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© 2003 American Society for Clinical Oncology Preoperative Therapy With Trastuzumab and Paclitaxel Followed by Sequential Adjuvant Doxorubicin/Cyclophosphamide for HER2 Overexpressing Stage II or III Breast Cancer: A Pilot Study
From the Departments of Medical Oncology and Biostatistical Science, Dana-Farber Cancer Institute; Departments of Medicine, Surgery, and Pathology, Brigham and Women’s Hospital and Massachusetts General Hospital; Department of Surgery, Faulkner Hospital; Department of Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA. Address reprint requests to Harold J. Burstein, MD, PhD, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; email: E: hburstein{at}partners.org.
Purpose: Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer. Patients and Methods: Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m2 every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially. Results: Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment. Conclusion: Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.
PREOPERATIVE SYSTEMIC therapy has been widely used in the treatment of locally advanced and operable breast cancer. Clinical trials of combination chemotherapy as initial treatment for operable breast cancer have consistently demonstrated high rates (> 70%) of clinical response. Complete pathologic response, usually defined as eradication of invasive cancer at the time of histologic analysis, is seen in 10% to 33% of patients receiving preoperative therapy with a variety of different regimens.1 For instance, preoperative therapy with paclitaxel led to complete pathologic response in 14% of patients with operable breast cancer, comparable to response rates seen with anthracycline-based combination neoadjuvant therapy.2 Randomized trials have demonstrated that preoperative systemic therapy is as effective as adjuvant chemotherapy with respect to disease-free and overall survival and that it increases the rate of breast-conserving surgery.1,3 By allowing clinical assessment of tumor response, preoperative therapy constitutes a valuable model for testing new breast cancer treatments.4,5 Patients with objective tumor response to primary chemotherapy, particularly those with complete pathologic response, have improved long-term cancer outcomes compared with patients who do not respond or have residual invasive tumor.3,6,7 Trastuzumab, a high-affinity humanized monoclonal antibody that recognizes the human epidermal growth factor receptor 2 (HER2), is a novel, targeted therapy for breast cancers that overexpress this receptor. Trastuzumab has been evaluated in women with HER2 overexpressing metastatic breast cancer, as a single agent following traditional chemotherapy,8 as a single agent before chemotherapy,9 and in combination with a variety of chemotherapy agents. In a large, randomized trial for women with HER2-positive metastatic breast cancer, standard chemotherapy was compared with chemotherapy administered with trastuzumab.10 Trastuzumab, in combination with either doxorubicin/cyclophosphamide (AC) or paclitaxel, led to higher response rates, longer progression-free survival, and improved overall survival compared with treatment with chemotherapy alone. Thus, trastuzumab combined with chemotherapy has become a standard of care for women with HER2 overexpressing metastatic breast cancer. An unexpected finding in the randomized trial of trastuzumab for metastatic breast cancer was the high rate of clinically significant cardiotoxicity, particularly among patients treated concurrently with trastuzumab and anthracycline-based chemotherapy.11 The safety and utility of trastuzumab-based therapy for earlier stage breast cancer are not known. We developed a preoperative treatment program of trastuzumab in combination with paclitaxel for women with HER2-positive stage II or III breast cancer. Because of available safety data on the use of sequential AC followed by paclitaxel chemotherapy for women with lymph node–positive breast cancer,12 this regimen became the foundation of the treatment program. To assess the clinical effects of trastuzumab, and because of the demonstrated safety and efficacy of trastuzumab in combination with every-3-week paclitaxel in metastatic disease, we reversed the treatment sequence and administered trastuzumab-paclitaxel before breast surgery. We sought to define the complete pathologic response rate to the trastuzumab/paclitaxel combination and to assess the safety and feasibility of incorporating trastuzumab into a systemic treatment program for early-stage breast cancer that included sequential use of anthracycline-based chemotherapy. In addition, we sought to characterize pathologic changes in response to trastuzumab-based therapy and utility of serologic assays for HER2 in such patients.
Eligibility Patients with histologically confirmed invasive breast cancer, clinical stage II or III, including inflammatory breast cancer, were eligible for this study. Patients with clinically negative axillae were required to have primary tumors of > 2 cm on physical examination or mammography. Patients were eligible after diagnostic core needle or incisional biopsy, provided that residual tumor in either the breast or lymph node measured at least 1 cm on mammography, ultrasonography, or physical examination. Patients with bilateral breast cancers were eligible provided that at least one tumor met the clinical staging requirements. Patients with HER2 2+ or 3+ tumors by immunohistochemistry using a modification of the DAKO HercepTest kit (Dako Corporation, Carpinteria, CA)13 were eligible. When possible, tumors were reanalyzed for HER2 expression by immunohistochemistry at the time of definitive breast surgery. Patients with prior history of breast cancer within the previous 2 years, ipsilateral tumor recurrence, prior anthracycline- or taxane-based chemotherapy, or prior high-dose chemotherapy with stem-cell transplant were ineligible.
