Originally published as JCO Early Release 10.1200/JCO.2006.09.9994 on May 21 2007

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Multicenter Phase II Trial of Neoadjuvant Therapy With Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2–Overexpressing Stage II or III Breast Cancer: Results of the GETN(A)-1 Trial

Bruno P. Coudert, Remy Largillier, Laurent Arnould, Philippe Chollet, Mario Campone, David Coeffic, Frank Priou, Joseph Gligorov, Xavier Martin, Véronique Trillet-Lenoir, Béatrice Weber, Jean Pierre Bleuse, Berangère Vasseur, Daniel Serin, Moïse Namer

From the Departments of Oncology and Pathology, CAC G.F. Leclerc and IFR 100, Dijon; Oncology, CAC A. Lacassagne, Nice; Oncology, CAC J. Perrin, Clermont Ferrand; Oncology, CAC R. Gauducheau, Nantes; Oncology, Clinique du Mail, Grenoble; Oncology, CH Les Oudairies, La Roche sur Yon; Oncology, Cancer Est, APHP Tenon; Oncology, Sanofi-aventis, Paris; Oncology, Clinique St Marie, Chalon sur Saone; Université Lyon 1, EA3738 et CH Lyon Sud, Lyon; Oncology, CAC A Vautrin, Nancy; Oncology, Roche, Neuilly; and Oncology, Institut St Catherine, Avignon, France

Address reprint requests to Bruno P. Coudert, MD, Centre GF Leclerc, 1 rue du Pr Marion, 21000 Dijon, France; e-mail: bcoudert{at}dijon.fnclcc.fr

	ABSTRACT

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Purpose: Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) –positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation.

Patients and Methods: Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m² every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens.

Results: Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization–positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred.

Conclusion: PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.

	INTRODUCTION

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Preoperative systemic chemotherapy is a standard treatment approach for inoperable locally advanced breast cancer, and may also be used for selected patients with operable disease to facilitate breast conservation.^1-4

Pathologic complete response (pCR), is a short-term surrogate marker correlating with long-term outcome⁵ and is an end point commonly used in neoadjuvant trials evaluating novel combinations. Despite the advances achieved with PST to date, novel treatment approaches are still necessary to enhance disease control and increase the proportion of patients achieving a pCR. The use of targeted therapy could be a means to reach this goal.

Human epidermal growth factor receptor-2 (HER-2) overexpression occurs early in the development of breast cancer leading to aggressive disease, high risk of recurrence or metastasis, and poor prognosis.^6-10 Furthermore, HER-2-positive breast cancer, when treated with primary surgery, demonstrates an early peak of local relapse or metastasis.¹¹ A link has also been reported between HER-2 overexpression and postsurgery growth stimulation of breast carcinoma cells.¹² The rationale for integrating trastuzumab into preoperative systemic therapy (PST) for HER-2-positive breast cancer is based on the association between its use and the activation of immunologic functions,^13,14 the inhibition of the HER-2 extracellular domain,¹⁵ and the reduction of HER-2 phosphorylation and downstream signaling.¹⁶

Trastuzumab binds selectively to the HER-2 receptor and provides significant clinical benefits (often including a survival advantage when combined with standard chemotherapy in HER-2-positive breast cancer) both in the metastatic^17,18 and adjuvant settings.^19-21 Furthermore, trastuzumab has a favorable safety and tolerability profile.^17-21 The addition of trastuzumab to preoperative docetaxel has been shown to result in a pCR of 54% in patients with confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization (FISH) -positive tumors.²² Data demonstrating experimental and clinical synergism between docetaxel-carboplatin and trastuzumab have led to promising results with this combination in patients with metastatic HER-2-positive breast cancer.^23,24 This open-label phase II study was initiated to evaluate weekly trastuzumab plus docetaxel every 3 weeks and carboplatin as PST for operable, HER-2-positive breast cancer.

	PATIENTS AND METHODS

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This open-label phase II study was carried out across 11 centers in France and was approved, in accordance with the Helsinki Declaration, by an ethics committee, the Comité Consultatif de Protection des Personnes en Recherche Biomédicale des Bouches du Rhône.

