2)-positive subtype disease had higher pCR.

Conclusions: Weekly PCb regimen was very active and tolerable as neoadjuvant treatment of breast cancer. This weekly PCb regimen should consider as a reasonable nonanthracycline-containing option in the neoadjuvant treatment of breast cancer.

introduction

Breast cancer is the most common malignancy affecting women and the second leading cause of cancer death in the United States; however, the overall mortality due to breast cancer has decreased, attributed in part to early diagnosis and application of various treatments [1]. Neoadjuvant chemotherapy has been widely accepted as the standard treatment of patients with locally advanced disease and now has become a frequently used option for systemic therapy in primary operable breast cancer [2]. Several randomized trials conducted in 1990s and a meta-analysis have demonstrated that neoadjuvant chemotherapy was apparently equivalent to adjuvant chemotherapy in terms of overall survival and distance metastasis and allowed a significantly more patients to receive breast-sparing treatment [3]. Furthermore, these randomized studies have shown that patients achieving a pathological complete remission (pCR) after neoadjuvant chemotherapy have superior outcome than those who are not [4–6]. So, another advantage of neoadjuvant chemotherapy is the possibility of quickly determining the response to treatment [2].

There are lots of chemotherapy regimens tested in the neoadjuvant setting in phase II and III trials. The introduction of the taxanes, including docetaxel and paclitaxel, realizing their cytotoxicity via tubulin stabilization and cell cycle arrest, has revolutionized breast cancer therapy [7]. The Early Breast Cancer Trialists’ Collaborative Group has revealed that taxane-based adjuvant chemotherapy can significantly improve the outcome of patients than those treated with anthracycline-based therapy [8]. In neoadjuvant treatment, National Surgical Adjuvant Breast and Bowel Project (NSABP) B27 and Aberdeen studies showed that addition of docetaxel to anthracyclines resulted in a doubling of the pCR rate than those treated with the standard arm [5, 9]. Nowadays, anthracycline- and taxane-based therapies are recommended in neoadjuvant treatment of breast cancer [2].

Dose density and intensity play an important role in breast cancer chemotherapy since Cancer and Leukemia Group B (CALGB) 9741 trial confirmed that dose dense was better compared with standard schedule in the adjuvant setting [10]. And then, Eastern Cooperative Oncology Group (ECOG) 1199 trial demonstrated that weekly administration of paclitaxel was superior to the every 3-week schedule [11]. In addition, in neodajuvant setting, M.D. Anderson Cancer Center study showed that weekly paclitaxel improved pCR in operable breast cancer when compared with paclitaxel once every 3 weeks [12].

Platinum complexes are active in a wide range of solid tumors [13]. Compared with cisplatin, carboplatin has shown same activity in breast cancer and may be the more appropriate choice for treatment because it might have lower toxicity without affecting antitumor efficacy [14]. Paclitaxel combined with carboplatin (PCb) has shown great activity in ovarian and non-small-cell lung cancer treatment. In addition, the overall response rate of PCb was between 53% and 62% in the first-line treatment of metastatic breast cancer [15]. Furthermore, Hellenic Cooperative Oncology Group group has reported that every 3-week PCb regimen had equal response rate and median survival compared with paclitaxel plus epirubicin group which indicated that PCb regimen can be considered as an effective therapeutic alternative to the anthracycline-containing regimen [16].

Three recent meta-analyses have indicated that anthracycline-containing regimens provide more benefit than nonanthracycline-containing regimens in patients with human epidermal growth factor receptor 2 (Her2)-overexpressed or -amplified breast cancer [17–19]. Furthermore, Breast Cancer International Research Group (BCIRG) 006 trial has demonstrated that nonanthracycline-containing regimen TCH (docetaxel + carboplatin + trastuzumab) had superior outcome than doxorubicin + cyclophosphamide followed docetaxel (AC→T) regimen in treatment of Her2-positive patients [20]. In addition, Jones et al. [21] reported that docetaxel and cyclophosphamide (TC) regimen was associated with a better outcome compared with conventional AC regimen. With the development of these new drugs, we now recognize that anthracylines may be not necessary for every patient in adjuvant chemotherapy of breast cancer and there are several clinical trials to directly evaluate the role of anthracyclines in breast cancer treatment.

