Japanese Journal of Clinical Oncology Advance Access originally published online on February 12, 2008
Japanese Journal of Clinical Oncology 2008 38(2):99-105; doi:10.1093/jjco/hym172
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© The Author (2008). Published by Oxford University Press. All rights reserved
High Pathologic Complete Response in HER 2-positive Locally Advanced Breast Cancer after Primary Systemic Chemotherapy with Weekly Docetaxel and Epirubicin
1 Department of Surgery, Chang Gung University Medical College, Taoyuan, Taiwan
2 Division of Medical Oncology, Chang Gung University Medical College, Taoyuan, Taiwan
3 Department of Pathology, Chang Gung University Medical College, Taoyuan, Taiwan
4 Department of Diagnostic Radiology, Chang Gung University Medical College, Taoyuan, Taiwan
5 Department of Radiation Oncology, Chang Gung Memorial Hospital, Chang Gung University Medical College, Taoyuan, Taiwan
For reprints and all correspondence: Shin-Cheh Chen, Department of Surgery, Chang-Gung Memorial Hospital, 199, Tung-Hwa North Road, Taipei, Taiwan. E-mail: chensc{at}adm.cgmh.org.tw
Received May 8, 2007; accepted November 18, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Background: To evaluate pathological complete response rate and to identify the predictor of response after primary systemic chemotherapy (PST) with weekly docetaxel and epirubicin for locally advanced breast cancer.
Methods: Sixty-three patients with locally advanced breast cancer received three cycles PST on day 1 and 8 of each 3-week cycle with epirubicin and docetaxel (epirubicin 45 mg/m2 intravenous bolus, docetaxel 35 mg/m2 in 100 ml normal saline infused 1 h), followed by surgery and adjuvant chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil. The pathological complete response was defined as no invasive carcinoma in breast and axillary nodes after PST.
Results: The median tumor sizes (by ultrasound) before and after PST were 6.2 and 2.5 cm, respectively. The negative estrogen receptor (ER) by immunochemical stain was found in 33 (52.4%) patients and HER-2/neu-overexpression in 12 (19.0%) patients. Clinical overall response rate (ORR) was 89% (95% confidence intervals (95% CI: 81–97), including 38% complete response (95% CI: 26–50), sonographical ORR was 97% (95% CI: 93–100). The pathological complete response were found in 11 patients (18%, 95% CI: 9–27), and 15(24%, 95% CI: 13–35) patients achieved breast only pathological complete response. Nine (27.3%) of thirty-three ER (–) patients and 5 (41.7%) of 12 HER2-positive patients achieved pathological complete response.
Conclusion: PST with weekly docetaxel and epirubicin were well-tolerated and very high pathological complete response rate was achieved in HER-2/neu-overexpression tumors.
Key Words: breast cancer • primary systemic chemotherapy • epirubicin • docetaxel • HER-2/neu
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Primary systemic chemotherapy (PST) is the standard treatment for locally advanced and large operable breast cancers, and a disease-free survival benefit had been found in patients who achieved pathologic complete response (pCR) (1,2). Anthracycline and taxane-based regimen in PST for breast cancer have been studied in randomized and non-randomized trials and yielded high response rates either given in sequential or combination (3–5). Recently, the addition of Transtuzumab to taxane-based chemotherapy achieved even higher pCR in patients with HER-2/neu overexpression tumors (6). However, the schedule of combination or sequential single agent in weekly or 3-weekly has not been established, as well as how many cycles are needed to achieve pCR. Conventionally, cytotoxic chemotherapy is regarded as a non-targeted treatment and is prescribed to all breast cancer patients according to the clinical evidence. Recently, the predictive biomarker of estrogen receptor (ER) and HER-2/neu amplification defined the subtypes that beneficial from certain type chemotherapy (7,8). The issue that identifies the predictive biomarker of pCR is also important, and there is no definite answer yet. We had reported the high response rate and good feasibility of weekly epirubicin and paclitaxel for locally advanced breast cancer (9), here we present the results of PST with higher dose of weekly epirubicin and docetaxel and looking for predictive biomarker of pCR.
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MATERIALS AND METHODS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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STUDY DESIGN
This study was an open label, phase II trial performed at a single center. The rates of objective responses, including complete and partial responses evaluated by clinical examination and ultrasonography, were the primary endpoint of the study.
PATIENTS SELECTION
Patients with newly diagnosed breast cancer were included. Eligible patients met the following criteria: histologically proven unilateral invasive breast carcinoma, aged 20–70 years, tumor diameter 
3 cm ultrasonographically, clinical nodal status N1-2, World Health Organization (WHO) performance status 
1, normal baseline blood count, normal serum creatinine, alanine aminofransferase, aspirate aminorransferase, alkaline phosphatase and bilirubin levels, negative pregnancy test and written informed consent. Exclusion criteria were: inflammatory cancer and presence of metastasis.