Patients were required to be more than 18 years of age, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and to be neither pregnant nor nursing. Eligible patients had baseline white blood cells of more than 4,000/mm3, platelet count more than 100,000/mm3, bilirubin, and SGOT within institutional limits of normal, and creatinine less than 1.5 mg/dL. Baseline evaluation also included an electrocardiogram to exclude ischemic changes or ventricular hypertrophy and chest radiogram to exclude active cardiac or pulmonary disease. Patients were required to have baseline left ventricular ejection fraction (LVEF) This study was conducted in accordance with guidelines established by the United States Department of Health and Human Services. The protocol was reviewed and approved by the institutional review boards of all participating centers. Patients were enrolled between February 1999 and December 2000.
Treatment Plan
Surgery. Definitive breast surgery was performed not less than 7 days and not more than 35 days after the last dose of trastuzumab. Patients underwent either modified radical mastectomy or lumpectomy with complete axillary dissection of the level I and II lymph nodes. Patients with involved or close surgical margins after lumpectomy underwent reexcision or mastectomy to obtain negative margins. To evaluate the feasibility of sentinel lymph node mapping following neoadjuvant therapy, it was suggested that surgeons perform sentinel lymph node mapping at the time of axillary dissection. Mapping was performed according to standard institutional practice using 1 mCi filtered technetium 99mTc sulfur colloid and 2 to 4 mL 1% isosulfan vital blue dye.
Adjuvant therapy.
Adjuvant AC chemotherapy14 at standard doses and with standard supportive measures began between 2 and 5 weeks after surgery and no less than 6 weeks and no more than 9 weeks after the last trastuzumab dose (Fig 1 Patients finished protocol-based therapy at the end of four cycles of adjuvant AC chemotherapy. Patients went on to receive radiation therapy and tamoxifen as indicated by standard practice guidelines.
Cardiac surveillance.
LVEF was determined at baseline, after 12 weeks of neoadjuvant trastuzumab/paclitaxel and after cycles 2 and 4 of adjuvant AC chemotherapy (Fig 1
Measurement of HER2 Extracellular Domain
Study Analysis Statistical methods. Accrual followed a two-stage design with the principal study end point being determination of the pCR rate. In the first phase, 25 patients were to be entered. If 0 or 1 pCRs were observed, accrual would terminate. If two or more pCRs were observed, another 15 patients were to be entered, for a total of 40 patients. It was believed based on historic experience that an observed pCR rate of 15%, representing a total of six or more pCRs among the 40 treated patients, would be of clinical interest and would justify further development of the regimen. If the true pCR rate was only 10%, there was a 27% chance of terminating accrual at the end of the first phase and only a 20% chance of deeming the regimen worthy of further study. If the true pCR rate was 20%, there was a 3% chance of terminating accrual at the end of the first phase and an 83% chance of deeming the regimen worthy of further study. The 95% confidence interval for pCR was based on the two-stage study design. Response rates were compared using a two-sided Fisher’s exact test for the 2 x 2 contingency table.
Patient Characteristics Forty women with stage II or III, HER2-overexpressing breast cancer participated in the study; median age was 48.5 years (range, 26 to 65 years). Clinical characteristics of the study population are shown in Table 1  . One patient was enrolled with an isolated ipsilateral supraclavicular lymph node metastasis as the sole site of stage IV disease. Nearly half the patients had stage III breast cancer, including six patients with inflammatory breast cancer. Half of the patients had clinically detectable axillary lymphadenopathy before start of neoadjuvant treatment. Median preoperative breast tumor size was 5 cm (range 0 to 11 cm). Hormone receptor status and HER2 status as determined by immunohistochemistry are shown in Table 1. Eighty percent of the tumors were HER2 3+ by immunohistochemistry.
Clinical and Pathologic Response to Neoadjuvant Therapy Clinical and pathologic response rates are shown in Table 2 . Complete pathologic response was seen in 18% of all patients (95% confidence interval, 7% to 33%). Residual carcinoma-in-situ was observed in three of the seven women with complete pathologic response and no evidence of residual invasive tumor; two such patients had ductal carcinoma-in-situ, one had lobular carcinoma-in-situ. Patients taken off study for toxicity (n = 1) or who did not proceed to definitive breast surgery after neoadjuvant paclitaxel/trastuzumab (n = 3) were considered to not have a pCR.
