Journal of Clinical Oncology, Vol 20, Issue 7
(April), 2002: 1800-1808
© 2002 American Society for Clinical Oncology
Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER-2–Overexpressing Metastatic Breast Cancer
By Francisco J. Esteva,
Vicente Valero,
Daniel Booser,
Laura T. Guerra,
James L. Murray,
Lajos Pusztai,
Massimo Cristofanilli,
Banu Arun,
Bita Esmaeli,
Herbert A. Fritsche,
Nour Sneige,
Terry L. Smith,
Gabriel N. Hortobagyi
From the Departments of Breast Medical Oncology, Ophthalmology, Laboratory Medicine, Pathology, and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Address reprint requests to Francisco J. Esteva, MD, PhD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 424, Houston, TX 77030; email: festeva{at}mdanderson.org
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ABSTRACT
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PURPOSE: To evaluate the safety and efficacy of weekly docetaxel plus trastuzumab in women with HER-2–overexpressing metastatic breast cancer. Efficacy was correlated with serum HER-2 extracellular domain (ECD) levels.
PATIENTS AND METHODS: Thirty women with metastatic breast cancer were treated with weekly docetaxel and trastuzumab as first- or second-line therapy. Both docetaxel 35 mg/m2/wk and trastuzumab 2 mg/kg/wk were delivered in 4-week cycles consisting of three weekly treatments followed by 1 week of rest. A loading dose of trastuzumab 4 mg/kg was administered 1 day before the start of the first cycle.
RESULTS: The median delivered dose-intensity of docetaxel was 24 mg/m2/wk (range, 18 to 27 mg/m2/wk). The intent-to-treat overall response rate (ORR) was 63% (95% confidence interval [CI], 44% to 80%). The ORR in patients whose tumors were HER-2–positive by fluorescence in situ hybridization was 67% (16 of 24 patients; 95% CI, 45% to 84%). In patients with elevated serum HER-2 ECD at baseline, the ORR was 76% (95% CI, 53% to 92%), compared with 33% (95% CI, 7% to 70%) in patients with low HER-2 ECD levels (P = .04). Variations in HER-2 ECD concentrations during treatment correlated with response to treatment. Median time to progression was 9 months. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and excessive tearing became more common with repetitive dosing.
CONCLUSION: Weekly docetaxel and trastuzumab is an active combination for treating patients with HER-2–overexpressing metastatic breast cancer. Serum HER-2 ECD testing may be a promising method for monitoring patients on trastuzumab-based therapy.
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INTRODUCTION
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AMPLIFICATION OF THE HER-2 gene, also known as erbB-2 or neu, was one of the first genetic changes associated with the pathogenesis of human breast cancer.1-3 The HER-2 gene is amplified in 20% to 30% of invasive breast cancers.4 Several studies have shown a correlation between HER-2 overexpression and short disease-free and overall survival in breast cancer patients.5,6 Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is a humanized monoclonal antibody directed against the HER-2 protein. Response rates to trastuzumab given as a single agent range from 12% to 40%, in part depending on the method used to determine HER-2 status and the prior treatment received.7-9 Slamon et al10 showed that combining trastuzumab with either doxorubicin plus cyclophosphamide or single-agent paclitaxel produces higher response rates and survival compared with chemotherapy alone. Although effective, the doxorubicin/cyclophosphamide plus trastuzumab regimen caused severe cardiac dysfunction. This led to the development of trastuzumab-based combinations that do not contain anthracyclines. Regimens evaluated to date with promising results include weekly paclitaxel,11 cisplatin,12 and vinorelbine.13
The most commonly used assays for assessing HER-2 status in breast cancer patients are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlation between IHC-detected protein overexpression (score, 3+) and FISH-detected gene amplification is generally strong.11,14-16 Conversely, it is rare for negative or weak IHC staining (score, 1+ or 2+) to be associated with gene amplification.14 Most reported clinical trials of trastuzumab have selected patients using IHC (with a score of 2+ or 3+ indicating HER-2 overexpression). A recent retrospective analysis indicated that HER-2 status in primary tumors as determined using FISH may be the most accurate predictor of response to trastuzumab therapy.17 Another method under investigation for predicting response to trastuzumab is the quantification of the extracellular domain (ECD) of the HER-2 protein in the serum. The HER-2 ECD is shed into the circulation and can be elevated in the serum of women with metastatic breast cancer.18 It has been suggested that serum HER-2 ECD measurement is clinically useful in breast cancer for detecting early recurrence or metastasis and for predicting response to hormonal therapy.19-21 The role of serum HER-2 ECD for selecting patients for and monitoring response to trastuzumab-based therapy has not been defined.
Docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) is one of the most active drugs for patients with metastatic breast cancer.22 Single-agent docetaxel is highly active for patients whose previous anthracycline treatment failed.22,23 In a randomized phase III study, docetaxel produced a higher response rate than doxorubicin in patients with metastatic breast cancer who had previously been exposed to cyclophosphamide, methotrexate, and fluorouracil chemotherapy.24 Administration of docetaxel on a weekly schedule is effective and well tolerated in women with metastatic breast cancer.25,26 Docetaxel does not enhance the cardiac toxicity caused by doxorubicin.27
Recently, Pegram et al28 reported a synergistic interaction between trastuzumab and docetaxel in HER-2–transfected MCF7 human breast cancer xenografts in nude mice. The combination resulted in a significant reduction in xenograft volume compared with chemotherapy alone. This synergistic interaction of trastuzumab and docetaxel provided the rational for testing this combination in the clinic. In this study, we sought to explore the safety and response rate of weekly docetaxel and trastuzumab therapy for women with HER-2–overexpressing metastatic breast cancer. As a secondary objective, we evaluated the role of circulating HER-2 ECD concentration as a potential predictor of response to trastuzumab-based therapy.
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PATIENTS AND METHODS
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Patient Population
Patients eligible for this study were women with metastatic breast cancer whose tumors overexpressed HER-2. The HER-2 status was assessed at study entry by IHC and FISH on formalin-fixed, paraffin-embedded tissue, as previously described.16 IHC was conducted using the Neomarkers monoclonal antibody e2-4001 (Labvision, Union City, CA). FISH was conducted using the PathVysion HER2 FISH assay (Vysis, Inc, Downers Grove, IL). A retrospective analysis was conducted in 24 available tumors using the CB11 antibody (Pathway HER2; Ventana) and the Inform HER-2/neu (FISH) (Ventana). Assays were preformed according to the manufacturers’ instructions.
Eligibility criteria included measurable disease, a Karnofsky performance status of at least 70, and adequate hematologic, liver, and renal function. The left ventricular ejection fraction (LVEF) had to be at least 50%. Patients with brain metastases, with a history of grade 3 or 4 peripheral neuropathy of any etiology, and who had received radiation to more than 50% of marrow-bearing bone were excluded. Patients who had received any number or type of exogenous hormonal therapies, either for treatment of metastatic disease or as adjuvant therapy, were permitted to enroll onto the study, as were patients who had received no more than three prior chemotherapy regimens in the adjuvant or neoadjuvant setting or for treatment of metastatic disease. Concomitant bisphosphonates were allowed for patients with bone metastases. Patients with previous taxane exposure in the adjuvant or neoadjuvant setting were permitted to enroll if the taxane had been administered more than 1 year before enrollment onto this study. Prior trastuzumab therapy was not allowed. Patients had to recover from the myelosuppressive effects of prior chemotherapy (normal blood counts for at least 3 weeks). Women of childbearing potential had a negative pregnancy test before enrollment and were advised to practice appropriate contraception while on study. The study protocol was reviewed and approved by the surveillance committee (institutional review board). Before study entry, each patient signed a written informed consent form.
