Originally published as JCO Early Release 10.1200/JCO.2005.07.032 on February 28 2005

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Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer

From the Departments of Breast Medical Oncology, Biostatistics, Surgical Oncology, Pathology, Cardiology, and Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Aman U. Buzdar, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030; e-mail: abuzdar{at}mdanderson.org

	ABSTRACT

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PURPOSE: The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2) –positive disease.

PATIENTS AND METHODS: Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. The primary objective was to demonstrate a 20% improvement in pCR (assumed 21% to 41%) with the addition of trastuzumab to chemotherapy. The planned sample size was 164 patients.

RESULTS: Prognostic factors were similar in the two groups. After 34 patients had completed therapy, the trial's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Of the 42 randomized patients, 26% in the chemotherapy arm achieved pCR compared with 65.2% in the trastuzumab plus chemotherapy arm (P = .016). The safety of this approach is not established, although no clinical congestive heart failure was observed. A more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively.

CONCLUSION: Despite the small sample size, these data indicate that adding trastuzumab to chemotherapy, as used in this trial, significantly increased pCR without clinical congestive heart failure.

	INTRODUCTION

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Systemic therapy is an integral part of the multidisciplinary curative treatment of primary breast cancer and results in significant reductions in risk of recurrence and death.^1-3 Combination chemotherapy regimens administered as postoperative adjuvant therapy are superior to single-agent chemotherapy, and anthracycline-containing regimens are superior to nonanthracycline-containing combinations. Primary induction chemotherapy has been evaluated in a number of studies in patients with breast cancer.⁴ Randomized studies indicated that the survival benefit from particular treatment regimens is similar, regardless of whether the treatment is administered preoperatively or postoperatively. A practical benefit of preoperative therapy is that it will downstage the primary tumor in most women, allowing a higher rate of breast preservation. It also provides an in vivo assessment of tumor response to the particular drug regimen and, hence, an opportunity to optimize therapy.⁵ Furthermore, pathologic complete response (pCR) after preoperative therapy is a powerful surrogate of long-term disease-free survival. It is hypothesized that a regimen that produces higher rates of pCR in the neoadjuvant treatment setting will also result in higher rates of long-term cure.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25% to 30% of breast cancers, suggesting a role for overexpression in tumorigenesis.⁶ This overexpression is most commonly the result of gene amplification. Several lines of evidence support the role of HER2 overexpression in the pathogenesis and poor clinical outcome of human tumors. A number of these studies have shown that breast cancers that overexpress HER2 have a more aggressive course and higher relapse and mortality rates. HER2 overexpression in retrospective analyses of adjuvant studies was also associated with resistance to cyclophosphamide, methotrexate, and fluorouracil chemotherapy.^7,8 With regard to response to hormonal therapies and anthracycline-based chemotherapy, the role of HER2 overexpression is unclear.^9,10

Trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA) is a humanized monoclonal antibody directed against the extracellular domain of HER2.¹¹ Trastuzumab as a single agent has modest antitumor activity.^12-14 In phase III randomized trials, trastuzumab in combination with standard chemotherapy (paclitaxel, docetaxel or doxorubicin, and cyclophosphamide combinations) demonstrated improvement in time to progression, overall response, and duration of response and a favorable impact on survival compared with the same chemotherapy alone as therapy for metastatic breast cancer overexpressing HER2.^15-17 Cardiac dysfunction was observed in 27% of patients treated with trastuzumab and anthracycline-based combination therapy.¹⁵ No randomized preoperative study has been performed with trastuzumab. Given the enhanced antitumor activity in these studies, we designed a study in which patients with HER2-positive operable breast cancer were randomly assigned to either chemotherapy (sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide [FEC]) with simultaneous weekly trastuzumab for 24 weeks or chemotherapy alone. The choice of chemotherapeutic agents was based on what we consider to be among the most active agents in breast cancer. The goal of the study was to demonstrate that the addition of trastuzumab to a complete 6-month preoperative chemotherapy regimen will increase pCR rate two-fold compared with chemotherapy alone. We selected epirubicin as part of the combination regimen in an effort to reduce cardiac toxicities compared with those attributed to trastuzumab and doxorubicin combination. The results of this prospective randomized phase III study were recently presented,¹⁸ and complete results are included in this article.