Initial staging included physical examination, mammography, ultrasonography of the breast and axillary lymph nodes, chest radiography, bone scan and whole body CT scan. All patients gave written informed consent to participate, and the study was approved by the institutional ethics committee.
Electrocardiogram and echocardiography with LVEF (left ventricular ejection fraction) assessment were performed in the first 30 patients at starting of chemotherapy, which was after the completion of three cycles PST and 2 months adjuvant therapy.
TREATMENT
PST consisted of epirubicin (45 mg/m2 by intravenous bolus) and docetaxel (35 mg/m2 by 1 h intravenous infusion) delivered in 2 weekly treatments followed by 1 weekly rest. All patients received this 3-week treatment for three cycles. Granulocyte colony-stimulating factor (G-CSF) and prophylactic antibiotics were not given. Dexamethasone (20 mg) was given intravenously before and after doetaxel. Antiemetic medication was consisted of dexamethasone and metoclopramide. Dose modification was based on nadir blood counts and interval toxicity. Surgery (mastectomy or breast conserving surgery) with axillary node dissection was performed 2 weeks after completing the three cycles of PST. Another six cycles of adjuvant CEF (epirubicin 70 mg/m2, cyclophosphamide 500 mg/m2 and 5-fluorouracil 500 mg/m2) chemotherapy were given to the patients on day 1 of every 3 weeks as adjuvant therapy after surgery.
LABORATORY STUDIES
Estrogen and progesterone receptors (ER, PR) and HER-2/neu analysis was performed on pretreatment core needle biopsy specimens using immunohistochemical staining techniques. Laboratory standards were used to assess hormone receptor positivity that according to Allred score, briefly, total scores >3 (weak intensity and positive staining of >10% cells) were considered as positive. HER-2/neu analysis was done using the Hercep test (DakoCytomation, Carpentaria, CA, USA). The staining intensity score was evaluated relative to the provided control slides from 0 to 3+ as follows: 0, no staining or membrane staining observed in <10% of the tumor cells; 1 +, a faint, barely perceptible membrane staining in >10 % of the tumor cells and /or cells with only partial membrane staining; 2 +, weak to moderate complete membrane staining in >10% of the tumor cells; 3 +, moderate to strong complete membrane staining observed in >10% of the tumor cells. Specimens staining 3+ were coded as positive. HER-2 FISH test was not done in this study.
DEFINITION OF RESPONSE
The response to chemotherapy was defined physically and sonographically. The pathological response rate was evaluated on the intention-to-treat population (those receiving one or more cycles of chemotherapy) and on the evaluable population (those receiving one or more cycles of chemotherapy with surgery after the last cycle). The response was considered complete if there was no evidence of the primary breast tumor by either clinical evaluation or sonographic examination. Response was considered partial (PR) if there was a reduction of 50% in the product of the two perpendicular diameters of the tumor. If the tumor area showed a reduction of <50% or an increase of <25%, no change stable disease (SD) was considered to have occurred. Progression was defined as an increase of 25% in the product of the diameters. Pathologic responses were codified according to the classifications proposed by Chevallier et al. (10). Grade 1, the disappearance of all tumor on macroscopic or microscopic assessment; Grade 2, the presence of in situ carcinoma but no invasive tumor and no tumor in the lymph nodes; Grade 3, the presence of invasive carcinoma with stromal alterations; Grade 4, few modification of the tumoral appearance.
TOXICITY ASSESSMENT
Toxicity was assessed through clinical examination at baseline and before each cycle. Laboratory tests, including a complete biochemical routine and a complete blood cell count, were performed at baseline and at the end of each cycle. A baseline cardiac assessment included electrocardiography (ECG) and evaluation of LVEF with echocardiography. To describe toxicity, the common Toxicity Criteria of the National Cancer Institute vesion 3.0 were applied. Toxicity was described for each patient and the worst grade for each side effect experienced by a given patient for all cycles received was reported.
STATISTICAL ANALYSIS
Categorical data were compared using 
tests. P values <0.05 were considered statistically significant. All P values were two-tailed and were adjusted for multiple comparisons when indicated. Univariate analysis was used to estimate the effects of clinical TNM stage, ER status, DNA flowcytometry and HER-2/neu overexpression on response to therapy. To identify variables independently related to the response, a multivariate analysis using a logistic regression mode was performed.