Treatment
Both docetaxel and trastuzumab were delivered in 4-week cycles consisting of three weekly treatments followed by 1 week of rest. With the exception of week 1 of the first cycle, the weekly treatments consisted of docetaxel 35 mg/m2 administered intravenously (IV) over 30 minutes immediately followed by trastuzumab 2 mg/kg administered IV over 30 minutes. In week 1 of the first cycle, a loading dose of trastuzumab (4 mg/kg) was delivered IV over 90 minutes on day 0, and docetaxel 35 mg/m2 was administered IV over 30 minutes on day 1. No loading dose of trastuzumab was delivered after the first cycle. All therapy was delivered in the outpatient clinic. Treatment was continued until disease progression or the appearance of prohibitively toxic effects.
Patients received three doses of prophylactic dexamethasone 4 mg orally every 12 hours, starting the night before docetaxel infusion. If patients had no hypersensitivity reactions and no significant fluid retention during the first 8 weeks, the dose of dexamethasone was reduced to 4 mg orally twice a day on the day of therapy. If patients remained free of fluid retention after 8 additional weeks, the dose of dexamethasone was further reduced to 4 mg orally before treatment.
Evaluation of Tumor Response and Toxicity Assessment
All patients had tumor measurements performed within 14 days of registration, after cycle 2 (week 8), after cycle 4 (week 16), and after every three cycles thereafter (weeks 28, 40, and 52). Standard Eastern Cooperative Oncology Group criteria were used to define measurable disease, assessable disease, and response.29
All cycles (day 1) were held pending recovery of absolute neutrophil count to 1,000 cells/mm3 and platelet count to more than 100,000/mm3 and resolution of nonhematologic toxicity (eg, neuropathy) to grade 2 or less. Patients who required more than 2 weeks for recovery to any of these parameters received a reduced dose of docetaxel. The dose levels were as follows: level 0, 35 mg/m2; level -1, 30 mg/m2; level -2, 25 mg/m2; and level -3, 20 mg/m2. The dose of docetaxel was reduced one level in patients who developed an absolute neutrophil count of less than 500/µL, neutropenic fever, or a platelet count of less than 50,000/mm3 and in patients with a normal platelet count who developed bacteremia or fever (temperature > 38°C with absolute neutrophil count < 1,000/µL). The dose of docetaxel was reduced one level for grade 2 nonhematologic toxicity and two levels for grade 3 nonhematologic toxicity (except fatigue). In patients who developed grade 3 fatigue, the dose of docetaxel was reduced one level.
Toxicities were graded according to the National Cancer Institute common toxicity criteria. Repeat multigated acquisition (MUGAs) or echocardiograms were performed after completion of cycle 2 (week 8), cycle 4 (week 16), and every three cycles thereafter (weeks 28, 40, 52). Trastuzumab was discontinued if patients developed congestive heart failure or the LVEF fell below 45%. If a patient developed asymptomatic reduction in LVEF of 15% but the LVEF remained above 45%, a cardiology consultation was obtained. The decision to discontinue trastuzumab at that point was discussed with the patient after the risks and potential benefits of trastuzumab therapy were assessed.
Analysis of Serum HER-2 Antigen and Serum HER-2 Native Antibodies
Blood samples were collected before initiation of docetaxel and trastuzumab therapy (baseline), after completion of two cycles and four cycles, and after every three cycles thereafter. The serum HER-2 ECD levels were measured using the Immuno-1 method (Bayer Diagnostics, Tarrytown NY). The method is an enzyme-linked sandwich immunoassay, which uses a double monoclonal antibody format. Briefly, capture antibody is conjugated with fluorescein, and the detector antibody is labeled with alkaline phosphatase. After the HER-2 molecule is complexed to the capture and detector antibodies, the complex is removed by binding to antifluorescein-labeled magnetic beads. The concentration of the phosphatase-substrate reaction product is directly proportional to the serum HER-2 ECD and is determined from a standard curve. The reference limit for this assay is 14.9 ng/mL. The sensitivity of the assay is 0.1 ng/mL, and the precision of the assay is less than 2.0% (coefficient of variation) for mean serum HER-2 ECD concentrations ranging from 10.0 to 100.0 ng/mL.30 The serum specimens were coded, and the laboratory personnel were unaware of the clinical response data at the time of HER-2 ECD measurement.
