Affiliations of authors: Division of HematologyOncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, and Jonsson Comprehensive Cancer Center, Los Angeles, CA (GEK, SD, LR, GP, MDP, DJS); Department of Biomathematics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles (HJW); Breast Cancer Study Group, Arbeitsgemeinschaft für Gynäkologische Onkologie, Germany (CT, HJL, MU, WK, HE, ADB, SO, DS, VM, GVM, FJ)
Correspondence to: Dennis J. Slamon, MD, PhD, University of California, Los Angeles, Peter Ueberroth Bldg., 3360B, 10945 Le Conte Ave., Los Angeles, CA 90095-7077 (e-mail: dslamon{at}mednet.ucla.edu)
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ABSTRACT |
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INTRODUCTION |
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Previous studies of the association between HER-2/neu status and the response to chemotherapy have been challenged because of the use of inappropriate control groups or inaccurate methods to detect the alteration of the HER-2/neu gene. To avoid such controversies, we analyzed HER-2/neu status in the present study with fluorescence in situ hybridization (FISH), as this method allows the most accurate detection of the HER-2/neu alteration in formalin-fixed paraffin-embedded tissue (1315). Furthermore, we studied the association between HER-2/neu amplification and response to a taxane in the context of a randomized controlled study investigating the use of a taxane in patients with metastatic breast cancer. This approach allowed us to assess the objective response rate (as a direct measure of chemosensitivity), progression-free survival, and overall survival and enabled us to separate taxane-specific effects from effects generally associated with chemotherapy. We obtained data for this retrospective subset analysis from a randomized trial of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) that compared an epirubicincyclophosphamide (EC) regimen with an epirubicinpaclitaxel (ET) regimen as first-line therapies for patients with metastatic breast cancer. Preliminary findings from the first analysis of 429 patients, which were reported previously (16), indicated that the two treatment arms were not demonstrably different in terms of overall efficacy, with comparable objective response rates for ET and EC (46% and 41%, respectively) and comparable median progression-free survivals for both ET and EC (39 and 33 weeks, respectively;P = .089) (16). In this retrospective subset analysis, we investigated whether HER-2/neu amplification is associated with an improved response to a taxane-based ET regimen compared with an EC regimen.
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PATIENTS AND METHODS |
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Before entry into the study, all patients underwent a complete physical examination, chest x-rays, an ultrasonographic examination of the liver, and a bone scan. Computed tomography examinations of the chest and abdomen were performed when clinically indicated. Response was determined at 12-week intervals. A complete response was defined as the disappearance of all radiographically and/or visually apparent tumor tissue. A partial response was defined as a greater than 50% decrease (two-dimensional measurements) of all measurable lesions. Disease progression was defined as a greater than 25% increase in any measurable lesion or the appearance of any new lesion. Objective responses were not routinely confirmed by a later evaluation. The objective response rate was defined as the percentage of patients achieving a complete or partial response. Progression-free survival was defined as the time from the date of randomization to the date of documented disease progression. The occurrence of a secondary malignancy or death from any cause was also considered to be disease progression. Overall survival was defined as the time from the date of randomization to the date of death from any cause or to the date of loss to follow-up.
Specimens
Archived primary tumor specimens from all 516 patients were requested from 71 institutions participating in the randomized AGO study of first-line treatment for patients with metastatic breast cancer. However, because the primary surgery was often performed at institutions other than those participating in the clinical AGO trial, tissue blocks of primary breast cancer biopsy samples were available for HER-2/neu analysis from 297 (58%) of the 516 patients. Each tissue block was sectioned for histologic analysis, and five blocks lacking residual invasive carcinoma were omitted, leaving a total of 292 samples. Of these 292 samples, 275 (94%) were technically satisfactory for analysis of HER-2/neu gene amplification.