On the basis of these data, we initiated this phase II study to evaluate the activity and safety of nonanthracycline-containing weekly PCb regimen as neoadjuvant treatment in women with locally advanced breast cancer or large operable disease.

patients and methods

patient population

Patients with histological confirmation (core needle biopsy) of large operable (T ≥3 cm and N0–1) or locally advanced breast cancer without prior chemotherapy, radiotherapy or hormone treatment were considered eligible.

Other inclusion criteria of eligible patients had to meet females at least 18 years and ≤70 years considered to be fit to receive chemotherapy; absence of systemic disease measured by bilateral mammogram, bilateral magnetic resonance imaging, chest computed tomography scan, abdominal ultrasound and bone scintigraphy; ECOG performance status of one or less; adequate bone marrow [absolute neutrophil count (ANC) ≥1.5 × 109/l, platelet count ≥100 × 109/l and hemoglobin level ≥100 g/l], liver [bilirubin level and aspartate aminotransferase and/or alanine aminotransferase <1.5 the upper limit of normal], renal (creatinine clearance ≥60 ml/min) and absence of severe cardiac arrhythmia or heart failure; no previous chemotherapy treatment for any previous malignancy and previous or concurrent malignancy were also considered as exclusion criteria, except for inactive nonmelanoma skin cancer and in situ carcinoma of the cervix. Patients with sensorial neurotoxicity more than grade 1 on the basis of the National Cancer Institute—Common Toxicity Criteria version 3.0 (NCI-CTC v3.0) score system were excluded. The protocol was reviewed and approved by the independent ethical committee/institutional review board, and all patients gave their written informed consent before inclusion in this study.

immunohistochemical evaluation and subtype classification

Immunohistochemical (IHC) assessment of the main biomarkers, like estrogen receptor (ER), progesterone receptor (PgR) and Her2 was conducted in paraffin-embedded tumor samples before treatment. The cut-off for ER positivity (ER+) and PgR positivity (PgR+) was 1% positive tumor cells with nuclear staining. Her2 positive (Her2+) was considered as Her2 3+ by IHC or positive on FISH, whereas cases with 0 to 1+ or 2+ without FISH detecting were regarded as negative (Her2−).

Hormonal receptor (HR) positive was defined as either ER+ or PgR+, and HR− was defined as both ER− and PgR−. Patients were categorized on the basis of IHC HR and Her2 status of their primary tumors. Therefore, four breast cancer subtypes were approximately classified as follows: luminal A (HR+/Her2−), luminal B (HR+/Her2+), triple negative (HR−/Her2−) and Her2 positive (HR−/Her2+) [22].

treatment

All eligible patients received four cycles of paclitaxel (Taxol; Bristol-Myers Sqiubb Company, NJ) 80 mg/m2 in a 1-h infusion immediately followed by carboplatin at an area under the curve (AUC) of 2 mg × min/ml in a 30-min infusion given on days 1, 8 and 15 of a 28-day cycle. Creatinine clearance was calculated using the Jelliffe formula [23] and AUC, the Calvert formula [24]. Patients received dexamethasone 10 mg, cimetidine 300 mg i.v. and promethazine 12.5 mg i.m. 30 min before chemotherapy. Furthermore, antiemetic prophylaxis (hydroxytryptamine-3 receptor antagonists) was also carried out before chemotherapy and prophylaxis granulocyte colony-stimulating factor was also allowed to use between cycles by investigator's discretion. Chemotherapy was delivered at full doses if ANC >1.0 × 109/l and platelets >75 × 109/l. The treatment was postponed a week in case of ANC <1.0 × 109/l and/or platelet count <75 × 109/l. Chemotherapy was administered at doses reduced to 25% <0.5 × 109/l, and/or platelet count <50 × 109/l, febrile neutropenia (temperature >38°C and ANC <1.0 × 109/l), any more than grade 2 non-hematological toxicity, except nausea and vomiting or alopecia.