Inclusion and Exclusion Criteria
Women were included if they were age 18 to 65 years with WHO performance status of 0/1 and with unilateral, histologically proven T2-3N0-1, nonmetastatic, noninflammatory breast cancer testing HER-2 3+ by immunohistochemistry (IHC), requiring a mastectomy (despite the patient's wish to conserve the breast). Other requirements were adequate hematologic, renal, and hepatic function as well as left ventricular ejection fraction (LVEF) within the normal range for each institution. Written informed consent was obtained from all patients before enrollment.

Patients were not eligible for inclusion if they had prior exposure to chemotherapy, diffuse microcalcifications detected on mammography, a history of any other cancer (except cervical carcinoma [in situ] or basocellular or squamous cell skin carcinoma), or pre-existing pulmonary and/or cardiac disease; were pregnant or sexually active women not using reliable contraception; or were unlikely to be available for appropriate follow-up.

Preoperative Chemotherapy
Patients received six 3-week cycles of concomitant trastuzumab, docetaxel, and carboplatin. A loading dose of trastuzumab was administered (4 mg/kg as a 90-minute intravenous [IV] infusion), and then trastuzumab was administered weekly at a dose of 2 mg/kg for a total of 17 injections. Carboplatin (area under the curve [AUC], 6) and docetaxel (75 mg/m²) were each administered as a 1-hour IV infusion every 3 weeks with standard recommended corticosteroids and antiemetics. Docetaxel and carboplatin were initially administered the day after the first dose of trastuzumab, then the same day as trastuzumab during the subsequent courses.

CBCs were carried out on days 7, 14, and 21 of each cycle. If a hematologic toxicity or grade 3 nonhematologic toxicity occurred, the dose of docetaxel was delayed and/or reduced. Prophylactic granulocyte colony-stimulating factor (G-CSF) was authorized in case of previous febrile neutropenic events. Treatment withdrawal was required in the event of hematologic toxicity ( 42 days), repeated episodes of prolonged neutropenia (> 7 days), febrile neutropenia (> 3 days), any grade 3 nonhematologic toxicity persisting until day 42 of any cycle, any grade 4 toxicity, or severe anaphylactic hypersensitivity reactions to docetaxel. Cessation of chemotherapy was required in patients showing signs of progressive disease or serious concomitant disease.

Surgery and Postoperative Treatment
After six cycles of chemotherapy, breast surgery (conservative whenever possible) and axillary node dissection were mandatory. Adjuvant radiotherapy and postsurgical hormonal therapy in patients with hormone receptor–positive tumors could be administered according to institutional practice. Hormone therapy was not allowed during PST. If an objective response was measured, adjuvant trastuzumab (6 mg/kg) was administered 3-weekly during the 52 weeks after surgery.

Study Assessments
Tumor samples were collected by needle core biopsy before enrollment, and tumor grade and HER-2 and hormone-receptor status were determined. HER-2 status was determined by each center's validated IHC procedure, using either the CB11 monoclonal (Novocastra, Newcastle on Tyne, United Kingdom) or A485 polyclonal (DAKO, Glostrup, Denmark) antibody. Pathologic response was assessed locally by a single pathologist. At the end of the study, pretreatment HER-2 status was retrospectively and centrally assessed using both IHC (A485, DAKO) and FISH (ONCOR, Ventana Medical Systems, Tucson, AZ).²⁵

Baseline assessments 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, ECG, and LVEF assessment. ECG was repeated every 21 days and mammary ultrasound and LVEF assessments every 42 days. LVEF assessments were performed using multiple gated acquisition scan or heart ultrasounds, and the same method was required at each subsequent evaluation. 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 warranted by the patient's clinical condition. Patients were withdrawn from the study if they developed clinical symptoms of cardiac insufficiency and/or experienced a confirmed reduction in LVEF below 50% or at least 20% of the baseline level.