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RESULTS |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Sixty-three patients were enrolled between 2002 and 2005. The characteristics of patients and tumors are outlined in Table 1. Median age was 46 years and median tumor size was 5.6 cm (range 3–20 cm) by physical examination and 6.2 cm (range 2.3–22 cm) by ultrasonography, including 25 patients with T2, 32 with T3 and 6 with T4b disease. Invasive ductal carcinoma was found in 58 patients, three invasive lobular cancer, one mucinous carcinoma and one medullary carcinoma. Negative ER status was found in 33 (52.4%) patients, and HER-2/neu overexpression was found in 12 (19.0%) patients.
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COMPLIANCE AND TOXICITY
All patients completed the three cycles of PST. There were no dose reduction among the cycles, and no patients withdrew from the study. Table 2 shows the non-hematological and hematological toxicities. Only four (6.3%) patients developed grade 3 or 4 non-hematological toxicity. Sixty-one (96.8%) patients experienced grade 2 alopecia. Febrile neutropenia occurred in 4 (6.3%) patient, and grade 3 or 4 neutropenia occurred in 13 (20.6%) patients. Two patients required G-CSF to maintain the PST dose intensity. There were 24 treatment cycles that were delayed for 1 week; 19 (5%) cycles were delayed due to hematological toxicity, and 5 cycles were delayed due to patients' preferences. The cardiac toxicity is summarized in Table 3. There were four (9.3%) patients who developed grade 1 cardiac toxicity after three cycles PST with ET. Two patients developed grade 2 or 3 cardiac toxicities after six cycles of adjuvant CEF chemotherapy completed.
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RESPONSE RATE
The overall response rate (ORR) was 89%, 95% CI:81-97, and 24 patients (38%, 95% CI: 26–50) had complete clinical responses (CCR) as assessed by clinical examination (Table 4). The sonographical ORR was 97%, 95% CI: 93–100, which included six patients with complete disappearance of sonographic evidence of their tumors. No patients experienced disease progression during chemotherapy. The median pre- and post-chemotherapy tumor sizes were 5.6 and 1.5 cm, respectively, by physical examination; the median sonographical tumor size was 6.2 and 2.5 cm, respectively. The median pathological tumor size after chemotherapy was 2.7 cm.
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Eight patients had pCR (complete disappearance of the primary tumor with negative axillary nodes), and another three patients had in situ lesions only in breast tissue (Table 5).
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Overall, 25 (39.7%) patients had negative axillary nodes on pathologic examination. All 63 patients underwent surgery without delay, and all were not suitable for conserving surgery because large tumor before PST, there were 32 patients were candidate for conserving surgery but breast conserving surgery was performed in 11 (17.5%) patients, and another 21 patients preferred total mastectomy.
PREDICTING PATHOLOGIC COMPLETE RESPONSE
The pCR and non-pCR of patients based on clinical and tumor charactericstics are shown in Table 6. ER status and HER-2/neu overexpression were significantly correlated with pCR in univariate analysis (odds ratio for ER-negative tumors with pCR, 5.2; 95% CI 1.03–26.7, odds ratio for HER-2 overexpression, 5.3; 95% CI 1.28–22.2). Multivariate analysis revealed an independent relationship of HER-2/neu overexpression (odds ratio: 5.7; 95% CI: 1.23–26.39) and ER-negativity (odds ratio: 5.56; 95% CI: 1.01–30.30) with pCR.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The results of current phase II trial have demonstrated the feasibility and good pCR rate of weekly epirubicin and docetaxel as PST for locally advanced breast cancer (LABC).
The incorporating taxanes into anthracycline-based PST improved the pCR rate in LABC and operable breast cancer (1,3). The schedule in most of PST containing anthracycline and taxanes were usually given in sequential setting in order to reduce the toxicities, and the cCR and pCR rates were usually <30%. Recently, the Aberdeen and NSABP B-27 trials with sequential doxorubicin and docetaxel had achieved pCR rate of 26% and 34%, respectively, in stages I–III breast cancer (1). The concomitant chemotherapy of taxanes and anthracycline for >4 cycles also achieved pCR rates >20% in stage II, III breast cancer (3,11), although more frequent episodes of febrile neutropenia occurred. Minckwitz et al. reported that a combination of anthracycline and taxanes can achieved a high pCR rate with only 8.6% febrile neutropenia with G-CSF support in relative shorter time, usually within 3 months (12). Green et al. reported a high pCR rate of 29% in node positive breast cancer with sequential weekly paclitaxel followed by FAC (fluorouracil/doxorubicin/cyclophosphamide) (3). At all, the pCR cannot be reached either with sequential or concomitant chemotherapy in 70% patients of LABC. Patients who receive sequential regimen would take much longer time (even 6 months) awaiting for definite surgery after chemotherapy. For an operable breast cancer, patient would be even more anxious if it is going take more than 6 months awaiting the non-reachable pCR after PST. In our current series, with concomitant administration of epirubicin and docetaxel in weekly schedule, the pCR rate was 17%, which was probably due to initial large tumor size (median size of 6.2 cm by ultrasonography) with only three cycles of combination chemotherapy given. Nevertheless, high clinical ORR (88.9%) and sonographical ORR (96.8%) were achieved with febrile neutropenia developed in only four (6.3%) patients. The proportion of delay treatment was 5%, which was much lower than that in NSABP B-27 trial, and the interval between PST and definite surgery usually was <3 months.