Patients with operable disease after chemotherapy should receive surgery within 4 weeks from the last scheduled chemotherapy cycle. An additional two cycles of weekly PCb were delivered after surgery in patients who achieved pCR. Four cycles of cyclophosphamide, epirubicin or two cycles of weekly PCb could be administrated after surgery in patients showing response at pathologic assessment. In case of confirmed progression disease at any time during the neoadjuvant treatment, chemotherapy was to be discontinued and the patient was asked to undergo salvage surgery and receive four cycles of cyclophosphamide, epirubicin chemotherapy. The decision about further radiotherapy and endocrine therapy was at the discretion of the treating physician.

response and toxicity evaluation

A pCR was defined as the absence of invasive tumor in the final surgical breast and axillary lymph nodes (ALNs) sample. Residual ductal carcinoma in situ was included in the pCR category. Standard RECIST guidelines were used to evaluate clinical and pathological response. No clinical evidence of palpable tumor in the breast and ALNs was defined as a clinical complete remission (cCR). Reduction in greatest tumor diameter of ≥30% was graded as a partial response (PR). An increase in greatest tumor diameter of >20% or appearance of new disease was considered as progressive disease (PD). Tumors that did not meet the criteria for objective PR or PD were considered as stable disease (SD). Toxicity was evaluated at every period of chemotherapy treatment and recorded according to the NCI-CTC v3.0.

statistics

The primary end point for this analysis was pCR rate. Logistic regression analysis was used to determine factors predictive of pCR. All statistical tests were two-sided and carried out at significance level of 0.05 using the SPSS statistical software package (version 13.0; SPSS Company, Chicago, IL).

results

patient characteristics

Overall, 107 consecutive patients with breast cancer were enrolled from December 2007 to December 2008 to receive weekly PCb neoadjuvant chemotherapy, and there was one case with bilateral breast cancer. A total of 108 cases were eligible for response evaluation. Table 1 summarizes the main clinical and pathological characteristics. The median age was 51 years (range 32–70 years). A total of 85.2% of patients were initially diagnosed with stage III diseases, whereas 83 patients had positive ALN confirmed by fine needle aspiration before chemotherapy. Twenty-four patients were Her2+ detected by IHC or FISH.

Table 1.

Pretreatment patient and tumor characteristics (N = 108)