Clinical response, either partial or complete, was seen in 75% of patients. The clinical response rate among women with HER2 2+ (n = 8; response rate, 38%) tumors was lower than that seen for women whose tumors were 3+ (n = 32; RR, 84%; P = .01). There was no difference in complete pathologic response rates between the HER2 subsets (HER2 3+ pCR in 6 of 32, HER2 2+ pCR in 1 of 8; P = 1.0). One patient had evidence of disease progression during treatment. Clinical responses were analyzed separately among patients with measurable tumor in either the breast (n = 39) or lymph node(s) (n = 21; Table 2  ). The overall clinical response rate did not differ between breast and lymph node sites (P = .56).
Response rates were also analyzed as a function of estrogen receptor status and of initial clinical stage (Table 2
Median follow-up was 25 months (range, 9 to 37 months). Seven patients had developed distant metastases. Distant disease-free survival is shown in Fig 2
Effect of Preoperative Trastuzumab and Paclitaxel on Tumor HER2 Status Tumor HER2 status was reanalyzed following preoperative trastuzumab/paclitaxel therapy at the time of definitive surgery. Patients with complete pathologic response (n = 7) had no residual tumor for evaluation. Tumors from six other patients were not assessable because they had stable or progressive disease during preoperative trastuzumab/paclitaxel (n = 4) and did not proceed to surgery or because of inadequate tumor for HER2 testing in the surgical specimen (n = 2). Table 3 shows the HER2 status as measured by immunohistochemistry following preoperative trastuzumab-based therapy. Of the 23 tumors with initial HER2 3+ status available for retesting, 17 retained the 3+ level of expression after trastuzumab and paclitaxel treatment. However, in six cases the HER2 status changed. In four instances, HER2 expression was now scored as 0. In two instances, 2+ expression was reported. Similar trends were seen for tumors originally scored as 2+, although fewer cases were available for analysis.
Serologic Assessment of HER2 Extracellular Domain Serologic measurement of HER2 extracellular domain (ECD) was made at baseline, following preoperative trastuzumab and paclitaxel, and after four cycles of adjuvant AC chemotherapy. Evaluable serum specimens were available for 37 patients at baseline, 30 patients after preoperative therapy, and 22 patients after adjuvant treatment. At baseline, 9 of 37 patients (24%) had serum HER2 ECD levels greater than the cutoff value of 20 ng/mL (mean level, 34.7 ng/mL; range, 21.4 to 57.2 ng/mL). All patients with elevated baseline HER2 ECD had HER2 3+ tumors by immunohistochemistry.
Serial data were available on seven of the nine patients with initially elevated HER2 ECD, and are shown in Fig 3
There were 28 patients with initially negative tests for HER2 ECD. Of these, all remained persistently negative during treatment, with the exception of one patient whose values oscillated around the cutoff value (19.8  21.5 18.3 ng/mL at baseline, following preoperative treatment, and following adjuvant treatment, respectively).
Treatment Following Preoperative Trastuzumab and Paclitaxel Therapy
Side Effects During Preoperative and Adjuvant Therapy
LVEF was measured at baseline, after 12 weeks of neoadjuvant paclitaxel and trastuzumab, and following cycles 2 and 4 of AC chemotherapy (Table 4 ; Fig 4). No patients developed symptomatic (grade 3 or 4) heart failure. Changes in LVEF (grade 1: decline of  10% but < 20%; grade 2: decline of 20% or below laboratory limit of normal [50% at our institutions]) were defined relative to the baseline LVEF before the start of neoadjuvant treatment. During the neoadjuvant phase of therapy, four patients had grade 1 decline in LVEF, and one patient had a grade 2 decrease. All these patients continued on with adjuvant therapy. During the adjuvant AC phase of therapy, five patients were observed to have grade 1 toxicity, and four patients had grade 2 toxicity. Newly arising changes in LVEF during AC treatment occurred in three of the five patients with grade 1 toxicity and three of four patients with grade 2 toxicity. The other patients had persistence of changes that appeared during the neoadjuvant paclitaxel/trastuzumab phase of therapy. One patient had LVEF decline from 57% to 40%. She was the only patient to develop an LVEF below 45%, and subsequent determination of LVEF after 3 months showed recovery to 50%.
