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Docetaxel Combined With Trastuzumab Is an Active Regimen in HER-2 3+ Overexpressing and Fluorescent In Situ Hybridization–Positive Metastatic Breast Cancer: A Multi-Institutional Phase II Trial

From the Vanderbilt Clinic, Vanderbilt University Medical Center, Nashville, TN; Department of Oncology, Oklahoma University Health Science Center, Oklahoma City, OK; Department of Oncology, Fox Chase Cancer Center, Philadelphia, PA; Department of Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago; Evanston Hospital, Evanston, IL; Department of Oncology, Indiana University Medical Center, Indianapolis, IN.

Address reprint requests to David H. Johnson, MD, Division of Hematology and Oncology, 777 Preston Research Bldg, 2220 Pierce Ave, Nashville, TN 37232-6307; e-mail: david.johnson{at}vanderbilt.edu

	ABSTRACT

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PURPOSE: To determine the efficacy and safety of weekly docetaxel and trastuzumab as first- or second-line therapy in women with HER-2–overexpressing metastatic breast cancer and to correlate the efficacy of trastuzumab with HER-2 status as determined by immunohistochemistry assay and fluorescent in situ hybridization (FISH).

PATIENTS AND METHODS: Twenty-six women with HER-2–positive (HercepTest [Dako Corp, Carpenteria, CA]2 to 3+) metastatic breast cancer were enrolled onto this study of trastuzumab (4 mg/kg load; 2 mg/kg/wk administered intravenously) and docetaxel (35 mg/m²/wk for 6 weeks).

RESULTS: Using an intent-to-treat analysis, the overall response rate was 50% (13 of 26 patients). Eight patients (31%) had a period of stable disease posttherapy. Among HER-2 3+ patients, the overall response rate was 63% (12 of 19 patients) compared with a 14% response rate (one of seven patients) for HER-2 2+ patients (P = .07). Patients with FISH-positive tumors experienced an overall response rate of 64%. Median time to progression was 12.4 months for the entire cohort (HER-2 3+ tumors, 12.3 months; HER-2 2+ lesions, 9.5 months) and median survival was 22.1 months. All HER-2 3+ patients were FISH-positive; the only HER-2 2+ patient responding to treatment was also FISH-positive. Grade 4 toxicities occurred in four patients; most toxicities were mild.

CONCLUSION: Trastuzumab plus docetaxel is an active and well-tolerated regimen in women with HER-2 3+ overexpressing or FISH-positive metastatic breast cancer.

	INTRODUCTION

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The HER-2 protein is an 185kd transmembrane tyrosine kinase with homology to the epidermal growth factor receptor. Approximately 25% to 30% of breast cancers overexpress HER-2/neu [1]. Overexpression of HER-2 is an adverse prognostic factor in breast cancer and is associated with nodal metastases, shortened time to relapse, shortened survival, and estrogen receptor negativity [2,3]. Furthermore, although standard single agent chemotherapy can yield response rates of 30% to 60% in women with metastatic breast cancer, HER-2 overexpressing tumors are more refractory to standard therapy [1,4-6]. As a single agent, trastuzumab (Herceptin; Genentech Inc, San Francisco, CA) has achieved response rates of up to 15% and 25% in HER-2–overexpressing metastatic breast cancer in previously treated and untreated patients, respectively [6-9]. Higher response rates and improved overall clinical benefit were seen among patients whose tumors exhibited more pronounced overexpression of HER-2 by immunohistochemical assay (eg, 3+ using HercepTest [Dako Corp, Carpenteria, CA]) and among patients with HER-2 gene amplification by fluorescent in situ hybridization (FISH) as compared with FISH-nonamplified tumors (34% v 7%) [8].

In preclinical studies, trastuzumab markedly potentiated the antitumor effects of selected chemotherapeutic agents [10-14]. In a landmark phase III trial published in 2001, women randomly assigned to receive trastuzumab in addition to chemotherapy experienced a statistically significantly longer time to progression and overall survival compared with their counterparts who received chemotherapy without trastuzumab [15]. Of note, overall response rates to chemotherapy plus trastuzumab were higher in FISH-positive patients compared with those who were FISH-negative (54% v 38%) [15]. Thus patients selected for HER-2 amplification using FISH derived more clinical benefit from trastuzumab than patients selected by immunohistochemistry (IHC) [11,16].