Native anti-HER-2 antibodies in serum were measured at baseline in 28 of 30 patients as previously described.31 Measurement of antibodies was not attempted in serial serum samples collected during therapy because this assay cannot differentiate between native HER-2 antibodies and trastuzumab.
Statistical Analysis
It was expected that the overall response rate with the weekly docetaxel and trastuzumab combination would be at least 50%. The trial accrued its planned maximum of 30 patients. This sample size provided an estimate of response rate with 95% confidence interval (CI) of width approximately 0.36. Consideration was given to stopping the trial if the following numbers of responses, or fewer, were observed among the specified numbers of assessable patients: two of 10, three of 11, four of 13, five of 16, six of 18, seven of 20, eight of 23, nine of 25, or 10 of 27 patients. These rates were computed using a Bayesian method and a noninformative prior. If the true response rate had been 40%, 50%, or 60%, the probability of terminating the trial early was .60, .24, or .05, respectively. Time to progression was computed from date of first chemotherapy, and curves were estimated by the method of Kaplan and Meier.32 Delivered dose-intensity was computed based on the docetaxel dose (mg/m2) administered per week. Docetaxel dose-intensity reflects dose per cycle (treatment 3 weeks out of 4).
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RESULTS
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A total of 30 patients with HER-2–overexpressing tumors were enrolled onto this study. The patient characteristics are listed in Table 1. The HER-2 status was determined for eligibility using monoclonal antibody e2-4001 (IHC) in 12 patients and PathVysion HER2 (FISH) in 18 patients. Ten patients who had been initially assessed by IHC were evaluated using the PathVysion HER2 assay. Out of the 28 patients available for FISH analysis, 24 patients had HER-2–positive tumors by FISH. The IHC score in the tumors that were HER-2–negative using FISH was 3+ in two patients and 2+ in two patients. Twenty-four specimens were evaluated retrospectively using the CB11 monoclonal antibody. Nineteen of these specimens were found to be positive (score, 3+), and five were considered HER-2–negative (0 to 2+). Twenty-one tumors were assessed using both the PathVysion HER2 and the Inform HER-2/neu assays. The concordance between the two FISH assays was 92%.
The median number of disease sites was two (range, one to five). Twenty-five patients (83%) had liver and/or lung metastases. The median number of prior chemotherapies was one (range, zero to two). Twenty-one patients (70%) had received adjuvant/neoadjuvant chemotherapy; four patients (13%) had received chemotherapy for metastatic disease only, and two patients (7%) had received chemotherapy in the adjuvant setting and for metastases. Five patients (16%) received no prior chemotherapy. Twenty-four patients (80%) received doxorubicin before participation in this study (19 in the adjuvant/neoadjuvant setting and five for metastatic disease). Five patients (16%) had been treated with adjuvant paclitaxel, and one patient (3%) had received docetaxel in the adjuvant setting.