HER-2/neu Analysis
HER-2/neu gene copy number was analyzed by use of FISH on 4-µm sections of paraffin-embedded and formalin-fixed tumor tissue. Specimen preparation, hybridization, and microscopy were performed as previously described (14). A SpectrumOrange-labeled HER-2/neu probe (Vysis, Downers Grove, IL) was used to determine gene copy number (number of gene signals per cell). In addition, to account for increased HER-2/neu gene copy number because of chromosome 17 polysomy (increased copy number of the entire chromosome, which is frequently seen in breast cancer), we also hybridized specimens with a probe for the chromosome 17 centromere labeled with the SpectrumGreen fluorochrome (PathVision 30-161060; Vysis). Data were expressed as the number of HER-2/neu genes per chromosome 17 centromere; we used two HER-2/neu genes per chromosome 17 centromere as the biological cutoff to distinguish tumors with and without HER-2/neu amplification, respectively (14).
FISH Scoring Criteria
FISH scores were analyzed as previously described (14). In brief, slides were initially scanned for the HER-2/neu signals and sorted into the following three groups: 1) tumors with obvious gene amplification (i.e., signal clusters of more than 1015 signals per cell), 2) tumors readily classified as single copy (i.e., no cells with more than four HER-2/neu signals detectable), and 3) an intermediate group with low-level copy number increases. In the intermediate group, 100 randomly selected nuclei were scored for both HER-2/neu and chromosome 17 centromere signals, and HER-2/neu amplification was defined as the mean ratio of the number of HER-2/neu signals to the number of chromosome 17 centromere signals. Tumors with a ratio of more than 2 were classified as HER-2/neu positive, and tumors with a ratio of 2 or less were classified as HER-2/neu negative.
Statistical Analysis
Baseline prognostic and patient characteristics between the 275 patients with FISH data available and the 241 patients without such data were compared by use of the chi-square test to exclude the possibility of selection bias. Baseline prognostic and patient characteristics were also compared between treatment groups (ET and EC) for patients with a known HER-2/neu status by use of the chi-square test. We explored associations between the frequency of HER-2/neu gene amplification, prognostic factors, and patient characteristics, including age, histology (ductal, lobular, or other), nuclear grade (1, 2, or 3), estrogen or progesterone receptor status of tumor, location of metastases (liver, lung, or other), number of metastatic sites (1, 2, or 3), and whether prior palliative hormonal therapy or prior adjuvant chemotherapy was received. The association of HER-2/neu gene amplification with each of these characteristics was tested individually by use of the chi-square test. The prognostic relevance of baseline factors for progression-free survival and overall survival was assessed with a univariate Cox model.
To determine whether HER-2/neu gene amplification was associated with therapeutic efficacy, we calculated objective response rates for both treatment regimens and patient subsets according to HER-2/neu status. Progression-free survival and overall survival were estimated with the KaplanMeier method. Of the 275 patients with evaluable FISH results, 258 (94%) had radiographically measurable disease at a later evaluation, and information on progression-free survival and overall survival was available for all 275 patients. Progression-free survival and overall survival were compared by using the log-rank test. We estimated the odds ratio (OR) for the objective response rate and the relative risks (RRs) for progression-free survival and overall survival by use of a Cox univariate model. In multivariable analysis, a logistic regression model (objective response rate) and a Cox proportional hazard regression model (progression-free survival and overall survival; the assumptions of proportionality for the Cox regression were verified by residuals plots. Martingale [or deviance] residuals were plotted against survival time or covariates. For logistic regression, goodness-of-fit statistics was used for model checking) were used to investigate associations between the probability of response and age, histology (ductal, lobular, or other), localization of metastasis (liver, lung, or other), number of metastatic sites (1, 2, or 3), whether palliative endocrine therapy or adjuvant chemotherapy had been received, nuclear grade (1, 2, or 3), and estrogen and progesterone receptor status determined at the primary diagnosis. A stepwise procedure was used for covariate selection. All statistical tests were two-sided. Data from patients whose tumors were HER-2/neu negative and patients whose tumors were HER-2/neu positive were tested for equality by adding an interaction term to the logistic regression or the Cox proportional hazards model and by testing its statistical significance with the Wald test.