	PATIENTS AND METHODS

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Patients with histologically confirmed invasive, but noninflammatory, carcinoma of the breast with stage II to IIIA disease were included in this study. Histologic confirmation of invasive tumor was performed by core needle biopsy. Fine-needle aspiration of clinically suspicious lymph nodes was performed. All tumors were HER2 positive by fluorescence in situ hybridization (FISH) or showed 3+ overexpression by immunohistochemistry. Before initiation of therapy, all patients underwent staging evaluation, which included a complete history, physical examination, CBC, chemistry profile, chest radiograph, ultrasound or computed tomography scan of the liver, and a bone scan. Mammography of both breasts was performed, and additional breast and axillary assessment of the tumor site was conducted by ultrasound. Before entry onto the study, each patient was informed about the investigational nature of the study, and a written informed consent, which was approved by the institutional review board, was obtained. All patients were required to have adequate bone marrow function as defined by an absolute granulocyte count of more than 1,500/µL and platelet count of more than 100,000/µL. Patients had to have adequate liver function, with bilirubin within normal laboratory values. In addition, patients had to have adequate renal function, which was defined as serum creatinine less than 2.5 mg/100 mL. Cardiac evaluation included a baseline echocardiogram or a cardiac scan. Patients with a history of uncompensated congestive heart failure or a cardiac ejection fraction less than 45% were excluded. Each patient was reviewed in a multidisciplinary conference with designation of whether breast conservation was a reasonable surgical option before treatment was initiated.

All patients were prospectively registered into our central research database. Patients were randomly assigned to receive either chemotherapy alone or the same chemotherapy with trastuzumab on a weekly basis for 24 weeks. Patients had a physical examination of breasts and regional lymph node basins before each cycle of chemotherapy. Antitumor activity was evaluated with imaging studies after four cycles of chemotherapy (at the completion of paclitaxel) and before surgery (at the completion of FEC). Tumor measurements were documented after the first 12 weeks of paclitaxel and at the completion of FEC therapy to determine the best clinical response before local therapy. CBCs, differential counts, and platelet counts were repeated weekly to monitor the myelotoxicity of chemotherapy in the first cycle, and subsequently, blood counts were performed on day 1 of each cycle. Cardiac evaluation was performed at baseline and then repeated after completion of paclitaxel and then again at the completion of FEC therapy. If there was a marked response to chemotherapy after one or more cycles of chemotherapy, the tumor site was marked with a stainless steel marker placed under ultrasound guidance. Follow-up ultrasound and mammography were performed after four cycles of paclitaxel and again after four cycles of FEC. After completion of chemotherapy and surgical and/or radiation therapy, patients with estrogen receptor (ER) –positive and/or progesterone receptor–positive tumors received adjuvant endocrine therapy. Patients were evaluated at 4-month intervals during the initial 2 years and then at 6-month intervals for the third year. Mammograms were performed yearly.

Clinical complete remission was defined as disappearance of all clinical evidence of active tumor per evaluation by physical examination. Partial response was defined as equal or greater than 50% decrease in measurable lesions for a minimum of 4 weeks as determined by the product of the longest perpendicular diameters of the lesion(s). Minor response was defined as a decrease in the tumor size that did not qualify for partial response, and progressive disease was defined as any increase in tumor size or appearance of new lesions. pCR was defined as no evidence of residual invasive cancer, both in breast and axilla.

The primary objective of the study was to compare pCR rates between the two arms. The projected pCR rate with the standard arm was estimated to be 21% based on previous experience with similar chemotherapy.¹⁹ The study was powered to detect a 20% improvement in the pCR rate (ie, from 21% to 41%). Accrual of 164 patients was planned. With this number of patients, the study would have had 80% power to detect a 20% difference (two-sided type I error = 0.05). Patients were assigned to treatment arms using a stratified blocked randomization, with strata based on age (< 50 years v 50 years) and stage of disease. One interim analysis was planned when pCR results were known for the first 82 patients. Stopping rules were provided in the event that accumulating evidence indicated a rate of cardiac toxicity more than 3%. All patients were included in the analysis of response and toxicity. Toxicities were tabulated by type and grade using the National Cancer Institute Common Toxicity Criteria, Version 2.0. Toxicity and response rates were compared using the ² test. In view of the apparently high pCR rate in the trastuzumab plus chemotherapy arm, the data were presented to the M.D. Anderson Data Monitoring Committee (DMC). The DMC requested information on the patient accrual rate, response, and adverse events by treatment. The DMC also requested an analysis based on Bayesian predictive probabilities,^20,21 addressing the question of how likely the final results of the study (ie, after the full planned sample size of 164 patients) would show statistical significance favoring the trastuzumab plus chemotherapy arm.