Clinical/radiologic response was evaluated by palpation after each treatment cycle and by mammary ultrasound and mammography before surgery, using the Response Evaluation Criteria in Solid Tumors (RECIST).²⁶ Pathologic response was assessed in surgical specimens of mammary tissue and lymph nodes using Sataloff et al²⁷ and Chevallier et al²⁸ criteria. According to Sataloff classification (tumor) and International Union Against Cancer (UICC) classification (nodes), tumor or node aggregates less than 2 mm or less than 0.2 mm, respectively, were not considered positive. All adverse events were evaluated according to National Cancer Institute Common Toxicity Criteria (NCI-CTC; version 2.0).

End Points and Statistical Analysis
The primary end point was pCR. Secondary end points were safety and tolerability, CR and partial response (PR) rates, level of breast-conserving surgery, disease-free survival, and local and distant relapses. The number of patients enrolled was dependent on a multistage Fleming plan.²⁹

The minimum expected pCR rate after six cycles of docetaxel/carboplatin/trastuzumab was estimated to be 15% equivalent to the study of Hurley³⁰ without trastuzumab. Doubling this result by obtaining a pCR rate of 30% with the addition of trastuzumab, was considered to be sufficient to propose this association in a phase III trial. With alpha and beta risks of 5% and 16%, respectively, and a power of 84%, achieving five or more pCRs within the first 30 patients would enable the inclusion of an additional 30 patients; if this was not achieved, it was planned to stop the study.

Statistical analyses were descriptive. Survival data were estimated using the Kaplan-Meier method.

	RESULTS

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Patient Characteristics
A total of 70 patients with stage II/III, HER-2-positive breast cancer were enrolled between January 2003 and December 2004. The initially planned 60 patients were increased to 70 because preliminary retrospective centrally analysis of pretreatment HER-2-3+ status did not confirm the positive status for all the tumors.

Sixty-seven patients (96%) received the planned six cycles of treatment. One patient (1%) progressed during chemotherapy after two cycles. Two patients (3%) were withdrawn from the study due to toxicity.

Patient baseline characteristics are shown in Table 1. When assessed clinically, median and mean baseline tumor sizes (longest diameter) were 40 and 45 mm respectively [range, 20 to 120 mm], which was in accordance with the median and mean mammography-assisted measurements of 30 and 32 mm [range, 15 to 70 mm].

Over the six cycles of completed treatment, the mean range relative (administered/theoretical) dose intensities of docetaxel and trastuzumab were 97% (73% to 105%) and 99% (81% to 138%), respectively. In the only 12 patients in whom all the data (age, weight, size, creatinine) were available to retrospectively calculate carboplatin AUC, the mean range relative dose intensity of carboplatin was 99% [82% to 113%]. Among 420 3-weekly cycles, docetaxel was reduced for 12 cycles (3%). Among 1,260 weekly cycles, trastuzumab was delayed for 22 cycles (1.7%).

Clinical and Pathologic Responses to Preoperative Chemotherapy
In the 70 patients, a clinical CR was achieved in 85% of patients, with clinical PR in 10%, providing an objective response rate of 95%. Only one patient experienced disease progression. After treatment, median and mean clinical and mammographic tumor sizes decreased to 0 and 9 mm (range, 0 to 40 mm) and 5 and 11 mm (range, 0 to 45 mm), respectively.

All 70 patients had surgery. Breast conservation was achieved in 45 patients (64%). The remaining 25 patients (36%) underwent mastectomy.

Using the Chevallier criteria,²⁸ 20 patients (29%) had no evidence of tumor at the primary site or in the lymph nodes. An additional seven patients (10%) had only a carcinoma in situ (with no lymph node involvement; Table 2). Thirty-five specimens (50%) had invasive carcinomas with stromal alterations, whereas six (9%) had no modification of the initial tumor. Chevallier classification was not available in two patients (2%) because of missing node data (Table 2). No evidence of invasive carcinoma with or without carcinoma in situ in the breast was diagnosed in 49% and in 30% of initial clinical T2 and T3 tumors respectively, and in 39% of initial clinical N0 or N1 disease.

At the end of the study, the retrospective pCR rate among the 56 tumors that were confirmed to be HER-2 IHC 3+ and/or FISH-positive tumors was 43% (24 of 56). Among the 15 tumors that were not confirmed as HER-2 IHC 3+ and/or FISH-positive, the pCR rate was 21% (three of 14).