In previously untreated women with metastatic breast cancer, docetaxel given every 3 weeks has produced response rates ranging from 43% to 68% in various phase II trials [17-20]. A weekly schedule of docetaxel administration is also effective and well tolerated, with decreased hematologic toxicity [21,22]. Furthermore, in patients with anthracycline-resistant disease, docetaxel yields response rates between 29% and 50% and is not associated with an increase in the incidence of cardiac toxicity occasionally produced by anthracyclines [23-26]. Thus the combination of docetaxel and trastuzumab is an attractive doublet for testing in women with advanced breast cancer, especially because preclinical data suggest that the combination of trastuzumab and docetaxel is synergistic [2,3,27,28]. Therefore, the rationale for this phase II trial is as follows: docetaxel is at least as effective as doxorubicin as a single agent, there may be less cardiac toxicity with trastuzumab and docetaxel as compared with doxorubicin and trastuzumab, and there seems to be cytotoxic synergy when docetaxel is combined with trastuzumab [29]. The efficacy of weekly docetaxel in combination with weekly trastuzumab was tested in patients with HER-2–overexpressing metastatic breast cancer in a multi-institutional phase II pilot trial. Although HER-2 status was initially assessed using the HercepTest, as a correlative study, HER-2/neu overexpression was also determined by FISH using two different probes (see below).

	PATIENTS AND METHODS

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Eligible patients included women with measurable, metastatic breast cancer whose tumors expressed HER-2 at 2 to 3+ by HercepTest assay as determined by central pathology review, age 18 years, and Eastern Cooperative Oncology Group performance status 2. Prior hormonal therapy and no more than one chemotherapy regimen for metastatic disease were permitted, provided the total dose of doxorubicin did not exceed 250 mg/m². Patients who had received prior taxanes or radiotherapy to more than 25% of their bone marrow were ineligible. Patients with carcinomatous meningitis or uncontrolled brain parenchyma disease were not eligible, as were individuals with a history of congestive heart failure, decreased ejection fraction (< 45%), or ischemic heart disease. Any patient with a history of a second malignancy within 5 years, with the exception of curatively treated basal cell or squamous cell carcinoma of the skin, carcinoma-in-situ of the cervix, or contralateral breast cancer, was ineligible. Patients with peripheral neuropathy of grade 2, allergy to polysorbate 80, or pregnancy were also ineligible. The following laboratory parameters documented within 2 weeks were required before enrollment: WBC count greater than 3,000/mL, absolute neutrophil count greater than 1,500/mL, and platelets greater than 100,000/mL; alkaline phosphatase of 2.5 times the upper limit of normal, AST and ALT 1.5 times the upper limit of normal, bilirubin within normal limits, and creatinine of 2 mg/dL. This study was conducted in accordance with guidelines established by the United States Department of Health and Human Services and approved by the institutional review boards at all participating institutions. All participants provided written informed consent. Patients were enrolled between January 1999 and January 2001.

Patients received docetaxel 35 mg/m²/wk for 6 consecutive weeks followed by a 2-week rest period. Trastuzumab was administered at a loading dose of 4 mg/kg on day 1 of cycle 1 and 2 mg/kg/wk thereafter. Each cycle represents 8 weeks. Docetaxel was infused over 30 minutes in 100 mL of 0.9% normal saline or 5% dextrose in water before trastuzumab. Dexamethasone was administered pre- and postdocetaxel. Diphenhydramine was optional. Trastuzumab was initially administered over 90 minutes. If well tolerated, subsequent infusions were given over 30 minutes. Trastuzumab was stopped if patients developed fevers, chills, allergic reactions, or any grade 3 or 4 toxicities during the infusion. If a patient developed congestive heart failure as defined by a decreased ejection fraction (< 45%) or a 15% decrease in ejection fraction, she was removed from the study. Patients were treated until disease progression or development of toxicity that precluded further therapy. Concurrent bisphosphonates were permitted.

Formalin-fixed paraffin-embedded blocks or cut slides from the primary lesion (or metastatic lesion when blocks from the primary were unavailable) were submitted to a central laboratory for HER-2 determination. The IHC assay used the HercepTest Kit according to the manufacturer's directions. Tumors were classified as 0, 1+, 2+, or 3+ based on the amount and intensity of the membrane staining per the manufacturer's instructions. Control slides, included in each kit, were used with each assay. Additional IHC and FISH assays were performed as correlative studies. Formalin-fixed paraffin-embedded sections were stained with anti–epidermal growth factor receptor (EGFR; 1005, diluted 1:200 overnight at 4°C; Santa Cruz Biotechnology, Santa Cruz, CA), or an antiphosphorylated erbB-2 (PN2A, diluted 5 µg/mL overnight at 4°C; Neomarkers Labvision, Fremont, CA) using previously published immunohistochemical methods [30,31]. Slides with any membrane staining of tumor cells were considered positive. FISH analyses were preformed using the HER-2 Inform Kit (Ventana Corp, Tucson, AZ) and the DNA Probe Kit (Abbott Labs, Lake Bluff, IL) following the manufacturer's directions. Slides were examined using an Olympus BX40 fluorescence microscope (Melville, NY) with a 100x oil immersion lens. HER-2 signals in 20 nuclei were counted in two different areas, and an average of each area was obtained using the Ventana kit. The HER-2 and centromere 17 signals in 30 nuclei in two separate areas were counted, and a ratio was obtained by dividing the average number of HER-2 signals by the average number of centromere 17 signals using the Abbott kit. The ratios of the two separate areas were then averaged to obtain a final ratio. Cases were classified as amplified if the average number of signals per nucleus exceeded 4.5 (using the Ventana probe) or the ratio of HER-2 signals per centromere 17 exceeded 2.1 (using the Abbott probe) as recommended by the manufacturers.