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RESULTS |
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Comparison of characteristics of the cohort of eligible patients with and without known HER-2/neu status detected no statistically significant differences between the group whose HER-2/neu status was known and the group whose HER-2/neu status was unknown (Table 1), indicating that our study sample was representative of the overall patient population. Among the 275 patients whose HER-2/neu status could be determined, 137 had been randomly assigned to receive EC and 138 had been randomly assigned to receive ET (Table 2). Patients in both treatment groups received a median of six cycles of chemotherapy. As indicated in Table 2, patient and disease characteristics were well balanced across the two treatment arms. Of the 275 evaluable primary tumor specimens, HER-2/neu gene amplification was detected in 97 (35%) tumors, 48 from the EC arm and 49 from the ET arm. The prognostic relevance of baseline factors for progression-free survival and overall survival for patients with known HER-2/neu status is shown in Table 3.
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HER-2/neu amplification was inversely associated with estrogen receptor status, in that 46 (52%) of the 89 HER-2/neupositive tumors were classified as estrogen receptor positive and 110 (67%) of the 163 HER-2/neunegative tumors were classified as estrogen receptor positive (P = .014). HER-2/neu amplification was also positively associated with a higher proportion of patients who had received prior adjuvant chemotherapy, in that 48 (49%) of the 97 patients with HER-2/neupositive tumors had received adjuvant chemotherapy compared with 52 (30%) of the 175 patients with HER-2/neunegative tumors (P = .001). HER-2/neu gene amplification, however, was not associated with the progesterone receptor status, number or site of metastatic lesions, the type of histology, the nuclear grade of the primary tumor, patient age, or the application of a prior palliative hormone therapy (data not shown).
Association Between HER-2/neu Status and Treatment Outcome
We initially investigated whether HER-2/neu amplification was associated with treatment outcomes in the entire study cohort of 275 patients. Patients with HER-2/neupositive tumors had a statistically significantly higher objective response rate (60% [95% CI = 51% to 70%] versus 41% [95 CI = 34% to 49%]; 2 P = .004; logistic regression OR = 2.19 [95% CI = 1.31 to 3.65]; P = .003) than patients with HER-2/neunegative tumors. Despite an increased primary response, patients with HER-2/neupositive tumors, however, had a poorer prognosis than patients with HER-2/neunegative tumors. Statistically significantly shorter progression-free survival was observed among the 97 patients with HER-2/neupositive tumors (median progression-free survival = 8.4 months, 95% CI = 7.3 to 10.3 months) than among the 178 patients with HER-2/neunegative tumors (median progression-free survival = 10.3 months, 95% CI = 7.6 to 11.7 months) (P = .020). In addition, statistically significantly shorter overall survival was observed among the 97 patients with HER-2/neupositive tumors (median overall survival = 19.0 months, 95% CI = 15.1 to 22.1 months) than among the 178 patients with HER-2/neunegative tumors (28.4 months, 95% CI = 20.9 to 35.2 months) (P = .023).
We next investigated the association between HER-2/neu status and treatment outcome separately for patients treated with EC and for patients treated with ET. Among those treated with EC, patients with HER-2/neupositive tumors and HER-2/neunegative tumors had comparable objective response rates (46% [95% CI = 32% to 60%] versus 33% [95% CI = 22% to 43%]; P = .130; Fig. 1). However, patients with HER-2/neupositive tumors had statistically significantly shorter progression-free survival (median progression-free survival = 7.1 months, 95% CI = 4.1 to 9.3 months) than patients with HER-2/neunegative tumors (median progression-free survival = 10.4 months, 95% CI = 6.9 to 14.9 months) (P = .010) (Fig. 2, A). Likewise, patients with HER-2/neupositive tumors had statistically significantly shorter overall survival (median overall survival = 16.4 months, 95% CI = 12.1 to 20.1 months) than patients with HER-2/neunegative tumors (median overall survival = 33.1 months, 95% CI = 20.9 to 50.6 months) (P = .010) (Fig. 2, C).