A total of 594 weekly infusions of docetaxel and trastuzumab were administered. The median number of cycles administered was six (range, two to 16). The median delivered dose-intensity for docetaxel was 24 mg/m2/wk (range, 18 to 27 mg/m2/wk), which equates to a median relative dose-intensity of 91%. Five doses of docetaxel were not given because of neutropenia (absolute neutrophil count less than 1,000/mm3). All patients received at least two cycles of weekly docetaxel and trastuzumab and were assessable for toxicity. In general, the treatment was tolerated well (Table 2). Grade 3 or 4 neutropenia occurred in eight patients (26%). One patient (3%) developed neutropenic fever. Grade 3 or 4 anemia or thrombocytopenia was not observed. Fatigue occurred in 25 patients (83%), and it was first noted at a cumulative median dose of docetaxel of 70 mg/m2 (range, 35 to 210 mg/m2). Six patients (20%) had grade 3 fatigue at a cumulative median dose of docetaxel of 157.5 mg/m2 (range, 70 to 540 mg/m2). Twenty-eight patients (93%) developed grade 1 to 2 epiphora (excessive tearing) at a median cumulative dose of docetaxel of 210 mg/m2 (range, 35 to 780 mg/m2). Twelve of these patients were found to have clinically detectable anatomic narrowing of the canaliculi as the underlying mechanism for epiphora and underwent silicone intubation of the nasolacrimal ducts to prevent further closure of the canaliculi.33 The cumulative median docetaxel dose for these 12 patients was 420 mg/m2 (range, 285 to 735 mg/m2). Grade 1 to 2 pleural effusions occurred in nine patients (29%) at a median cumulative dose of docetaxel of 600 mg/m2 (range, 240 to 735 mg/m2). One patient developed grade 3 pleural effusions (requiring thoracentesis) after receiving docetaxel 420 mg/m2. Edema occurred at a median cumulative docetaxel dose of 220 mg/m2 (range, 35 to 525 mg/m2). Infusion-related reactions were infrequent. Nineteen patients required reductions in the dose of docetaxel. The frequency of docetaxel dose reductions is presented in Table 3. Docetaxel was discontinued because of toxicity in seven patients (23%). The reasons for docetaxel discontinuation were pleural effusions (five patients) fatigue (one patient), and fungal infection (one patient). One patient developed a bleeding duodenal ulcer after two cycles of docetaxel and trastuzumab therapy. This was attributed to dexamethasone premedication and docetaxel was discontinued. The dose of dexamethasone was successfully decreased as planned in all eligible patients who received therapy beyond week 8. Responding patients who required docetaxel discontinuation because of toxicity continued to receive single-agent trastuzumab until disease progression.
Cardiac function was monitored using MUGA cardiac scans at baseline and after completion of two cycles and four cycles of weekly docetaxel and trastuzumab therapy. Subsequently it was monitored every three cycles at 12-week intervals. The mean LVEF values were 63% before treatment (baseline), 61% after two cycles, 61% after four cycles, 62% after seven cycles, 64% after 10 cycles, and 60% after 13 cycles of docetaxel and trastuzumab therapy (Fig 1). Eight patients developed asymptomatic decreases in LVEF. Three patients (10%) developed grade 1 LVEF dysfunction. The prior median cumulative dose of doxorubicin in these patients was 300 mg/m2 (range, 200 to 350 mg/m2). Five patients (16%) developed grade 2 LVEF dysfunction. The prior median cumulative dose of doxorubicin in these patients was 300 mg/m2 (range, 240 to 350 mg/m2). Weekly docetaxel was continued in two of these patients without dose modification. Trastuzumab was discontinued in one of these patients at the patient’s request. A patient who had received a cumulative dose of doxorubicin of 240 mg/m2 developed bilateral pleural effusions, lower-extremity edema, and dyspnea at rest after four cycles of docetaxel and trastuzumab. At the time of this cardiac event, the cumulative dose of docetaxel was 404 mg/m2. A MUGA scan revealed a reduction in LVEF from 60% at baseline to 48%. A diagnosis of acute pulmonary edema was made and the patient received medical management with diuretics and digoxin. The patient had received a total cumulative dose of docetaxel of 404 mg/m2. At the time of this adverse event, the patient was found to have progressive metastatic disease and was taken off protocol. Eleven days after the acute episode, and while the patient was still receiving diuretics and digoxin, an echocardiogram showed normal LVEF (50% to 59%), normal systolic function, and normal diastolic function. The patient developed progressive disease after two cycles of single-agent capecitabine. She then received vinorelbine in combination with trastuzumab for 3 months without any evidence of clinical congestive heart failure.