Patients were restaged at the start of each cycle. Tumor response was determined using standard bidimensional criteria. All enrolled patients were included in the intention-to-treat analysis. The primary study end point was overall response rate (complete response [CR] and partial response [PR]). Disease responses were classified as follows: CR, disappearance of all objective evidence of disease; PR, decrease of 50% or more in sums of the products of diameters of measurable lesions as determined by two tumor measurements; stable disease, decrease of less than 50% or increase of less than 25% in the sums of the products of diameters of measurable lesions; progressive disease, increase of more than 25% in the sums of the products of diameters of measurable lesions or the appearance of new lesions. Toxicities were classified by the National Cancer Institute Common Toxicity Criteria.

Patients were accrued in a minimax two-stage study design described by Simon to minimize patient exposure to this therapy [32]. If there was evidence that the true overall response rate (CR plus PR) was at least 30%, consideration would be given to further testing. However, if weekly docetaxel and trastuzumab was inactive, the study would be terminated early. Initially, 15 patients were enrolled onto the study. If there were fewer than two responses in the first 15 patients, the trial would have been terminated with the conclusion that there is little evidence to suggest the overall response rate would reach 30%. If there were 2 responses in the first 15 patients, the trial would continue until 25 eligible patients were enrolled. This design provides at least 80% power to detect a 20% difference (30% v 10%) with two-sided type I error of 5%. Response rate was estimated using the exact two-sided 95% CI method based on the binomial proportions. The Fisher's exact test was applied for studying the association between the response rate and the possible risk factors (eg, FISH status). For lifetime data analyses, the possible risk factors were compared for survival with Kaplan-Meier estimates and log-rank tests.

	RESULTS

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Twenty-six women were enrolled. Tables 1 and 2 list the clinical characteristics of the participants and the correlative laboratory findings of their tumors respectively. The median age was 53 years; all women had Eastern Cooperative Oncology Group performance status of 0 or 1. Twelve patients' tumors were estrogen receptor–positive or progesterone receptor–positive, eight were negative for both receptors, and the receptor status of six was not known. Fourteen women (54%) had received prior chemotherapy in the adjuvant or metastatic setting, five (19%) of whom had previously received a doxorubicin-based regimen. Eleven patients (42%) had received hormonal therapy. Nineteen patients (73%) were HER-2 3+ and seven (27%) were HER-2 2+. Patients received 91% and 94% of the planned docetaxel and trastuzumab treatments, respectively. Four hundred ninety (91%) of the docetaxel doses and 675 (94%) of the trastuzumab treatments were given at full dose. The other planned treatments were omitted entirely. The median dose-intensity for docetaxel was 23.8 mg/m²/wk for the total cycle of 8 weeks.

It has been suggested that HER-2 2+ cases should be verified using FISH techniques before trastuzumab therapy. Therefore, we examined the cases that were 2+ by HercepTest to determine whether the addition of FISH testing would improve our ability to discriminate responders from nonresponders among this group of patients. All tumors categorized as HER-2 3+ by the HercepTest were amplified using the FISH probes (Table 3). Among the six HER-2 2+ patients who had FISH testing, four (67%) of six patients using the Ventana probe and four (80%) of five patients using the Abbott probe would have been deemed ineligible as no gene amplification was noted. A single patient with a 2+ tumor by HercepTest was found to have gene amplification using the Ventana probe but was nonamplified using the Abbott probe. This patient achieved a PR. Additional correlative studies included an assessment of phosphorylated HER-2 and EGFR (HER-1). As shown in Table 3, 43% of the HER-2 phosphonegative and 62% of the HER-2 phosphopositive tumors responded to trastuzumab therapy. Of the tumors tested for EGFR, 44% of the negative and 58% of the positive tumors responded to trastuzumab. Neither of these results was statistically significant.