This pilot study sought to examine the safety and efficacy of preoperative therapy with trastuzumab in combination with chemotherapy as part of a multimodality treatment plan for stage II and III breast cancer. This experience with 40 women demonstrated a high rate of clinical activity, with objective responses to trastuzumab in combination with paclitaxel observed in 75% of women. Complete pathologic response was seen in 18% of patients. In general, the noncardiac toxicity experience did not differ from that expected from adjuvant treatment with AC followed by paclitaxel, as reported without the addition of trastuzumab. Sequential therapy, first with trastuzumab and paclitaxel and then with AC, proved feasible. In the available, short follow-up, there have been no recurrences among women whose tumors had complete clinical or pathologic response to preoperative therapy. Anecdotally, a seemingly large percentage of distant recurrences seen to date have been isolated CNS metastases. Pathologic complete response has been shown to predict improved disease-free and overall survival for women treated with anthracycline-based neoadjuvant chemotherapy when compared with women with less than complete pathologic response.3,7 It remains to be demonstrated whether increased rates of pCR will translate into step-wise improvement in disease-free and overall survival. Previous studies with single-agent paclitaxel as preoperative therapy have yielded complete pathologic response rates of 14%.2 However, comparing pCR rates between different clinical trials is fraught with difficulty, owing to differences in patient populations, initial tumor burden, duration of therapy, definitions of pathologic clearance, and use of concurrent hormonal treatment. Our a priori hypothesis was that a pCR rate of 15% using trastuzumab-based treatment would be of clinical interest, given the historic rates observed in clinical trials and the relative resistance of HER2-positive tumors to paclitaxel chemotherapy in the metastatic setting.10 Although the pCR rate to single agent paclitaxel in HER2 positive primary tumors is not known, the observed rate of 18% using trastuzumab and paclitaxel is promising, particularly given the relatively advanced stage of presentation in our study population, and justifies further investigation of preoperative trastuzumab-based treatment. Most of the ongoing randomized adjuvant trials of trastuzumab-based therapy involve treatment with anthracycline-based chemotherapy followed by trastuzumab. Our study shows that up-front therapy with trastuzumab in combination with paclitaxel is possible before standard anthracycline-based chemotherapy. There is reason to believe that earlier initiation of trastuzumab-based treatment with chemotherapy may be superior to later use of trastuzumab-based treatment. When used as monotherapy among women with advanced breast cancer, trastuzumab achieved higher response rates as first-line treatment than when administered after tumor progression on chemotherapy.8,9 The schema in our study potentially lends itself to use in trials addressing the sequencing of trastuzumab and chemotherapy for early-stage breast cancer. Cardiac toxicity is an ongoing concern related to use of trastuzumab, particularly for women with more favorable long-term prognoses. In our study, trastuzumab was not administered concurrently with anthracycline-based chemotherapy, and a planned delay was introduced to minimize overlap between trastuzumab and initiation of anthracycline treatment. No patients developed symptomatic congestive heart failure. A number of patients did develop asymptomatic declines in their ejection fraction, and four patients dropped their ejection fraction to a level below institutional limits of normal (50%)—three during the AC phase of therapy. At the time the study was initiated, the half-life of trastuzumab was believed to be on the order of 7 days. Subsequent data indicate a half-life of 28 days.15 Thus, our attempts to reduce overlap between trastuzumab and anthracycline exposure may have been less effective than anticipated, and this overlap may account for the changes in left ventricular function that were observed in the trial. Recently, the ECOG reported preliminary cardiac toxicity data from a pilot study of sequential adjuvant treatment with trastuzumab-paclitaxel, followed by AC, followed by maintenance trastuzumab therapy.17 In the ECOG trial, median LVEF declined from 63% to 59% through the AC phase of therapy, with 6% of patients developing an LVEF less than normal after AC treatment. Collectively, our study and the ECOG results provide some reassurance that sequential trastuzumab-paclitaxel followed by AC chemotherapy is not likely to be associated with prohibitive short-term cardiotoxicity. However, experience from randomized trials of adjuvant trastuzumab will be needed to define the short- and long-term cardiac sequelae. This clinical trial included patients whose tumors were either HER2 3+ or 2+ by immunohistochemistry, based on treatment standards for women with metastatic breast cancer at the time of study accrual. Data on HER2 gene amplification were not collected prospectively. The rapidly evolving literature on HER2 testing indicating that the vast majority of patients whose tumors are 3+ will, in fact, be fluorescence in situ hybridization positive; by