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Fig 1. Mean LVEF after weekly docetaxel and trastuzumab therapy at baseline (BL), after cycle 2, after cycle 4, and every three cycles thereafter. The number of patients (pts) on study is indicated below the x-axis. Error bars reflect SD.
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The overall response rates are presented in Table 4. Partial response occurred in 19 (63%) of 30 patients (95% CI, 44% to 80%). Three patients (10%) had a minor response, and three patients (10%) had stable disease as their best response to therapy. No patient had a complete response. The response rate in patients whose tumors were HER-2–positive by FISH (n = 24) was 67%. Four (80%) of five patients previously exposed to paclitaxel in the adjuvant setting responded to weekly docetaxel plus trastuzumab therapy. Sites of response included liver, lung, and soft tissue. The estimated median time to progression was 9 months. Patients treated with weekly docetaxel and trastuzumab as first-line therapy for metastatic disease had longer time to progression than did patients treated as second-line therapy (Fig 2). Three patients had brain metastases at the time of recurrence. In two of them, the brain was the only site of disease. These patients were treated with whole-brain irradiation and trastuzumab was continued for 4 and 12 months, until disease progression outside the CNS.
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Fig 2. Time to progression: proportion of patients without disease progression as a function of prior chemotherapy for metastatic breast cancer.
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Circulating HER-2 ECD levels were measured at baseline and at the time of response evaluation (after cycle 2, after cycle 4, and every three cycles thereafter) in all 30 patients. The median level at baseline was 41.9 ng/mL (range, 7.1 to 666.5 ng/mL). Twenty-one patients (70%) had elevated HER-2 ECD levels at baseline (> 14.9 ng/mL). The overall response rate in these patients was 76%, compared with 33% in patients with low HER-2 ECD levels (P = .04). Serum HER-2 ECD levels improved in 14 (87%) of 16 responding patients and were below the reference limit of the assay (< 14.9 ng/mL) in 12 (75%) of 16 responding patients (Fig 3). The response rates defined by IHC, FISH, and serum HER-2 ECD are listed in Table 5.
Two of 28 patients were found to have elevated native anti–HER-2 antibodies at baseline (6.49 µg/mL and 3.68 µg/mL). One of these patients responded to docetaxel and trastuzumab therapy and the other one did not. The remaining 26 patients had undetectable native anti–HER-2 antibodies before treatment. Antibody levels were not measured during therapy because the assay could not discriminate between trastuzumab and native anti–HER-2 antibodies.
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DISCUSSION
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This is the first full report of docetaxel plus trastuzumab for patients with HER-2–overexpressing metastatic breast cancer. The weekly regimen was active and generally well tolerated. The overall response rate achieved was 63%. When patients with minor responses and stable disease are considered, 83% of patients obtained some clinical benefit from the combination of weekly docetaxel and trastuzumab.
In general, the weekly docetaxel-trastuzumab combination was well tolerated. Most toxicities were consistent with prior reports of weekly docetaxel for patients with metastatic breast cancer.25 In this study, patients with excessive lacrimation were evaluated by an ophthalmologist (B.E.), and 12 patients were found to have canalicular stenosis as the underlying mechanism.33 This complication was managed successfully using silicone intubation of the nasolacrimal ducts.34 Another alternative in reducing the rate of excessive tearing may be dose reduction. The rate of fluid retention (pleural effusions and edema) observed in this trial was similar to the rates reported by Burstein et al25 but higher than the rate reported by Hainsworth et al.26 In these two studies, patients received docetaxel for 6 consecutive weeks followed by 2 weeks of rest. Dexamethasone prophylaxis consisted of 8 mg orally 12 hours before docetaxel administration, at the time of docetaxel administration, and 12 hours after treatment (total, 24 mg/wk). In our study, we used half the dose of dexamethasone used in Hainsworth’s study. This may explain the higher rate of edema and pleural effusions. Aggressive use of diuretics at the start of peripheral edema may be required with this regimen, before pleural effusions occur. However, the optimal corticosteroid regimen required to prevent fluid retention in patients undergoing weekly docetaxel therapy is not well defined and merits further investigation.