Safety and Tolerability
All patients were assessable for toxicity. Two patients stopped chemotherapy because of a transient, asymptomatic decrease in LVEF to less than 50%. In the first patient, isotopic LVEF decreased from 58% to 37% after three courses of the study trastuzumab-based chemotherapy, but without clinical cardiac symptoms. In two separate assessments, echocardiographic LVEF returned to normal (63% and 68%) and revealed a mitral insufficiency. Because isotopic LVEF remained at 48%, the next three courses of chemotherapy were administered without trastuzumab. The patient had a nonconservative surgery, and a pCR was diagnosed. She had no adjuvant chemotherapy. In the second patient, LVEF fell from 55% to 46% after two courses of the study trastuzumab-based chemotherapy without clinical cardiac symptoms. Echocardiographic LVEF returned to normal (55%) and revealed an asymptomatic myocardiopathy of unknown origin, which led to cardiologic treatment. The third and fourth courses of treatment were administered without trastuzumab. Isotopic LVEF returned to normal (52%) and the fifth and sixth courses incorporated trastuzumab again. Despite trastuzumab reintroduction, LVEF remained normal. The patient had a conservative surgery, and a pCR was diagnosed. She had adjuvant trastuzumab without LVEF degradation. There was no evidence of clinical cardiac events in any patient. At the end of treatment, a 10% and 20% relative reduction in LVEF was seen in 14 (29%) and six patients (12%), respectively. The most common clinical grade 3/4 adverse events (related and unrelated to treatment) during chemotherapy were constipation (7%), asthenia (4%), and nausea/vomiting (3%; Table 3). Grade 1/2 alopecia occurred in 61% of patients; grade 1/2 neurotoxicity was noted in 12% of patients.

Follow-Up Data
All patients received adjuvant radiation therapy. Hormone therapy was used in case of positive hormone receptors. One year of adjuvant trastuzumab was used if an objective response to neoadjuvant therapy was observed. Follow-up data are available for all patients. Numbers have to be taken with caution because median follow-up was 25 months (range, 16 to 43 months). Local or regional recurrences occurred in five patients (Fig 1A). Metastatic recurrence (alone or with locoregional recurrence) occurred in eight patients (Fig 1B). One patient died as a result of progressive disease at 36 months (Fig 1C). None of the patients with local or metastatic recurrence had been diagnosed with pCR.

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Survival data of 70 patients treated with neoadjuvant trastuzumab, carboplatin, and docetaxel followed by adjuvant trastuzumab in case of clinical objective response. (A) Survival without local recurrence, (B) survival without metastasis, and (C) overall survival. Numbers have to be taken with caution as median follow-up was 25 months (range, 16 to 43 months).

	DISCUSSION

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This study included rigorous pathologic evaluation of surgical specimens according to two established grading systems. The intent-to-treat breast and node pCR rate, assessed using Chevallier and Sataloff criteria,^27,28 reached 39% (43% in the confirmed retrospective centralized HER-2-3+/FISH-positive tumors). Most of the pCRs (23 of 27) were diagnosed in FISH-positive tumors, a result that correlates with some studies^31,32 and contrasts with other ones.³³

The discrepancies between routine and centralized HER-2 testing have been described previously for larger randomized studies with similar rates of routine IHC failures.^34,35 The initial local determination of HER-2 status followed by retrospective analysis, however, was potentially a limitation of the present study, and centralized validation of HER-2 status before enrollment may have been a more accurate method of HER-2 testing and selection.

The present study showed that trastuzumab plus docetaxel and carboplatin has favorable safety and tolerability. The predominant adverse events reported were characteristic of those described in the studies associated with metastatic disease.^17,24 Although decreased cardiac function has been reported in 10% of patients treated with trastuzumab,³⁶ none of the patients of the present study experienced symptomatic cardiac dysfunction even when LVEF decrease was encountered. Even in the two patients discontinuing treatment due to a transient, asymptomatic decrease in LVEF to less than 50% (37% and 46%), LVEF normalized after treatment discontinuation. It should be noted that the patients enrolled onto the study were chemotherapy naïve and had no known previous risk of cardiac toxicity, an adverse effect related to trastuzumab treatment.^36,37

