Annals of Oncology Advance Access originally published online on December 6, 2005
Annals of Oncology 2006 17(3):409-414; doi:10.1093/annonc/mdj096
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© 2005 European Society for Medical Oncology
Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial
1 Oncology, Surgery, Radiology CAC GF Leclerc, Dijon; 2 Oncology, Clinique des Domes, Clermont Ferrand; 3 Oncology, CAC J Perrin, Clermont Ferrand; 4 Oncology, CAC A Vautrin, Nancy; 5 Oncology, CAC O Lambret, Lille; 6 Oncology, CHU, Limoges; 7 Oncology, Hal St Louis, Paris; 8 Oncology, Sanofi-Aventis, Paris; 9 Oncology, Roche, Neuilly sur Seine, France
* Correspondence to: Dr B. P. Coudert, Centre GF Leclerc, 1 rue du Pr Marion, 21000 Dijon, France. Tel: +33-380-737-720; Fax: +33-380-737-712; E-mail: bcoudert{at}dijon.fnclcc.fr
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Abstract |
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Background: Trastuzumab plus chemotherapy has become the standard of care for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Trastuzumab-based pre-operative systemic (neo-adjuvant) therapy (PST) also appears promising, warranting further investigation.
Patients and methods: Patients with HER2-positive, stage II/III non-inflammatory, operable breast cancer requiring a mastectomy (but who wished to conserve the breast) received weekly trastuzumab and 3-weekly docetaxel for six cycles before surgery. The primary end point was pathological complete response (pCR) rate, determined from surgical specimens.
Results: Thirty-three patients were enrolled. The majority (79%) had T2 tumors, with 42% being N1/2. Twenty-nine patients completed six cycles of therapy and one patient withdrew prematurely due to progressive disease. A complete or partial objective clinical response was seen in 96% (73% and 23%, respectively) of patients. Surgery was performed in 30 patients, breast conserving in 23 (77%). In an intention-to-treat analysis, tumor and nodal pCR was seen in 14 (47%) patients. Treatment was generally well tolerated. Grade 3/4 neutropenia occurred in 85% of patients while febrile neutropenia was encountered in 18%. Only three patients withdrew prematurely due to toxicity. No symptomatic cardiac dysfunction was reported.
Conclusions: PST with trastuzumab plus docetaxel achieved promising efficacy, with a high pCR rate and good tolerability, in women with stage II or III HER2-positive breast cancer.
Key words: breast cancer, docetaxel, efficacy, neo-adjuvant treatment, safety, trastuzumab
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsReferences |
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Pre-operative systemic chemotherapy (PST) is the treatment of choice for women with locally advanced breast cancer [1
]. It aims to reduce the tumor size and may allow for breast-conserving surgery. Tumor response can be assessed clinically and pathologically and is valuable for testing new therapies. Pathological complete response (pCR) also provides a surrogate for disease-free and overall survival [2].
Here we report the results of a phase II trial of trastuzumab (Herceptin®; F. Hoffmann-La Roche, Basel, Switzerland) and docetaxel (Taxotere®; Sanofi-Aventis, Paris, France) as PST for women with human epidermal growth factor receptor 2 (HER2)-overexpressing stage II/III breast cancer. The rationale for integrating trastuzumab into PST for HER2-positive breast cancer is based on the association between HER2 overexpression and poor prognosis [3, 4]. Trastuzumab binds selectively to the HER2 receptor, provides significant clinical benefits including a survival advantage when combined with standard chemotherapy in HER2-positive metastatic breast cancer [5, 6], and has a favorable safety and tolerability profile [7]. Furthermore, when combined with docetaxel in patients with HER2-positive metastatic breast cancer, trastuzumab significantly improved all efficacy parameters, including overall survival, compared with docetaxel alone [6].
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patients and methods |
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study design
This open-label phase II study, conducted at seven centers in France, evaluated weekly trastuzumab plus 3-weekly docetaxel as PST for operable, HER2-positive breast cancer. The primary end point was pCR. Secondary end points were safety and tolerability, complete and partial response rates (CR, PR), breast-conserving surgery, disease-free survival, and local and distant relapses. Figure 1 shows a schematic of the study design.