Three patients had CNS progression after an initial response to therapy. These patients were withdrawn from study. In two of these patients, the CNS was the first and only site of disease progression. These patients continued to receive trastuzumab therapy after whole-brain irradiation and remained without evidence of other systemic progression outside the CNS for 4 and 12 months. The CNS seems to be a sanctuary for disease in patients treated with trastuzumab and docetaxel therapy. This could be due in part to the low penetration of trastuzumab and the taxanes into the brain.35
One of the most serious toxicities to be associated with trastuzumab-based therapy is congestive heart failure. In this study, left ventricular function was maintained during study treatment, reflected by the relatively consistent mean LVEF that was observed through 1 year of therapy (Fig 1). Only one patient developed clinical congestive heart failure. This patient presented with bilateral pleural effusions, lower-extremity edema, and dyspnea after receiving four cycles of weekly docetaxel and trastuzumab. A MUGA scan revealed a 12% absolute reduction in LVEF (from 60% at baseline to 48%). She improved with medical treatment. Interestingly, an echocardiogram obtained 11 days after this acute episode, while the patient was still taking digoxin and diuretics, showed a completely normal left ventricular function. The mechanism of potential trastuzumab-induced cardiac toxicity is not defined, and patients should be monitored while receiving antibody therapy. In addition, docetaxel-induced fluid retention may confuse the clinical picture, making a diagnosis of congestive heart failure more difficult.
The response rates reported in this trial are comparable to those reported by Seidman et al11 in a trial of weekly trastuzumab (4 mg/kg at week 1, 2 mg/kg at subsequent weeks) and paclitaxel (90 mg/m2/wk) performed in a similar patient population of which 57% expressed HER-2 (2+ or 3+ by IHC). The overall response rate reported for weekly paclitaxel plus trastuzumab was 61.4% and ranged from 67% to 81% in patients with HER-2–overexpressing tumors, depending on the method of HER-2 detection. Both taxanes are well tolerated on weekly schedules and can be given safely with trastuzumab. However, the docetaxel/trastuzumab combination seems to be associated with less neurotoxicity, an adverse effect that can diminish patient quality of life. Other severe toxicities, including edema/fluid retention and febrile neutropenia, were comparable in both studies. Because no randomized comparisons of the two treatment regimens have been performed and because the methods used to determine HER-2 expression were different for each trial, the response rates cannot be directly compared. Both combination therapies are promising, and both should be considered viable treatment options for patients with HER-2–overexpressing metastatic breast cancer. Ongoing clinical trials are evaluating two additional schedules of docetaxel in combination with trastuzumab. In one study, docetaxel is administered every 3 weeks; the other is evaluating a weekly schedule using 6 weeks on followed by 2 weeks of rest.36,37
HER-2 overexpression has been associated with resistance to a variety of chemotherapeutic drugs.38 However, it is not known whether there is an association between HER-2 overexpression and response to taxane therapy. Baselga et al39 reported a retrospective study in which patients with HER-2–overexpressing metastatic breast cancer were more likely to respond to paclitaxel compared with patients with HER-2–negative tumors. In contrast, in a prospective randomized study, the response to paclitaxel as first-line chemotherapy for HER-2–overexpressing metastatic breast cancer was 17%,10 suggesting resistance rather than sensitivity. There are no data available regarding HER-2 overexpression and response to docetaxel in patients with metastatic breast cancer. Retrospective data suggest that FISH may be the best HER-2 testing method for predicting response to trastuzumab monoclonal antibody therapy.17 Our study showed a good correlation between the PathVysion HER2 and the Inform HER-2/neu FISH assays. Correlation of HER-2 status and response to therapy was attempted using IHC and FISH in paraffin-embedded tissues. However, this analysis was limited because the number of cases under evaluation was small and no patients testing negative for HER-2 were enrolled onto the trial. In general, HER-2 positivity trended with response, but strongly positive patients also were found in the populations that showed minor response, stable disease, and progressive disease. The results when analyzed by FISH or IHC (score, 3+) were similar, which is not to be expected with the high level of concordance between the two tests.