The efficacy of combination chemotherapy would be compromised if the dose was reduced or schedule was delayed due to toxicities. The optimal dose intensity of combination chemotherapy is a function of both the dose level and schedule. The FASG05 trials confirmed the dose–response relationship and suggested that a moderate higher dose density was a reasonable approach (13). Piccart et al. reported the adequate dose of epirubicin at 100 mg/m2 for every 3 weeks resulted in significant benefit over classical CMF (cyclophosphomide, methotrexate and 5-flurouracil) in adjuvant chemotherapy (14). While the therapeutic benefit was not demonstrated with increased dose of doxorubicin from 60–90 mg/m2 (15). Those data suggested that dose for epirubicin in adjuvant setting were 90–100 mg/m2. Although CALGB-9741 and AGO trials found the dose-dense regimens significantly improved DFS and OS in adjuvant chemotherapy of breast cancer (15,16), dose-dense regimen of PST didn't produce similar results in most of clinical studies, including EORTC-NCIC-SAKK multicenter study (17).
The weekly schedule of PST with sequential single agent or in combination resulted in higher pCR rate and lower incidence of toxicities in comparison to every 3 weeks schedule (3). Wenzel et al. suggested the weekly combination dose of epirubicin and docetaxel were 30 and 35 mg/m2, respectively (18). Taucher et al. reported pCR rate was 12.4% with weekly combination schedule of epirubicin and docetaxel (19). In the current trial, pCR rate was increased and patients still had good compliance; this was accomplished by an increased weekly epirubicin dose from 30–45 mg/m2 for 2 weeks and one week off while maintaining the intensity of epirubicin dose at 30 mg/m2/week.
There were a few studies evaluated biomarkers for predicting pathological response, and the results were discordant due to the heterogeneity of breast cancer and different chemotherapy regimens (19,20). High tumor proliferation rate assessed by mitotic index or Ki-67 and negative ER status in several studies have been reported to correlate with pCR (21), whereas some other studies did not find the correlation (22).
There were some evidence suggested that HER-2/neu overexpression and/or topoisomerase-II
aberrations predicted chemosensitivity to anthracycline-based chemotherapy in adjuvant, neoadjuvant or metastatic chemotherapy settings (8,20). The association of HER-2/neu with response to taxane-based or anthracycline-taxane combination chemotherapy is unclear. The in vitro studies demonstrated that c-erbB-2 overexpression cell lines were resistant to taxane treatment (17), and there were several reports using single agent taxane in neoadjuvant or metastatic chemotherapy failed to identify a relationship between HER-2/neu overexpression and response rate (23,24). Learn et al. reported an interesting findings that the addition of docetaxel to the standard neoadjuvant treatment may not improve the clinical response rate in patients with HER-2/neu overexpression tumors. However, it markedly improved the response rate among HER-2/neu negative tumors (25). In contrast, Leo et al. reported that HER-2/neu positive patients derived a large benefit from the use of docetaxel (26). Konecny et al. reported the combination of epirubicin with paclitaxel significantly improved the objective response rate, progression-free survival and overall survival in comparison to the combination of epirubicin with cyclophosphamide in metastatic HER-2/neu-positive breast cancer patients (27). In the subgroup analysis of BCIRG 001 trial, survival benefit also demonstrated in HER-2 positive patients who received TAC (docetaxel–doxorubicin–cyclophosphamide) in comparison to FAC (28). Our data, as well as most of the other studies, demonstrated that the ER-negative tumors were associated with higher pCR rate (29). Meanwhile, HER-2/neu overexpression tumors were also associated with significantly higher pCR (Table 6). The synergistic effect of anthracycline and taxanes may contribute the good response rate in HER-2/neu overexpression tumors.
Despite the common limitation of small sample size in most PTS trials, including ours, the current trial of combining anthracycline and docetaxel in weekly schedule demonstrated a high clinical response good pCR rate and good compliance to patients with LABC; it also shortened the period between PST and definite surgery. Early identification of poor responder can spare the patients from unnecessary toxicities of further chemotherapy. although the combination of anthracycline and taxanes demonstrated a high pCR rate in HER-2/neu overexpression tumors, it needs a larger prospective trial to confirm the hypothesis of synergistic effect.
Conflict of interest statement
None declared.
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References |
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