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The study was conducted in accordance with the Declaration of Helsinki and approved by an ethics committee, the Comité Consultatif de Protection des Personnes en Recherche Biomédicale de Bourgogne. Written informed consent was obtained from all patients prior to enrolment.
eligibility criteria
Women aged 18–65 years with a WHO performance status of 0/1 and a unilateral, histologically confirmed T1c, T2–3, N0–1, non-metastatic, non-inflammatory breast cancer testing HER2 3+ by immunohistochemistry (IHC) and requiring mastectomy (despite the patient's wish to conserve the breast) were eligible. Results of IHC had to be confirmed by telepathological review by at least two pathologists.
Patients were required to have normal blood counts and liver and kidney function tests. All patients had to have a normal left ventricular ejection fraction (LVEF) either by multiple-gated acquisition scan or cardiac ultrasound.
Excluded were: patients with previous exposure to chemotherapy, diffuse microcalcifications, a history of cancer (except in situ carcinoma of the cervix or basocellular or squamous cell skin carcinomas), pre-existing pulmonary and/or cardiac disease; pregnant or sexually active women not using reliable contraception; and patients likely to be unavailable for appropriate follow-up.
study assessments
Tumor samples were collected by needle core biopsy before enrolment and tumor grade, HER2 and hormone receptor status determined. HER2 status was determined by each center's own validated IHC procedure, using either the CB11 monoclonal (Novocastra, Newcastle, UK) or A485 polyclonal (DAKO, Glostrup, Denmark) antibody. Images of the IHC staining were sent, via telepathology, for review and confirmation by two other pathologists. At the end of the study, HER2 status was retrospectively and centrally assessed using both IHC (A485; DAKO) and fluorescence in situ hybridization (FISH) (HER2 FISH pharmDx; DAKO) [8].
Baseline assessment included a full medical history, a general physical examination, routine laboratory and blood chemistry analyses, clinical tumor assessment, bilateral mammography and mammary ultrasound, chest X-ray, hepatic ultrasound, bone scan, electrocardiogram (ECG) and LVEF assessment. ECG was repeated every 21 days and mammary ultrasound and LVEF assessments every 42 days. Bilateral mammography was repeated before surgery. Additional LVEF assessments were carried out 3 months and 1 year after the last cycle of treatment or as the patient's clinical condition warranted. Patients were withdrawn from the study if they developed clinical symptoms of cardiac insufficiency and/or experienced a confirmed reduction in LVEF of 
20% as compared with baseline or below 50%.
Clinical/radiological response was evaluated by palpation after each treatment cycle, and by mammary ultrasound and mammography before surgery, using the RECIST criteria [9]. Pathological response was assessed in surgical specimens of mammary tissue and lymph nodes, using the criteria of Sataloff et al. [10] and Chevallier et al. [11]. The entire area(s) of interest was submitted for microscopic analysis. Surgical tissue specimens were fixed in 10% neutral buffered formaldehyde solution or in Bouin fluid (Richard-Allan Scientific, Kalamazoo, MI, USA) and embedded in paraffin wax. Gross axillary dissections were fixed, then each lymph node macroscopically sectioned in consecutive 2-mm slices, all of which were submitted for analysis. Sections were stained with hematoxylin, eosin and saffron. According to Sataloff (tumor) and UICC (nodes) classification, tumor or node aggregates <2 mm or <0.2 mm, respectively, were not considered as positive.
All adverse events were evaluated according to National Cancer Institute Common Toxicity Criteria (version 2.0).
pre-operative chemotherapy
Patients received six cycles of concomitant trastuzumab and docetaxel. A loading dose of trastuzumab was administered (4 mg/kg by 90-min intravenous infusion) on the day before the first dose of docetaxel, and then weekly at a dose of 2 mg/kg. After the first well-tolerated docetaxel cycle, the chemotherapy could be administered after trastuzumab. Docetaxel (100 mg/m2) was administered as a 1-h intravenous infusion every 3 weeks with standard recommended corticoids and antiemetics from the first cycle.
Complete blood counts were determined on days 7, 14 and 21 of each cycle. In the event of hematological toxicity, docetaxel administration could be delayed and/or the dose reduced and/or prophylactic granulocyte colony-stimulating factor administered. Docetaxel dose delay and reduction were also required in patients developing grade 3 non-hematological toxicity (apart from alopecia). Patients were withdrawn if they developed hematological toxicity lasting for at least 42 days, repeated episodes of prolonged neutropenia (>7 days), febrile neutropenia (>3 days), any grade 3 non-hematological toxicity persisting until day 42 of any cycle or any grade 4 toxicity or severe anaphylactic hypersensitivity reactions to docetaxel. Patients were also withdrawn if they developed progressive disease or serious concomitant disease.
surgery and post-operative treatment
After six cycles of chemotherapy, breast surgery (conservative whenever possible) and axillary node dissection were mandatory. Adjuvant radiotherapy and post-surgical hormone regimens for patients with hormone receptor-positive tumors could be administered according to institutional practice. No hormonal therapy was permitted during PST.