Chemotherapy
Each patient was to receive four cycles of paclitaxel followed by four cycles of FEC. Paclitaxel was administered at 225 mg/m² as a 24-hour continuous intravenous (IV) infusion; cycles were repeated every 3 weeks for four cycles. Each patient was premedicated with either dexamethasone 20 mg orally, 12 and 6 hours before administration of paclitaxel, or dexamethasone 20 mg IV 30 minutes before chemotherapy. Patients received diphenhydramine 50 mg IV and cimetidine 300 mg IV 30 minutes before paclitaxel infusion. The dose and schedule of paclitaxel was selected based on information available at the time of study inception in 1999. At that time, the optimal dose and schedule of paclitaxel was unclear, and there were data to suggest that a 24-hour continuous infusion and somewhat higher doses might be beneficial compared with short infusion.^22,23 These assumptions today do not seem to be validated. On the basis of current evidence, the most effective schedule may be weekly administration.^19,24 FEC consisted of fluorouracil 500 mg/m² IV on days 1 and 4, cyclophosphamide 500 mg/m² IV on day 1 only, and epirubicin 75 mg/m² on day 1 only. Patients randomly assigned to the trastuzumab arm of the study received trastuzumab at a dose of 4 mg/kg IV on day 1 of the first treatment cycle, administered over 90 minutes. Subsequent doses of weekly trastuzumab were administered at a dose of 2 mg/kg over 30 minutes. Patients were monitored for 1 hour after the first infusion and for 30 minutes after subsequent infusions. Trastuzumab was administered before chemotherapy. A total of 24 doses of trastuzumab were administered on a weekly basis. In the first cycle, trastuzumab was administered 1 day before paclitaxel to monitor any potential infusion reaction; on subsequent courses, therapies were administered on the same day if there was no adverse event with the first cycle. After completion of 24 weeks of systemic therapy, patients received local therapy. After completion of systemic and local therapy, patients with ER-positive tumors received tamoxifen at a dose of 20 mg daily or anastrozole 1 mg daily if the patient was postmenopausal. This was planned for 5 years, regardless of the menopausal status of the patient.

Dose Modification Criteria
The dose of paclitaxel was reduced by 50% in subsequent cycles if a patient developed grade 3 neurotoxicity. Patients were required to have more than 1,500/µL granulocytes and more than 100,000/µL platelets before the administration of the next cycle of chemotherapy. Doses of the chemotherapy drugs (both FEC and paclitaxel) were not altered if the patient's lowest granulocyte count was more than 250/µL, there was no other organ toxicity greater than grade 2, and the lowest platelet count was more than 50,000/µL. Patients did not receive prophylactic hematopoietic growth factor unless neutropenic fever occurred. If a patient experienced neutropenic fever, either on the paclitaxel or the FEC phase of therapy, granulocyte colony-stimulating factor was added to the treatment at 5 µg/kg on days 5 through 18 or until the granulocyte count was more than 2000/µL, and chemotherapy dose was not modified. In subsequent cycles, if a patient experienced fever after the addition of granulocyte colony-stimulating factor, the dose of the drug(s) was reduced by 20%. The dose of the drug(s) was reduced by 20% if a patient experienced organ toxicity other than myelosuppression of grade 3.

Local Therapy
After completion of neoadjuvant therapy, each patient was evaluated. Patients who were considered appropriate candidates for breast conservation therapy (BCT) were offered segmental mastectomy (lumpectomy). Patients who were considered inappropriate for BCT or who did not desire BCT underwent total mastectomy. All patients (mastectomy and BCT) with persistent axillary disease detected by physical examination or by ultrasonography and verified by ultrasound-guided fine-needle aspiration underwent axillary lymph node dissection. Patients who were clinically node-negative after neoadjuvant therapy proceeded to lymphatic mapping and sentinel lymph node biopsy. Clinically node-negative patients who showed microscopic residual disease in the sentinel lymph node(s) were recommended for axillary lymph node dissection, although some elected to receive postoperative radiation therapy to the regional lymph nodes instead.