Characteristics Number of patients 
Age 51 (32–70) years 
    ≤35 6.5 
    35–55 69 63.9 
    >55 32 29.6 
BMI index 
    <24 63 58.3 
    ≥24 45 41.7 
Menopausal status 
    Pre-/perimenopausal 54 50.0 
    Postmenopausal 54 50.0 
Histology 
    Infiltrating ductal carcinoma 68 63.0 
    Infiltrating (mixed) carcinoma 37 34.3 
    Others 2.8 
Tumor status 
    0–2 38 35.2 
    3 38 35.2 
    4 32 29.6 
Lymph node status 
    0 15 13.9 
    1 24 22.2 
    2 60 55.6 
    3 8.3 
Lymph node metastasis 
    Negativea 25 23.1 
    Positive (confirmed by FNA) 83 76.9 
Tumor stage 
    II 16 14.8 
    IIIA 57 52.8 
    IIIB 26 24.1 
    IIIC 8.3 
Estrogen receptor status 
    Negative 46 42.6 
    Positive 62 57.4 
Progesterone receptor status 
    Negative 49 45.4 
    Positive 59 54.6 
Her2 status 
    Negative 84 77.8 
    Positive 24 22.2 
Characteristics Number of patients 
Age 51 (32–70) years 
    ≤35 6.5 
    35–55 69 63.9 
    >55 32 29.6 
BMI index 
    <24 63 58.3 
    ≥24 45 41.7 
Menopausal status 
    Pre-/perimenopausal 54 50.0 
    Postmenopausal 54 50.0 
Histology 
    Infiltrating ductal carcinoma 68 63.0 
    Infiltrating (mixed) carcinoma 37 34.3 
    Others 2.8 
Tumor status 
    0–2 38 35.2 
    3 38 35.2 
    4 32 29.6 
Lymph node status 
    0 15 13.9 
    1 24 22.2 
    2 60 55.6 
    3 8.3 
Lymph node metastasis 
    Negativea 25 23.1 
    Positive (confirmed by FNA) 83 76.9 
Tumor stage 
    II 16 14.8 
    IIIA 57 52.8 
    IIIB 26 24.1 
    IIIC 8.3 
Estrogen receptor status 
    Negative 46 42.6 
    Positive 62 57.4 
Progesterone receptor status 
    Negative 49 45.4 
    Positive 59 54.6 
Her2 status 
    Negative 84 77.8 
    Positive 24 22.2 
a

Clinical negative lymph node or clinical positive lymph node with negative result by FNA.

BMI, body mass index; FNA, fine needle aspiration; Her2, human epidermal growth factor receptor 2.

treatment compliance and surgery

One hundred and two (94.4%) patients have completed all four cycles of weekly PCb treatment. Two patients only received three cycles and one patient received six cycles of treatment due to patients’ willing. Two patients who suffered from PD were asked to undergo salvage surgery at the end of first cycle and second cycle of treatment and another one experienced brain metastasis after three cycles of treatment.

Among these 108 cases, 106 patients received modified radical mastectomy, only one patient received breast-conservation surgery and one patient treated with immediate breast reconstruction with latissimus dorsi muscular flap, respectively.

response rates

The overall clinical response rate was 86.1% with cCR rate 32.4% (Figure 1). A total of 100 patients (92.6%) experienced pathological response [PR + Complete Remission (CR)] and 21 patients achieved pCR after four cycles of treatment, with pCR rate 19.4%. Table 2 shows the clinical and pathological response rate. Furthermore, there were 27 cases (25.0%) without invasive residual disease in breast after treatment. In addition, 30 cases who were positive for ALN before chemotherapy showed negative result in the surgery specimen after treatment; the ALN downstage rate was 36.6%.

Table 2.

Clinical and pathological response

Response Number of patients 
Clinical tumor response 
    CR 35 32.4 
    PR 58 53.7 
    SD 11 10.2 
    PD 3.7 
Pathological response (breast) 
    CR 27 25.0 
    PR 73 67.6 
    SD 3.7 
    PD 3.7 
Pathological response (breast + ALN) 
    CR 21 19.4 
    PR 79 73.1 
    SD 3.7 
    PD 3.7 
Post-treatment ALN status (n = 82)a 
    Negative 30 36.6 
    Positive 52 63.4 
Response Number of patients 
Clinical tumor response 
    CR 35 32.4 
    PR 58 53.7 
    SD 11 10.2 
    PD 3.7 
Pathological response (breast) 
    CR 27 25.0 
    PR 73 67.6 
    SD 3.7 
    PD 3.7 
Pathological response (breast + ALN) 
    CR 21 19.4 
    PR 79 73.1 
    SD 3.7 
    PD 3.7 
Post-treatment ALN status (n = 82)a 
    Negative 30 36.6 
    Positive 52 63.4 
a

A total of 83 patients had metastasis lymph node confirmed by fine needle aspiration before treatment, one patient did not receive surgery due to brain metastasis.

CR: complete remission; PR, partial response; SD, stable disease; PD, progression disease; ALN, axillary lymph node.

Figure 1.