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results |
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patient characteristics (Table 1)
Between April 2001 and November 2003, 33 women with stage II/III, HER2-overexpressing breast cancer were enrolled. Twenty-nine patients (88%) completed six cycles of treatment. One patient experienced disease progression after two cycles of chemotherapy and was withdrawn. Three patients stopped treatment due to toxicity. Therefore, 30 patients were evaluable for efficacy and 32 patients for toxicity. The tumor HER2 status of all patients was IHC 3+ by initial assessment. Retrospective centralized testing confirmed tumor HER2 status as IHC 3+ and/or FISH positive in 26 patients (87%).
clinical and pathological responses to pre-operative chemotherapy
In the efficacy population, 22 patients (73%) achieved a CR and seven (23%) a PR (overall response rate 96%). Only one patient experienced disease progression. Mean tumor size decreased from 46 mm (range 25–100) to 7 mm (range 0–100) after treatment.
All 30 patients had surgery and breast conservation was achieved in 23 patients (77%). Pathological evaluations of surgical specimens showed that initial clinical T2 (>2 cm but <5 cm in size) and T3 tumors (>5 cm in size) were either downstaged to pT0 (no evidence of primary tumor, 40%) and pT1 (tumors 
2 cm in size, 47%), or stabilized to pT2 (7%) or pT3 (4%). Only one T2 tumor progressed to pT3 (3%). Carcinoma in situ was found in 12 patients (40%). No lymph node involvement could be detected in 22 patients (73%). The tumor aggregates were <2 mm in two out of the 14 pT1 tumors. Two of the patients with N0 axillary dissection (no regional lymph node metastasis histologically) displayed small tumor cell clusters of <0.2 mm.
When pathological tumor and node responses were assessed according to Sataloff criteria in an intention-to-treat analysis, pCR [tumor A (TA)/node A (NA) or TA/NB] was confirmed in 14 patients (47%), pPR (>50% therapeutic response, TB/NA or TB/NB) in seven (23%), minor response (TC/NA-NB-NC or TA-TB/NC) in five (16%) and no response (any TD and/or and ND) in four patients (13%). In one patient showing no response, a clinical progression was observed (Sataloff classification, Table 2). All 14 tumors demonstrating a pCR were IHC 3+ and/or FISH positive. At the end of the study, 26 patients were confirmed to have a retrospective centralized HER2 IHC 3+ and/or FISH-positive tumors and the retrospective pCR rate among these patients was 54%. Among the seven other patients, three were not analyzed because they stopped the treatment early due to toxicity. Two samples were re-classified as IHC 1+ and FISH negative (one of these had an IHC 3+ in situ component that was misinterpreted). The last two samples re-assessed as IHC 2+ displayed polysomy of chromosome 17.
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Using the Chevallier criteria, 23% of patients had no evidence of tumor at the primary site or in the lymph nodes, and an additional 13% had only a carcinoma in situ (with no lymph node involvement). Over half (57%) of the specimens had invasive carcinomas with stromal alterations, while 7% had no modification of the initial tumor.
safety and tolerability
Twenty-nine patients completed 18 weeks, i.e. six cycles, of therapy. For these patients, the mean delivered doses of docetaxel and trastuzumab were 97% (range 84% to 101%) and 96% (range 78% to 104%) of the planned doses, respectively.
In three patients, side-effects led to treatment cessation: a grade 3 cutaneous toxicity and a prolonged grade 4 elevation in aspartate aminotransferase (both after cycle one) and a transient, asymptomatic decrease to 46% in LVEF (after cycle 3). The decrease in LVEF normalized 1 month after discontinuation of treatment.
Apart from alopecia, which occurred in 78% of patients, the most common clinical grade 3 adverse events (related and unrelated to treatment) during chemotherapy were asthenia (3%), mucositis (6%), cutaneous toxicity (3%) and infection (3%) (Table 3). Grade 2 neurotoxicity was noted in 6% of patients. There was no clinical evidence of grade 3/4 cardiac events.