All patients treated with a segmental mastectomy received whole-breast irradiation. The breast was treated with standard medial and lateral tangent fields using 6 to 15 MV photons to a total dose of 50 Gy delivered in 25 fractions. Subsequently, the tumor bed was treated with an additional 10 Gy in five fractions with electrons. Regional nodal irradiation to the supraclavicular fossa-axillary apex was used in patients with clinical stage III disease, in patients with four or more positive lymph nodes, and in selected patients with one to three positive lymph nodes. Radiation treatments were not offered to patients with initial clinical stage II breast cancer who were treated with mastectomy and had negative lymph nodes. Radiation treatment of the chest wall and draining lymphatics was used for patients with stage III disease, patients with four or more positive lymph nodes, and selected patients with one to three positive lymph nodes. In these patients, the chest wall was typically treated with opposed lateral tangent fields matched to a medial electron field that included the internal mammary lymph nodes and a separate matched photon field that treated the supraclavicular fossa-axillary apex. These regions were treated to 50 Gy in 25 fractions with a subsequent 10 Gy boost to the chest wall and areas of unresected, initially positive, adenopathy.

Pathologic Evaluation
After chemotherapy, resected specimens were evaluated by breast pathologists using the standard protocol of The M.D. Anderson Cancer Center.^25,26 In brief, the surgeon oriented the specimen with sutures and accompanied it to the pathology suite. In cases showing significant clinical response, the breast resection specimen was radiographed to identify metallic markers, which were placed under ultrasound examination before chemotherapy. The specimen was inked using multiple colors to identify each face of the specimen. It was then sectioned into 3- to 5-mm slices. The sliced specimen was radiographed, and a radiologist reviewed the films to determine the presence and extent of residual tumor. The pathologist examined the sliced specimen grossly to identify suspicious areas and note their proximity to margins. The radiographic and pathologic evaluations were discussed with the surgeon who decided whether additional margin should be obtained or not. Permanent paraffin sections of the suspicious areas and margins were obtained. The number of sections taken was based on the gross inspection, radiographic features, and size of the resection specimen. The entire radiographic abnormality as well as firm and suspicious-appearing breast tissue was submitted for histologic evaluation. In general, for nonpalpable (clinical complete response) cases, at least 10 to 15 blocks were examined to assess the presence of residual microscopic disease. In cases with residual palpable mass (partial clinical response or no response), the resection specimen was inked and sectioned into 3- to 5-mm slices. The pathologist examined the slices and determined the tumor size and gross evaluation and confirmed the tumor size by microscopic evaluation. The largest area of residual disease was included to document the extent of disease in a patient with multiple foci of persistent invasive cancer. All axillary lymph nodes were also carefully evaluated by serial gross sectioning. One or two representative histologic sections were evaluated for lymph nodes that contained grossly identifiable metastatic carcinoma. Lymph nodes that did not show grossly identifiable tumor were submitted for histologic evaluation in their entirety. One representative histologic section was evaluated per paraffin block. Immunohistochemical staining for cytokeratin was not routinely performed on negative nodes.

	RESULTS

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Between June 2001 and October 20, 2003, 42 patients were registered onto this study and randomized. Of those 42 patients, 19 patients were randomly assigned to chemotherapy alone, and 23 patients were assigned to chemotherapy with trastuzumab. Pretreatment characteristics of the patients in the two groups were similar and are listed in Table 1. The median age was slightly higher for the patients treated with chemotherapy plus trastuzumab. The distributions by the tumor T and N status were similar in the two groups, except for one patient who had T3b disease and was included in the chemotherapy plus trastuzumab arm. Two patients in the chemotherapy plus trastuzumab arm had synchronous bilateral breast cancers. Approximately half of the patients had hormone receptor–positive tumors. Most patients had HER2/neu status of tumors confirmed by FISH. For four patients, HER2 status was determined by immunohistochemistry only. One patient in each arm was subsequently found to be HER2 negative by FISH.