Clinical and pathological response. cRR, clinical response rate; pRR (T), pathological response rate in breast; ALN, axillary lymph node; pRR (T + ALN), pathological response rate in breast and ALN; CR, complete remission; PR, partial remission; SD, stable disease; PD, progression disease.

Figure 1.

Clinical and pathological response. cRR, clinical response rate; pRR (T), pathological response rate in breast; ALN, axillary lymph node; pRR (T + ALN), pathological response rate in breast and ALN; CR, complete remission; PR, partial remission; SD, stable disease; PD, progression disease.

molecular subtypes and response

Table 3 shows that pCR rate associates with the main biological features at diagnosis including HR, molecular subtypes and Her2 status. Patients with absence of ER expression were associated with a higher probability of achieving pCR (ER− versus ER +, 32.6% versus 9.7%; P = 0.005). A significantly higher pCR probability was also observed in PgR− patients (30.6% versus 10.2%; P = 0.010). Overall, Her2+ tumors apt to have a higher pCR rate than Her2− tumors. Furthermore, we approximately classified breast cancer into different subtypes using IHC ER, PgR and Her2 status, which could predict the response of weekly PCb neoadjuvant treatment. Patients classified with luminal A subtype had the lowest pCR rate, which was 8.3% less than 22.2% in luminal B, 33.3% in triple-negative and 40.0% in Her2-positive subtype patients, P = 0.017. However, three patients with PD were also classified into triple-negative subtype, which needed further investigation.

Table 3.

Pathological response according to ER, PR and Her2 status

 pCR (n = 21) Non-pCR (n = 87) pCR rate P valuea 
ER status    0.005 
    Negative 15 31 32.6  
    Positive 56 9.7  
PgR status    0.010 
    Negative 15 34 30.6  
    Positive 53 10.2  
Her2 status    0.057 
    Negative 13 71 15.5  
    Positive 16 33.3  
Molecular classification    0.017 
    Luminal A 55 8.3  
    Luminal B 22.2  
    Triple negative 16 33.3  
    Her2 positive 40.0  
 pCR (n = 21) Non-pCR (n = 87) pCR rate P valuea 
ER status    0.005 
    Negative 15 31 32.6  
    Positive 56 9.7  
PgR status    0.010 
    Negative 15 34 30.6  
    Positive 53 10.2  
Her2 status    0.057 
    Negative 13 71 15.5  
    Positive 16 33.3  
Molecular classification    0.017 
    Luminal A 55 8.3  
    Luminal B 22.2  
    Triple negative 16 33.3  
    Her2 positive 40.0  
a

P value was calculated by Logistic regression.

pCR, pathological complete remission; ER, estrogen receptor; PgR, progesterone receptor; Her2, human epidermal growth factor receptor 2.

toxicity

Table 4 summarizes the main treatment-related toxicity observed in 107 patients. There was one patient with long history of diabetes experienced monocular deprivation after four cycles of treatment. No episode of death, symptomatic cardiac adverse event or life-threatening event was recorded. The incidence of grade 3–4 neutropenia was 40.2% and only one patient was reported with febrile neutropenia. Severe anemia and thrombocytopenia only occurred in 4.7% and 0.9% of patients, respectively. Alopecia was almost universal. Peripheral neuropathy was frequent, but never severity, only five (4.7%) patients recorded had more than grade 1 toxicity. The incidence and severity of gastrointestinal toxic effects were frequent, but none of them suffered from severe toxicity.

Table 4.