contrast, most 2+ tumors will not have HER2 gene amplification. It is likely that only those patients with tumors that are 3+ and/or fluorescence in situ hybridization-positive derive substantial clinical benefit from trastuzumab-based therapy.18 Thus, the clinical activity for trastuzumab-based therapy reported in this trial may differ modestly from that seen among patients selected using different pathologic criteria. The HER2 status of breast tumors treated with trastuzumab has not previously been reported. In this study, we analyzed HER2 expression before and after trastuzumab and paclitaxel therapy. For most patients with residual tumor after 12 weeks of neoadjuvant treatment, HER2 expression as measured by immunohistochemistry was unchanged. However, a subset of patients whose initial tumors were 3+ were found, on testing after induction therapy, to have lost immunohistochemical expression of HER2. The clinical significance of this finding is not known. It may represent downregulation of HER2 expression following anti-HER2 antibody exposure, as reported in preclinical tumor models.19 It may also represent intrinsic heterogeneity of HER2 expression and tumor response, or an artifact of tumor sampling or testing. It is not clear whether this finding implies resistance or sensitivity to trastuzumab. Further studies of tumor changes at the cellular and molecular level brought on by trastuzumab therapy are warranted. The role of HER2 ECD in selecting patients for trastuzumab-based therapy, or monitoring response to such therapy, remains unclear.20 A recent report indicates that changes in HER2 ECD correlate with response to trastuzumab-taxane therapy in women with HER2-positive metastatic breast cancer.21 Our results indicate similar findings among patients with stage II/III breast cancer, but larger prospective trials will be needed to define whether HER2 ECD should be routinely and/or serially measured. The administration of trastuzumab for patients with early-stage breast cancer remains investigational. Our trial of preoperative therapy demonstrates the feasibility of using trastuzumab treatment as part of a multimodality treatment program for stage II and III breast cancer. Other studies using trastuzumab in combination with different antineoplastic agents, and in other sequences of treatment, may further define possible treatment approaches that incorporate trastuzumab-based therapy into early-stage breast cancer, while we await the results from large, randomized studies.
Supported in part from research grants-in-aid from Bristol Myers Squibb, Bayer, and Genentech.
1. Wolff AC, Davidson NE: Primary systemic therapy in operable breast cancer. J Clin Oncol 18:1558–1569, 2000
2. Buzdar AU, Singletary SE, Theriault RL, et al: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol 17:3412–3417, 1999 3. 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]
4. Fisher B, Mamounas EP: Preoperative chemotherapy: A model for studying the biology and therapy of primary breast cancer. J Clin Oncol 13:537–540, 1995
5. Valero V, Hortobagyi GN: Primary chemotherapy: A better overall therapeutic option for patients with breast cancer. Ann Oncol 9:1151–1154, 1998
6. Ellis P, Smith I, Ashley S, et al: Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer. J Clin Oncol 16:107–114, 1998
7. 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
8. 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
9. 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
10. 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
11. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215–1221, 2002 12. Henderson IC, Berry D, Demetri G, et al: Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in adjuvant chemotherapy of patients with node-positive primary breast cancer. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390A)
13. Jacobs TW, Gown AM, Yaziji H, et al: Specificity of HerceptTest in determining HER-2/neu: Status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol 17:1983–1987, 1999 14. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483–1496, 1990[Abstract] 15. Harris KA, Washington CB, Lieberman G, et al: A population pharmacokinetic (PK) model for trastuzumab (Herceptin) and implications for clinical dosing. Proc Am Soc Clin Oncol 21:123a, 2002 (abstr 488) 16. Breuer B, Smith S, Thor A, et al: Erb-2 Protein in sera and tumors of breast cancer patients. Breast Cancer Res Treat 49:261–270, 1998[CrossRef][Medline] 17. Sledge GW, O’Neill A, Thor AD, et al: Pilot trial of paclitaxel-Herceptin adjuvant therapy for early stage breast cancer (E2198). Breast Cancer Res Treat 69:209, 2001 (abstr 4)[CrossRef][Medline] 18. Mass RD, Press M, Anderson S, et al: Improved survival benefit from Herceptin (trastuzumab) in patients selected by fluorescence in situ hybridization (FISH). Proc Am Soc Clin Oncol 20:22a, 2000 (abstr 291) 19. Drebin JA, Link VC, Stern DF, et al: Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41:697–706, 1985[CrossRef][Medline] 20. Nunes RA, Harris LN: The HER2 extracellular domain as a prognostic and predictive factor in breast cancer. Clin Breast Cancer 3:125–135, 2002[Medline]
21. Esteva FJ, Valero V, Booser D, et al: Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 20:1800–1808, 2002. Submitted March 22, 2002; accepted September 5, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