The pCR data for the first 34 patients, as reviewed by the DMC, and for all 42 patients randomized are listed in Table 2. Among the total patients, 26.3% of patients in the chemotherapy alone arm achieved pCR compared with 65.2% of the patients treated with trastuzumab plus chemotherapy. This difference was statistically significant (P = .016). The 95% CI for the 65.2% pCR rate observed on the trastuzumab plus chemotherapy arm ranged from 43% to 84%. An update of the Bayesian analysis incorporating results for 42 patients indicated a 96% probability that the trastuzumab plus chemotherapy arm would be found superior if accrual were continued to 164 patients. Of the patients who achieved pCR, one in the chemotherapy alone arm and five in the trastuzumab plus chemotherapy arm had residual ductal carcinoma-in-situ.

Clinical Response
The clinical response data are listed in Table 2. The clinical response was assessed by physical evaluation of the breast and nodes. Nine patients (47.4%) in the chemotherapy alone arm and 20 patients (86.9%) in the trastuzumab plus chemotherapy arm had clinical complete response. Most of the pCRs were observed in patients who had clinical complete responses. A small number of patients clinically judged to have partial response or no change in their disease status had pCR. Imaging studies included mammogram and ultrasound before surgery. In a number of patients who had pCRs, there were persistent abnormalities on imaging studies (Table 2). A number of patients with partial response on the paclitaxel phase of therapy achieved clinical complete response on the FEC phase of therapy. Response data are listed in Table 3 by each phase of therapy (paclitaxel and FEC).

	DISCUSSION

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The objective of this prospective study was to determine the impact of the addition of trastuzumab on the pCR rate when patients with primary breast cancer were treated with sequential neoadjuvant paclitaxel and FEC chemotherapy. The pCR rate was 65% for patients treated with trastuzumab plus chemotherapy compared with 26% for patients treated with chemotherapy alone. For women treated with anthracycline-based neoadjuvant chemotherapy, pCR has been shown to predict improved disease-free and overall survival when compared with patients with less than pCR.^27-29 However, it remains to be determined whether increased pCR rate, as observed in this study with the sequential use of two chemotherapy regimens and limited exposure to trastuzumab, will result in improved disease-free and overall survival. A number of phase II studies have evaluated trastuzumab in the neoadjuvant setting with nondoxorubicin-containing chemotherapies.^30-34 In these studies, pCR rates have ranged from 19% to 35%. In this study, our objective was to achieve a 20% improvement in pCR rate with the addition of trastuzumab to chemotherapy. The results of this study demonstrated a higher pCR rate than anticipated. As a result, the study was modified, and the control arm was stopped at the recommendation of the DMC. In the revised, ongoing study, all patients with HER2-positive disease are being offered chemotherapy plus trastuzumab. With additional patients, the CI of the pCR rate will be narrowed, and follow-up of all patients will provide additional safety data.

Despite the high pCR rate, BCT was performed in only approximately half of the patients. This may be a reflection of a number of factors that include persistent abnormalities on imaging studies and patient preferences. Better imaging modalities or cancer markers are needed that provide accurate information regarding persistent (or lack thereof) invasive disease. With this approach, a larger fraction of patients with no invasive cancer, if accurately identified before local therapy, may be candidates for breast preservation.

Cardiac toxicity has been an ongoing concern related to the use of trastuzumab in early-stage breast cancer. In this study, trastuzumab was administered concurrently with paclitaxel- and epirubicin-based chemotherapy. Since the publication of the pivotal trial in metastatic, HER2-overexpressing breast cancer, it has been known that the simultaneous combination of doxorubicin and trastuzumab resulted in a high rate of clinical and subclinical cardiotoxicity, but data from large multicenter trials have not resulted in toxicity rates sufficiently high to curtail enrollment.³⁵ On the basis of those results, subsequent studies, especially those performed in the adjuvant or neoadjuvant setting, have avoided the simultaneous administration of anthracyclines and trastuzumab. However, retrospective analyses of the correlation of HER2 overexpression and chemotherapy response have suggested that anthracyclines had an important role in the management of HER2-overexpressing breast cancer.^9,36-42 Therefore, we reasoned that the simultaneous combination of trastuzumab with an anthracycline could be advantageous, as long as cardiac toxicity could be prevented or minimized.