Toxicity

Toxicity Grade 1–2, number of patients (%) Grade 3–4, number of patients (%) 
Neutropenia 53 (49.5) 43 (40.2) 
Thrombocytopenia 35 (32.7) 1 (0.9) 
Anemia 77 (71.9) 5 (4.6) 
Nausea and vomiting 92 (86.0) 0 (0.0) 
Diarrhea 38 (35.5) 0 (0.0) 
Liver 21 (19.6) 0 (0.0) 
Neurotoxicity 51 (47.7) 0 (0.0) 
Alopecia 107 (100.0) 0 (0.0) 
Skin toxicity 25 (23.4) 1 (0.9) 
Toxicity Grade 1–2, number of patients (%) Grade 3–4, number of patients (%) 
Neutropenia 53 (49.5) 43 (40.2) 
Thrombocytopenia 35 (32.7) 1 (0.9) 
Anemia 77 (71.9) 5 (4.6) 
Nausea and vomiting 92 (86.0) 0 (0.0) 
Diarrhea 38 (35.5) 0 (0.0) 
Liver 21 (19.6) 0 (0.0) 
Neurotoxicity 51 (47.7) 0 (0.0) 
Alopecia 107 (100.0) 0 (0.0) 
Skin toxicity 25 (23.4) 1 (0.9) 

discussion

In our present study, we aimed at evaluating the efficacy and safety of nonanthracycline-containing weekly PCb regimen as neodajuvant treatment of breast cancer. Four cycles of weekly PCb yield a pCR rate of 19.4% in large operable or locally advanced breast cancer. Furthermore, this nonanthracycline-containing regimen achieved a high pCR rate in Her2+ disease (33.3%). In view of the later stage of tumors, the high pCR rate obtained is particularly interesting which deserves further investigation.

Neoadjuvant chemotherapy has become the standard treatment of locally advanced breast cancer, which can downstage the disease and improve the surgery option [2, 3]. Our anthracycline-sparing weekly PCb regimen achieved a pCR rate as high as 19.4% with the definition of no invasive disease in breast and ALN, which was much higher than our previous study conducted in locally advanced disease with vinorelbine + epirubicin regimen [25]. Furthermore, the pCR rate was improved a lot compared with previous study, like paclitaxel + epirubicin regimen with pCR rate 10% [26] and adriamycin + docetaxel with pCR rate from 7.7% to 15% [27–29]. If we applied the NSABP pCR definition [4, 5], then the pCR rate in our study would increase to as high as 25%, which was similar with the AC→T regimen in NSABP B27 trial (26.3%) [5].

There are two main features that make our regimen substantially different from other regimens, including the application of a weekly schedule for these two drugs and the usage of carboplatin instead of anthracyclines. Meta-analysis and several large randomized trials have demonstrated that taxanes can improve the outcome compared with anthracyclines in the adjuvant treatment of breast cancer [8]. Weekly administration of paclitaxel was also associated with a better treatment efficacy compared with the every 3-week schedule [11, 12]. In recent years, there are increasing trials about the platinum compounds in the management of breast cancer [14]. The replacement of anthracyclines with platinum compounds combination with trastuzumab has been widely used in Her2-overexpressing patients in order to reduce the risk of cardiac toxicity [29]. Furthermore, there are several cisplatin-containing regimens, including or not taxanes, which have been tested in the neoadjuvant setting, showing a high antitumor activity [30–32].

Overall, in our study, a total of 82 patients with proven ALN metastasis received surgery indicated that our study population was not at all a favorable one and showed that 30 patients were free of metastasis after neoadjuvant chemotherapy with axillary downstage rate 36.6%, which was similar with previous study conducted in early operable disease [4, 33].

Several trials like NSABP B27 [5] and German Preoperative Adriamycin and Docetaxel Study II [34] have demonstrated that patients with HR-negative disease had a higher pCR rate compared with HR-positive cases. One favorable feature of our study population which can explain the high pCR rate achieved by non-anthracycline-containing PCb regimen was the relative high proportion of ER− patients. In our study, we also found that ER− or PgR− diseases, which accounted for ∼45% patients, were associated with higher pCR rate.