All 26 patients were assessable for toxicity (Table 4). In general, treatment was well tolerated, although seven patients (27%) went off study because of toxicity, including grade 3 thrombosis/embolism (two patients), a decrease in ejection fraction (one ineligible patient), a grade 4 electrolyte disturbance and gastric ulcer (one patient), and one patient each with grade 3 fatigue, peripheral neuropathy, and allergy to docetaxel. Hematologic toxicity was noted in the majority of patients, but was generally mild (Table 4). Grade 3 or 4 neutropenia was noted in three patients. No patient experienced grade 3 or 4 anemia. Although cardiac toxicities also were generally mild, 15 patients (58%) developed grade 1 or 2 edema. In most cases the edema was attributable to cumulative docetaxel doses but in two cases venous thromboembolism may have played a contributing role. Nine patients (35%) developed grade 1 or 2 dyspnea, consisting of minimal shortness of breath on exertion. The dyspnea was felt to be due to multiple factors including anemia, weight gain, pleural effusions, and deconditioning. One patient experienced grade 4 dyspnea and one patient developed a grade 4 pericardial effusion. A third patient, who did not meet eligibility criteria because of a baseline ejection fraction of 33%, experienced a further decrease in ejection fraction to 28% after 4 weeks of therapy. Grade 3 neuropathy, fatigue, and diarrhea occurred in two (8%), three (12%), and four patients (15%), respectively. Fifteen patients (58%) experienced grade 1 or 2 fatigue. The worst grades of selected toxicities for each patient are listed in Table 4.

	DISCUSSION

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Our results mirror those observed in similar phase II trials [33-35]. For example, docetaxel administered every 3 weeks at a standard dose (75 mg/m²) combined with weekly trastuzumab in women with HER-2–overexpressing metastatic breast cancer demonstrated PR rates ranging between 28% and 44% [33]. Additional studies are underway in which weekly docetaxel is delivered in conjunction with weekly trastuzumab in HER-2–positive disease. Partial responses have been seen in 50% to 63% of patients [34,35]. One group of investigators reported a higher overall response in patients found to be HER-2–positive by FISH analysis [35].

In general, the acute toxicities associated with this combination were mild, although seven patients did withdraw because of toxicity. None of these patients, however, received recommended docetaxel dose reductions before discontinuation. The peripheral neuropathy rates observed in this trial were slightly higher than those previously reported; however, the overall toxicity profile did not substantially differ from that expected when docetaxel is used alone [21,22]. In particular, the rates of fatigue and edema were similar to what can be anticipated with single-agent docetaxel [21,22]. Although cardiac toxicity has been a concern with trastuzumab, particularly when combined with other cardiotoxic agents, it was anticipated that this combination would be less cardiotoxic than others. Nonetheless, two patients (8%) did experience cardiac toxicity. However, one of these patients was actually ineligible for the study because of a preexisting low ejection fraction at study entry. This patient experienced further deterioration of left ventricular dysfunction with treatment. A second patient developed a grade 4 pericardial effusion. Neither patient had received prior doxorubicin. The observed weekly dose-intensity of docetaxel in our study was 23.8 mg/m² for the entire 8-week cycle. This is lower than that observed in some trials of docetaxel alone but similar to that used in the trial by Esteva et al [35,36]. There were, however, instances in which physicians opted to hold doses of docetaxel because of toxicity, rather than give reduced doses on schedule as required by the protocol. Thus although this combination seems relatively safe, given the limited data on the cause of trastuzumab-mediated cardiac dysfunction, caution should be exercised when treating patients with borderline cardiac function or prior anthracycline exposure.

The optimal method of combining trastuzumab and chemotherapy is not yet known. Previous clinical trials have evaluated trastuzumab in combination with a variety of chemotherapy regimens [2,10,15,35,37]. Overall response rate, duration of response, time to progression, and survival have been higher with the addition of trastuzumab to chemotherapy than those with chemotherapy alone [15]. In many of these studies, there were trends toward higher response rates among patients with greater overexpression of HER-2 or gene amplification. However, direct comparison between these studies is difficult because of small sample sizes, differences in selection criteria, and differences in techniques used to measure HER-2 overexpression. Although further investigation of the combination of docetaxel and trastuzumab would be useful, it is unlikely that this will occur given the upswing in adjuvant taxane use, which would limit accrual of taxane-naïve patients in similar studies. In conclusion, weekly administration of trastuzumab and docetaxel seems safe and effective for patients with metastatic breast cancer whose tumors are HER-2 3+ or FISH-positive.

	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. Acted as a consultant within the last 2 years: G.W. Sledge Jr, Genentech, Aventis. Received more than $2,000 a year from a company for either of the last 2 years: G.W. Sledge Jr, Genentech, Aventis; David H. Johnson, Aventis.

	NOTES

 
Supported in part by National Cancer Institute grant Nos. CA-21115 and CA-68485. Funding was provided by Aven-tis, Bridgewater, NJ, and trastuzumab was provided by Genentech Inc, South San Francisco, CA.

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

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

 
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Submitted October 8, 2003; accepted December 25, 2003.

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