The role of serum HER-2 ECD for selecting patients for trastuzumab-based therapy is unknown. Trastuzumab can bind the shed HER-2 antigen in the circulation, and this could, theoretically, prevent access of the antibody to tumor cells. However, in our study, patients with high HER-2 ECD levels at baseline had a high response rate to therapy (76%). In addition, changes in serum HER-2 ECD correlated very well with clinical response to weekly docetaxel and trastuzumab therapy. However, the number of patients evaluated in this study is small and these data should be considered hypothesis-generating rather than final.
In conclusion, weekly administration of docetaxel and trastuzumab is safe and effective for patients with metastatic breast cancer whose tumors overexpress HER-2. Further research is warranted to determine the value of serum HER-2 ECD testing in selecting and monitoring patients undergoing trastuzumab-based therapy.
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ACKNOWLEDGMENTS
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Supported by grants from Aventis Pharmaceuticals, Bridgewater, NJ, and Genentech Inc, South San Francisco, CA. F.J.E. is the recipient of Career Development Award K23 CA82119 from the National Cancer Institute, Bethesda, MD.
We thank Nikki Manuel, University of Texas M.D. Anderson Cancer Center, for processing and coding the serum specimens and Vivian Goodell and Mary Disis, MD, University of Washington, for completing the HER-2 antibody assays. We also thank Connie Johnson for her secretarial assistance and Stephanie Deming for her editorial assistance.
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Submitted August 7, 2001;
accepted November 28, 2001.
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[Abstract]
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G. Bianchi, J. Albanell, W. Eiermann, G. Vitali, D. Borquez, L. Vigano, R. Molina, G. Raab, A. Locatelli, B. Vanhauwere, et al.
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5944 - 5951.
[Abstract]
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B. Leyland-Jones, K. Gelmon, J.-P. Ayoub, A. Arnold, S. Verma, R. Dias, and P. Ghahramani
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[Abstract]
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R. Nahta and F. J. Esteva
HER-2-Targeted Therapy: Lessons Learned and Future Directions
Clin. Cancer Res.,
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[Abstract]
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Y. Suzuki, Y. Tokuda, Y. Saito, M. Ohta, and T. Tajima
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Jpn. J. Clin. Oncol.,
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W. P. Carney, R. Neumann, A. Lipton, K. Leitzel, S. Ali, and C. P. Price
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Clin. Chem.,
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[Abstract]
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H. J. Burstein, L. N. Harris, P. K. Marcom, R. Lambert-Falls, K. Havlin, B. Overmoyer, R. J. Friedlander Jr., J. Gargiulo, R. Strenger, C. L. Vogel, et al.
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Oncologist,
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[Abstract]
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R. Nahta, S. Trent, C. Yang, and E. V. Schmidt
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R. Nahta, G. N. Hortobagyi, and F. J. Esteva
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Oncologist,
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[Abstract]
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H. J. Burstein, L. N. Harris, R. Gelman, S. C. Lester, R. A. Nunes, C. M. Kaelin, L. M. Parker, L. W. Ellisen, I. Kuter, M. A. Gadd, 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
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M. Jahanzeb, J. E. Mortimer, F. Yunus, D. H. Irwin, J. Speyer, A. J. Koletsky, P. Klein, T. Sabir, and L. Kronish
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Oncologist,
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[Abstract]
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TOP
ABSTRACT
INTRODUCTION