With the development of gene chip technology, we now can classify breast cancer into different molecular subtypes which at least contain five subtypes, including luminal A, luminal B, basal-like (triple-negative), Her2-positive and normal-like subtype [35]. Rouzier et al. [36] has demonstrated that patients with basal-like and Her2-positive diseases were associated with the highest rate of pCR, 45% and 45%, respectively, whereas the luminal tumors had a pCR rate of only 6% . Furthermore, Carey et al. used IHC profiles (ER, PgR and Her2) to subtype patients with breast cancer and found that triple-negative and Her2-positive subtypes were more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal diseases, which indicated that using IHC profiles to subtype breast cancers can also predict the response of chemotherapy. However, patients with triple-negative or Her2-positive subtype diseases had the worse outcome and higher relapse, which may be due to those with residual disease after treatment [22]. In our present study, we also found that patients with triple-negative or Her2-positive subtype disease had higher pCR rate compared with luminal A patients. However, there were three patients with PD and all of them were classified with triple-negative disease, which was paradox in triple-negative subtype disease treatment. Different biological activities can be invoked for these subtypes, which can result in different probability of achieving a pCR.

Several studies have showed that Her2 status may be a predictor of anthracycline or taxane response and Her2+ diseases may get more benefit for anthracycline- or taxane-containing chemotherapy [37]. Patients with Her2− disease may get little benefit from anthracycline-containing regimen compared with nonanthracycline-containing regimen, like CMF (combination chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil). Furthermore, US Oncology 9735 [21] and BCIRG 006 [20] trials showed that anthracyclines may be not an essential drug for breast cancer adjuvant treatment. pCR rate of nonanthracycline-containing weekly PCb regimen was 19.4% in all patients and increased to 33.3% in Her2+ diseases, which was also of interest because the anthracycline drugs were not used. Frasci et al. [38] has reported that a 2-month cisplatin–epirubicin–paclitaxel weekly combination as neoadjuvant therapy for large operable breast cancer achieved pCR rate as high as 32% and even higher in triple-negative disease (62%) [39]. However, the differences in trial design, eligibility criteria and treatment duration make it very hard to compare our study regimen with others. Finally, we should take these data into account when designing a new clinical trial, like nonanthracycline-containing weekly PCb regimen versus weekly PCb + anthracycline or cisplatin–epirubicin–paclitaxel regimen, as well as to detect some biological predictive markers, which can directly evaluate the role anthracycline in breast cancer treatment.

The incidence of severe adverse events was low in our study besides the alopecia. At the beginning of this trial, we really concerned about the risk of severe anemia and thrombocytopenia toxicity, but with the 1-week rest between every cycle, the incidence was relatively low. Besides these, severe gastrointestinal toxicity was rare which was very attractive for patients to receive this neoadjuvant regimen. Furthermore, we found that no episode of symptomatic cardiac adverse event was recorded for this anthracycline-sparing regimen, which can be used for some patients with high risk of cardiotoxicity and as an attractive option for trastuzumab combination treatment of Her2-positive breast cancer. At last, there were only five patients recorded had more than grade 1 of peripheral neuropathy toxicity, which was much lower than the previous study [11, 12] and the major reason we believe is the administration schedule allowing 1-week rest after 3-week treatment, which has been reported can reduce the incidence of toxicity [40, 41].

In conclusion, four cycles of nonanthracycline-containing weekly PCb regimen achieved a pCR rate of 19.4% in large operable or locally advanced breast cancer with acceptable safety profiles. Patients with ER−, PgR−, triple-negative or Her2-positive subtype disease had a higher probability to achieve pCR. This weekly PCb regimen should consider as a reasonable nonanthracycline-containing option in neoadjuvant treatment of breast cancer.

funding

Multidiscipline Comprehensive Treatment Cooperation Group Foundation of Fudan University Cancer Hospital, Shanghai, China (DXK200801).

disclosure

We declare that we have no conflict of interest.

The authors thank the patients and family members for their willingness to cooperate with our study.

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Author notes

These authors have contributed equally to this work.