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Association Between HER-2/neu Status and Response to Paclitaxel
The central hypothesis tested in the present study was whether the ET regimen is more effective than the EC regimen among patients with HER-2/neupositive tumors than in patients with HER-2/neunegative tumors. We found that the objective response rate associated with the ET regimen was better than that associated with the EC regimen among patients with HER-2/neupositive tumors (76% [95% CI = 63% to 88%] versus 46% [95% CI = 32% to 60%]; P = .004) and among patients with HER-2/neunegative tumors (50% [95% CI = 39% to 61%] versus 33% [95% CI = 22% to 43%]; P = .002; Fig. 1). The difference in objective response rates associated with the ET and EC regimens, however, was greater for patients with HER-2/neupositive tumors (adjusted OR = 3.64, 95% CI = 1.48 to 8.92; P = .005) than for patients with HER-2/neunegative tumors (adjusted OR = 1.92, 95% CI = 1.01 to 3.64; P = .046) (Table 4).
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DISCUSSION |
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Although patients with HER-2/neupositive tumors have a poor prognosis, our results underscore the fact that HER-2/neu amplification is not an intrinsic marker of chemoresistance to either the EC regimen or the ET regimen. When response rates of patients with HER-2/neupositive and patients with HER-2/neunegative tumors were compared separately by treatment arm, chemotherapeutic sensitivity in patients with HER-2/neupositive tumors, compared with patients with HER-2/neunegative tumors, appeared to be particularly pronounced after treatment with the ET regimen. Among patients treated with the ET regimen, but not among those treated with the EC regimen, HER-2/neu amplification was statistically significantly associated with improved response rates. These findings support the following two hypotheses: 1) that a HER-2/neupositive status does not appear to confer unique clinical chemoresistance to the EC or ET regimen and 2) that patients with HER-2/neupositive tumors might be particularly sensitive to the paclitaxel-containing regimen.
For further validation, we compared the outcomes after treatment with the ET regimen and after the EC regimen separately in patients with HER-2/neupositive tumors and in patients with HER-2/neunegative tumors. In patients with HER-2/neupositive tumors, substitution of paclitaxel for cyclophosphamide resulted in a statistically significantly increased objective response rate (adjusted OR = 3.64, 95% CI = 1.48 to 8.92; P = .005), which was more pronounced than the increase observed in HER-2/neunegative patients (adjusted OR = 1.92, 95% CI = 1.01 to 3.64; P = .046). We also found evidence for better progression-free survival and better overall survival after treatment with the ET regimen than after treatment with the EC regimen in patients with HER-2/neupositive tumors than in patients with HER-2/neunegative tumors. Although these differences in progression-free survival and overall survival did not reach statistical significance, they may be clinically meaningful because the relative risk for disease progression associated with the ET regimen, compared with that of the EC regimen, was reduced by 35% (adjusted RR = 0.65, 95% CI = 0.42 to 1.02; P =.062), but not statistically significantly so. However, we believe that this association should be studied further in a larger study with more statistical power. Similar evidence of an improved overall survival after treatment with the ET regimen among patients with HER-2/neupositive tumors was also observed (adjusted RR = 0.60, 95% CI = 0.36 to 1.02; P = .059), which is remarkable in view of the fact that many of the patients had received taxane-based second-line chemotherapy after EC treatment failure. Although we could not confirm a statistically significant interaction between treatment and HER-2/neu status, the data are suggestive for such an interaction for progression-free survival (P = .109) and for overall survival (P = .136). The estimated power for detecting a statistically significant interaction in the present study cohort, however, was only 40% for progression-free survival and 25% for overall survival; thus, this study was not large enough to allow meaningful interaction studies between treatment and HER-2/neu status.