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Grade 3/4 neutropenia occurred in 85% of patients (Table 3). Febrile neutropenia occurred in only six patients (18%) and 4% of cycles. Hematological growth factors were administered in 11% of cycles. Apart from neutropenia, the only grade 4 laboratory abnormality was elevated gamma-glutamyl transferase in 3% of patients.
follow-up data
All patients received adjuvant radiation therapy. Follow-up data are available for 30 patients. Median follow up is 26 months. Three local recurrences were reported at 15, 17 and 29 months, respectively. The recurrence at 29 months was in a patient with a pCR. Four metastatic recurrences were reported at 12, 15, 17 and 19 months, respectively. Of these, two occurred in patients with a pCR (12 and 19 months). Recurrences at 15 and 17 months were both local and metastatic. No deaths were reported during the follow-up period.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsReferences |
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PST is the standard of care for patients with locally advanced breast cancer [1
]. This study shows that trastuzumab plus docetaxel is highly active in women with HER2-overexpressing locally advanced breast cancer. The study included rigorous pathological evaluation of surgical specimens, according to two established grading systems [10, 11]. Good concordance was seen between the two systems: 47% pCR rate (Sataloff criteria) and 37% with either no evidence of tumor or a reduced stage (carcinoma in situ with no lymph node involvement; Chevallier criteria). Accurate HER2 testing is essential for optimal patient selection. Thus the rigorous determination of tumor HER2 status may have contributed to the observed high activity of PST in this study. Indeed, the pCR rate reached 54% among patients with retrospective, centrally confirmed IHC 3+ and/or FISH-positive tumors.
One explanation for the improved efficacy of this combination in the present study is that the patients were ideal candidates for PST. They were relatively young, mostly premenopausal women, and with predominantly high-grade T2 tumors at baseline. Forty-two percent of the tumors were hormone receptor negative.
Trastuzumab plus docetaxel showed favorable safety and tolerability in the present study; predominant adverse events were characteristic of the already described association in metastatic disease [6]. No patient experienced symptomatic cardiac dysfunction. The only patient discontinuing treatment for a transient, asymptomatic decrease in LVEF to <50% (46%) had none of the known risk factors for the cardiac dysfunction previously reported in patients receiving trastuzumab [12, 13], and the LVEF normalized 1 month after treatment was discontinued.
Several other phase II or phase III studies have evaluated PST with trastuzumab in combination with cytotoxic therapy [14–23] (Table 4). Among taxanes, docetaxel associated with trastuzumab shows evidence of better efficacy in obtaining complete pathological response rates. Additional combination with platinum remains to be confirmed. Initial association of trastuzumab with taxane and anthracycline (paclitaxel, epirubicin) is demonstrated to be superior to chemotherapy alone [17], but long-term cardiac toxicity monitoring remains an open question. While awaiting more data and approval on anthracycline–trastuzumab associations, trastuzumab combined with docetaxel is a good opportunity for PST in breast cancer. Major results from three adjuvant trastuzumab trials were presented during the American Society of Clinical Oncology 2005 annual meeting, with particular emphasis on the early introduction of trastuzumab therapy [24–26]. A new study of neo-adjuvant versus adjuvant use of trastuzumab could be tested in larger group of patients.
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conclusions |
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TopAbstractintroductionpatients and methodsresultsdiscussionconclusionsReferences |
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We have shown that the combination of trastuzumab with docetaxel as PST for the treatment of HER2-positive breast cancer is active and well tolerated. The histological complete response rate in IHC 3+ and/or FISH-positive locally advanced breast cancer patients was 54% and the rate of breast conservation was high (77%). No clinical cardiac events were observed and non-symptomatic LVEF decrease is rare and reversible. As the sample size for this study was relatively small, further assessment in a large trial is warranted.
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Acknowledgements |
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The authors would like to thank Emma Beatty and Karen Runcie for assistance in manuscript preparation, Marie Christine Porteret for data management, all the surgeons, radiologists, oncologists and pathologists who contributed, Roche laboratories, Sanofi-Aventis laboratories, the 2001–2003 Programme Hospitalier de Recherche Clinique (PHRC) and the Ligue Bourguignonne contre le Cancer for partial financial support of this project. This work was presented at the San Antonio Breast Cancer Symposium, December 2004.
Received for publication June 16, 2005. Revision received October 12, 2005. Accepted for publication November 4, 2005.
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References |
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