Several other phase II or phase III studies have evaluated PST with trastuzumab in combination with cytotoxic therapy (Table 4). Studies may differ in patient and tumor size selection, criteria of positivity in IHC and/or FISH testing,^38,39 and adherence to strict pCR criteria, resulting in different pCR results. Although cross-study comparisons must be interpreted with caution, trastuzumab has been shown to improve the efficacy of PST substantially in HER-2-positive patients. Buzdar et al³² reported that the addition of trastuzumab to paclitaxel followed by fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy was superior to paclitaxel and FEC alone, providing a pCR of 65% versus 26%, respectively (P = .16). A pCR of 54% was confirmed with trastuzumab plus paclitaxel and FEC in a follow-up phase II study that included an additional 23 patients.³¹ However long-term cardiac toxicity monitoring of anthracyclines and trastuzumab associations remains an open question. Further evidence that trastuzumab improves the efficacy of PST in HER-2-positive patients is supported by a French study in which six cycles of preoperative trastuzumab and docetaxel achieved a clinical response rate of 73% and a retrospective pCR rate of 54% using Sataloff criteria.²² The superior pCR rate that was observed may be explained by the higher dose of docetaxel compared with that used in the present study (100 v 75 mg/m², respectively). In a recent study, four cycles of docetaxel, cisplatin, and trastuzumab achieved a pCR rate of 17% in the breast and axilla with an additional 15% of only microscopic residual disease.³³ Among taxanes, docetaxel (100 mg/m²) associated with trastuzumab shows evidence of better efficacy in obtaining complete pathologic response rates. The role of adding platinum or vinorelbine to trastuzumab remains to be clarified. The limited experience of lapatinib in this setting has also to be further explored.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Jean Pierre Bleuse, Sanofi-aventis; Berangere Vasseur, Roche Leadership: Berangere Vasseur, Roche Consultant: Bruno P. Coudert, Roche; Joseph Gligorov, Sanofi-aventis; Moise Namer, Sanofi-aventis Stock: N/A Honoraria: Bruno P. Coudert, Sanofi-aventis; Joseph Gligorov, Sanofi-aventis; Moise Namer, Roche, Sanofi-aventis Research Funds: Philippe Chollet, Roche, Sanofi-aventis Testimony: Philippe Chollet, Roche, Sanofi-aventis Other: Philippe Chollet, Roche, Sanofi-aventis

	AUTHOR CONTRIBUTIONS

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Conception and design: Bruno P. Coudert, Laurent Arnould, Jean Pierre Bleuse, Daniel Serin, Moise Namer

Administrative support: Moise Namer

Provision of study materials or patients: Bruno P. Coudert, Remy Largillier, Laurent Arnould, Philippe Chollet, Mario Campone, David Coeffic, Franck Priou, Joseph Gligorov, Xavier Martin, Véronique Trillet-Lenoir, Beatrice Weber, Daniel Serin

Collection and assembly of data: Bruno P. Coudert, Remy Largillier, Laurent Arnould, David Coeffic, Joseph Gligorov, Véronique Trillet-Lenoir, Moise Namer

Data analysis and interpretation: Bruno P. Coudert, Remy Largillier, Laurent Arnould, Moise Namer

Manuscript writing: Bruno P. Coudert

Final approval of manuscript: Bruno P. Coudert, Remy Largillier, Laurent Arnould, Philippe Chollet, Mario Campone, David Coeffic, Franck Priou, Véronique Trillet-Lenoir, Jean Pierre Bleuse, Berangere Vasseur, Daniel Serin

	ACKNOWLEDGMENTS

 
We thank all the surgeons, radiologists, oncologists, and pathologists who contributed; Pierre Attali, Philippe Caille, Sylvie Detry, Oudi Asma, Zahir Brakchi, Jana Paquet, Pierre Nicolas, and Véronique Lotz for assistance with this study; and Sanofi-aventis laboratories and Roche laboratories for their financial and logistic help.

	NOTES

 
published online ahead of print at www.jco.org on May 21, 2007.

Presented at the 28th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 20, 2006; accepted April 9, 2007.

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