Previous studies reported higher response rates after taxane-based therapies for patients with HER-2/neupositive tumors than for patients with HER-2/neunegative tumors (11,12). However, these earlier studies did not have appropriate control cohorts that would allow separate analyses of taxane-specific treatment effects and of general treatment effects associated with chemotherapy. A more recent study conducted by the Breast Cancer International Research Group (BCIRG) provides more comprehensive data in support of our findings. The BCIRG Study 001, in which 1491 patients with lymph nodepositive primary breast cancer were randomly assigned to an adjuvant chemotherapy regimen of docetaxeldoxorubicincyclophosphamide or a regimen of fluorouracildoxorubicincyclophosphamide, provided an important control group to investigate taxane-specific effects. Results of the first analysis of this study are consistent with our results because they indicate that a better outcome was associated with the docetaxeldoxorubicincyclophosphamide regimen than with the fluorouracildoxorubicincyclophosphamide regimen, especially among patients with HER-2/neupositive tumors (for disease-free survival, hazard ratio [HR] = 0.60; P = .009) compared with patients with HER-2/neunegative tumors (for disease-free survival, HR = 0.76; P = .046) (21).
Experimental results regarding HER-2/neu overexpression and the response to taxane-based regimens are contradictory, with some investigators reporting unique resistance to such regimens (22,23) and others reporting the lack of such resistance (17). In a previous study investigating the association of HER-2/neu overexpression with taxane sensitivity, we stably transfected six human breast and ovarian cancer cell lines with a full-length human HER-2/neu cDNA (17) to directly compare drug sensitivity in parent and daughter cells that differed genetically because one member of the pair overexpressed the human HER-2/neu gene. In three of six human breast or ovarian cancer cell lines, HER-2/neu overexpression resulted in a statistically significantly increased sensitivity toward paclitaxel; this result led us to conclude that HER-2/neu overexpression was most likely not associated with in vitro resistance to paclitaxel (17).
Previous results indicated an interaction between HER-2/neu overexpression and the dose of an anthracycline-based combination chemotherapy (24), in which a statistically significantly better outcome was found for patients with HER-2/neupositive primary breast cancer treated with standard doses of fluorouracildoxorubicincyclophosphamide than for patients treated with lower doses of these drugs. In our study, however, the ET and EC regimens were given at standard doses, indicating that the observed treatment outcomes most likely did not result from an interaction between HER-2/neu amplification and the dose level of chemotherapeutic agents.
Because preceding adjuvant chemotherapy reduces the response to first-line chemotherapy, it is noteworthy that patients with HER-2/neupositive tumors (who received more adjuvant chemotherapy than patients with HER-2/neunegative tumors) still responded better than patients with HER-2/neunegative tumors to first-line chemotherapy for metastatic breast cancer. However, exposure to an anthracycline-based adjuvant chemotherapy might increase sensitivity of metastatic cancer to a noncross-resistant taxane-containing regimen and lead to a better response to the ET regimen than to the EC regimen. Nevertheless, the independence of the observed treatment effects from other potentially confounding variables in multivariable analysis (such as a negative estrogen receptor status, localization and number of metastatic sites, or the prior application of adjuvant chemotherapy) does strengthen our hypothesis that HER-2/neu amplification might be associated with increased response to taxane-based first-line chemotherapy.
The results of the present study, nonetheless, should be interpreted cautiously because the study was based on a retrospective subgroup analysis whose objective was not part of the original randomized study. Although our results are not yet useful for determining the best treatment for patients with metastatic breast cancer, they do suggest that there may be an interesting biological question regarding the role of HER-2/neu and response to treatment with a taxane-based regimen. The best way to evaluate the association between treatment and HER-2/neu status would be a prospective controlled study; however, it is unlikely that such a study could be conducted now because chemotherapy alone as a first-line treatment has been replaced with a combination of chemotherapy and trastuzumab, which is associated with a statistically significant survival advantage for patients with HER-2/neupositive metastatic breast cancer (25). Therefore, confirmatory studies including sufficiently powered retrospective analysis are needed and would be of great interest to those for whom the efficacy of taxane-based regimens is currently a matter of debate.
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NOTES |
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Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 1215, 2001
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REFERENCES |
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Manuscript received January 7, 2004; revised May 19, 2004; accepted May 20, 2004.
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