There are ongoing studies of combinations that include trastuzumab with epirubicin or doxorubicin HCl liposome injection, two anthracyclines with reported lower cardiac toxicity effects than doxorubicin.^43-47 These preliminary safety data and the intent to limit cumulative dose of the anthracycline in the sequential combination with a taxane suggested that the combination with trastuzumab could be administered safely, without excessive cardiac toxicity. Epirubicin, the anthracycline included in the combination in this study, has been reported to have a better cardiac safety margin. There is no evidence of steep dose-dependent response with doxorubicin beyond 50 to 60 mg/m² in the adjuvant setting. However, for epirubicin, there is a dose-dependent response in the adjuvant setting. Administration of FEC100, using epirubicin 100 mg/m² per cycle, results in significantly improved 10-year survival compared with FEC50, using epirubicin 50 mg/m².⁴⁸ We selected 75 mg/m² as a safe compromise between efficacy and cardiac safety because concurrent trastuzumab was planned. Four cycles of epirubicin at this dose would result in a cumulative dose of 300 mg/m², which is approximately one third of the cardiotoxic threshold of epirubicin. With this approach, we expected to reduce the risk of cardiac dysfunction. In this study, the duration of trastuzumab was also limited to 24 weeks. The limited exposure of epirubicin concomitantly with trastuzumab has not resulted in any clinical cardiac dysfunction. A small number of patients did show a transient drop in the cardiac ejection fraction; however, cardiac ejection fractions returned to original normal levels on follow-up evaluation.

In this study, pCR rates were high both in patients with hormone receptor–positive and hormone receptor–negative disease. This was in contrast to our earlier experience in patients unselected by HER2 status treated with neoadjuvant therapy. In a retrospective review of more than 1,000 patients with primary breast cancer, pCRs in studies with anthracycline-based chemotherapies ranged from 2% to 14% (mean, 5%) in patients with hormone receptor–positive disease compared with 7% to 55% (mean, 21%) in patients with hormone receptor–negative disease.⁴⁹ In that analysis, the HER2 status of the tumors was not known. Unlike our previous experience with preoperative chemotherapy, pCR rates in this study were similar for ER-positive and ER-negative tumors. HER2 status seems to be of more influence in pCR outcome. Further clinical and laboratory evaluation of this interaction of ER and HER2 and response to chemotherapy is warranted. Additional follow-up of these patients and continued accrual on the ongoing trial will provide additional efficacy and safety data for this treatment approach.

These results represent the highest reported pCR rate in this patient population. The most logical explanation for this high pCR rate is the use of two potentially non–cross-resistant chemotherapies administered sequentially in combination with trastuzumab. Other possibilities include longer duration of neoadjuvant therapy compared with earlier studies. Additional studies are needed to define the pCR rate with a narrow CI and establish the cardiac risk of this combination. Follow-up of our study patients will provide data that will establish whether pCR rate will translate into high disease-free and overall survival rates as observed in other neoadjuvant studies. If the long-term follow-up confirms prolonged overall survival and low or modest incidence of cardiac toxicity, this combination may have a favorable risk to benefit ratio for patients with HER2-positive breast cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have 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. Employment: Michael S. Ewer, Pfizer. Honoraria: Aman U. Buzdar, Pfizer; Debra K. Fyre, Pfizer, Pharmacia; Aysegul A. Sahin, Genentech; Michael S. Ewer, Alza. Research Funding: Aman U. Buzdar, Bristol-Myers Squibb, Genentech, Pfizer; Banu K. Arun, AstraZeneca, NCI, Pfizer. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

	Acknowledgment

 
We thank the following faculty members for their support of this study: Edgardo Rivera, James L. Murray, Marguerite F. Rosales, Ronald Walters, Karin Gwyn, and Vicente Valero.

	NOTES

 
Supported in part by research grants from Genentech, Pfizer, and Bristol Myers Squibb.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline]

2. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]

3. Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-1196, 1996[CrossRef][Medline]

4. Valero V, Buzdar AU, McNeese M, et al: Primary chemotherapy in the treatment of breast cancer: The University of Texas M. D. Anderson Cancer Center experience. Clin Breast Cancer 3:S63-S68, 2002 (suppl 2)

5. Hortobagyi GN, Buzdar AU: Locally advanced breast cancer: A review including the M.D. Anderson experience, in Ragaz J, Ariel IM (eds): High-Risk Breast Cancer. Berlin, Springer-Verlag, 1991, pp 382-415

6. Rubin I, Yarden Y: The basic biology of HER2. Ann Oncol 12:S3-S8, 2001 (suppl 1)

7. Di Leo A, Larsimont D, Beauduin M, et al: CMF or anthracycline-based adjuvant chemotherapy for node-positive breast cancer patients: 4 year results of a Belgian randomised clinical trial with predictive markers analysis. Proc Am Soc Clin Oncol 18:69a, 1999 (abstr 258)

8. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer: International (Ludwig) Breast Cancer Study Group. J Clin Oncol 10:1049-1056, 1992[Abstract]

9. Ravdin PM: Prognostic factors in breast cancer in Perry MC (ed): 1997 ASCO Educational Book. Alexandria, VA, American Society of Clinical Oncology, 1997, pp 217-227, 1997

10. Elledge RM, Green S, Ciocca D, et al: HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: A Southwest Oncology Group Study. Clin Cancer Res 4:7-12, 1998[Abstract]

11. Goldenberg MM: Trastuzumab, a recombinant DNA-derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. Clin Ther 21:309-318, 1999[CrossRef][Medline]

12. Baselga J, Tripathy D, Mendelsohn J, et al: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737-744, 1996[Abstract/Free Full Text]

13. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719-726, 2002[Abstract/Free Full Text]

14. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999[Abstract/Free Full Text]

15. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001[Abstract/Free Full Text]

16. Norton L, Slamon D, Leyland-Jones B, et al: Overall survival advantage to simultaneous chemotherapy plus the humanized anti-HER2 monoclonal antibody Herceptin in HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol 18:127a, 1999 (abstr 483)

17. Extra JM, Cognetti F, Chan S, et al: First-line trastuzumab (Herceptin) plus docetaxel versus docetaxel alone in women with HER2-positive metastatic breast cancer (MBC): Results from a randomised phase II trial (M77001). Breast Cancer Res Treat 82:S47-S48, 2003 (suppl)

18. Buzdar AU, Hunt K, Smith T, et al: Significantly higher pathological complete remission (PCR) rate following neoadjuvant therapy with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy (CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/2 positive disease. Proc Am Soc Clin Oncol 23:7a, 2004 (abstr 520)

19. Green MC, Buzdar AU, Smith T, and et al: Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC: Final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 135)

20. Berry DA: Monitoring accumulating data in a clinical trial. Biometrics 45:1197-1211, 1989[CrossRef][Medline]

21. Berry DA: Statistical innovations in cancer research, in Holland J, Frei T, Kufe DW, et al (eds): Cancer Medicine. London, United Kingdom, BC Decker, 2003, pp 465-478

22. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991[Free Full Text]

23. Mamounas E, Brown A, Smith R, et al: Effect of Taxol duration of infusion in advanced breast cancer (ABC): Results from NSABP B-26 trial comparing 3- to 24-hr infusion of high-dose Taxol. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 389)

24. Seidman,AD, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3-h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc Am Soc Clin Oncol 22:6S, 2004 (suppl 14, abstr 512)

25. Schnitt SJ, Connolly JL: Processing and evaluation of breast excision specimens: A clinically oriented approach. Am J Clin Pathol 98:125-137, 1992[Medline]

26. Sahin A: Surgical margin evaluation in patients treated with breast-conserving therapy, in Advanced Therapy of Breast Disease. Hamilton, Ontario, Canada, BC Decker Inc, 2004, pp 341-348

27. Feldman LD, Hortobagyi GN, Buzdar AU, et al: Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578-2581, 1986[Abstract/Free Full Text]

28. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]

29. Kuerer HM, Newman LA, Smith TL, et al: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 17:460-469, 1999[Abstract/Free Full Text]

30. Hurley J, Franco S, Velez P, et al: Primary therapy with Herceptin, Taxotere and cisplatin in locally advanced and inflammatory breast cancer. Proc Am Soc Clin Oncol 20:31b, 2001 (abstr 1871)

31. Burstein HJ, Harris LN, Kaelin CM, et al: Preoperative Herceptin and paclitaxel (Taxol) for HER2 overexpressing stage II/III breast cancer. Proc Am Soc Clin Oncol 20:26a, 2001 (abstr 100)

32. Hurley J, Doliny P, Silva O, et al: Neoadjuvant Herceptin/Taxotere/cisplatin in the treatment of locally advanced and inflammatory breast cancer. Proc Am Soc Clin Oncol 21:50a, 2002 (abstr 196)

33. Limentani SA, Brufsky AM, Erban JK, et al: Dose dense neoadjuvant treatment of women with breast cancer utilizing docetaxel, vinorelbine and trastuzumab with growth factor support. Breast Cancer Res Treat 82:S55, 2003 (suppl 1)

34. Burstein HJ, Harris LN, Gelman R, et al: Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: A pilot study. J Clin Oncol 21:46-53, 2003[Abstract/Free Full Text]

35. Friedrich MJ: Cardiotoxicity concerns prompt data review in breast cancer trial. J Natl Cancer Inst 94:650-651, 2002[Free Full Text]

36. Cooke T, Reeves J, Lanigan A, et al: HER2 as a prognostic and predictive marker for breast cancer. Ann Oncol 12:S23-S28, 2001 (suppl 1)

37. Di Leo A, Larsimont D, Gancberg D, et al: HER-2 and topo-isomerase II alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol 12:1081-1089, 2001[Abstract/Free Full Text]

38. Harris LN, Yang L, Liotcheva V, et al: Induction of topoisomerase II activity after ErbB2 activation is associated with a differential response to breast cancer chemotherapy. Clin Cancer Res 7:1497-1504, 2001[Abstract/Free Full Text]

39. Petit T, Borel C, Ghnassia JP, et al: Chemotherapy response of breast cancer depends on HER-2 status and anthracycline dose intensity in the neoadjuvant setting. Clin Cancer Res 7:1577-1581, 2001[Abstract/Free Full Text]

40. Gianni L, Capri G, Mezzelani A, et al: HER-2/neu (HER2) amplification and response to doxorubicin/paclitaxel (AT) in women with metastatic breast cancer. Proc Am Soc Clin Oncol 16:139a, 1997 (abstr 491)

41. Muss HB, Thor AD, Berry DA, et al: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260-1266, 1994[Abstract/Free Full Text]

42. Ravdin PM, Chamness GC: The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers—A review. Gene 159:19-27, 1995[CrossRef][Medline]

43. Ryberg M, Nielsen D, Skovsgaard T, et al: Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. J Clin Oncol 16:3502-3508, 1998[Abstract]

44. Ranson MR, Cheeseman S, White S, et al: Caelyx (stealth liposomal doxorubicin) in the treatment of advanced breast cancer. Crit Rev Oncol Hematol 37:115-120, 2001[Medline]

45. Safra T, Muggia F, Jeffers S, et al: Pegylated liposomal doxorubicin (Doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m². Ann Oncol 11:1029-1033, 2000[Abstract/Free Full Text]

46. Wolff AC, Bonetti M, Sparano JA, et al: Cardiac safety of trastuzumab (H) in combination with pegylated liposomal doxorubicin (D) and docetaxel (T) in HER2-positive metastatic breast cancer (MBC): Preliminary results of the Eastern Cooperative Oncology Group trial E3198. Proc Am Soc Clin Oncol 22:18a, 2003 (abstr 70)

47. Venturini M, Nicoletto O, Bighin C, et al: A multicenter phase II study of trastuzumab with epirubicin and docetaxel as a first line treatment in metastatic breast cancer. Proc Am Soc Clin Oncol 22:34a, 2003 (abstr 134)

48. Bonneterre J, Roche H, Kerbrat P, et al: French Adjuvant Study Group 05 Trial (FEC50 vs FEC100): 10 year update of benefit/risk ratio after adjuvant chemotherapy (CT) in node positive (N+) early breast cancer (EBC) patients (pts). Proc Am Soc Clin Oncol 22:24a, 2003 (abstr 93)

49. Buzdar AU, Valero V, Theriault R, et al: Pathological complete response to chemotherapy is related to hormone receptor status. Breast Cancer Res Treat 82:S69, 2003 (suppl 1)

Submitted July 8, 2004; accepted November 28, 2004.

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