HER2 and Choice of Adjuvant Chemotherapy for Invasive Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15

Soonmyung Paik, John Bryant, Elizabeth Tan-Chiu, Greg Yothers, Chanheun Park, D. Lawrence Wickerham, Norman Wolmark

Affiliations of authors: S. Paik, C. Park, Division of Pathology, National Surgical Adjuvant Breast and Bowel Project (NSABP), Allegheny General Hospital, Pittsburgh, PA; J. Bryant, NSABP and Departments of Statistics and Biostatistics, University of Pittsburgh; E. Tan-Chiu, D. L. Wickerham, N. Wolmark, NSABP Operations Center, Pittsburgh; G. Yothers, NSABP and Department of Statistics, University of Pittsburgh.

Correspondence to: Soonmyung Paik, M.D., Division of Pathology, National Surgical Adjuvant Breast and Bowel Project, East Commons Professional Bldg., Four Allegheny Center–5th Floor, Pittsburgh, PA 15212–5234 (e-mail: soon.paik{at}nsabp.org).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: Recent retrospective analyses have suggested that breast cancer patients whose tumors overexpress HER2 derive preferential benefit from treatment with anthracyclines such as doxorubicin. This has led some clinicians to propose that HER2 should be used as a predictive marker in choosing between anthracycline-based regimens and combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). We evaluated this recommendation in a retrospective study of National Surgical Adjuvant Breast and Bowel Project Protocol B-15, in which patients received a combination of doxorubicin and cyclophosphamide (AC), CMF, or AC followed by CMF. We hypothesized that AC would be superior to CMF only in the HER2-positive patients. Methods: Immunohistochemical detection of HER2 was performed on tumor sections from 2034 of 2295 eligible patients. We used statistical analysis to evaluate the interaction between the efficacy of the assigned treatments and HER2 overexpression. All statistical tests were two-sided. Results: Tumor sections from 599 patients (29%) stained positive for HER2. AC was superior to CMF in HER2-positive patients only, although differences in outcomes did not reach statistical significance. In the HER2-positive cohort, relative risks of failure (i.e., after AC treatment as compared with CMF treatment) were 0.84 for disease-free survival (DFS) (95% confidence interval [CI] = 0.65–1.07; P = .15), 0.82 for survival (95% CI = 0.63–1.06; P = .14), and 0.80 for recurrence-free survival (RFS) (95% CI = 0.62–1.04; P = .10). Tests for interaction between treatment and HER2 status were suggestive but not statistically significant (P = .19 for DFS, P = .11 for survival, and P = .08 for RFS). Conclusions: These results, together with overview results indicating minor overall superiority for anthracycline-based regimens relative to CMF, indicate a preference for the AC regimen in patients with HER2-positive tumors. Both AC and CMF regimens may be considered for patients with HER2-negative tumors.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
During the past 15 years, chemotherapy regimens that combine either doxorubicin and cyclophosphamide (AC) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have become widely accepted standard adjuvant treatments for early-stage invasive breast cancer (1). Controlled clinical trials directly comparing these or similar regimens either have failed to demonstrate a difference in effectiveness between the two treatment regimens or, in some cases, have reported results in favor of the anthracycline regimen (2,3). An Early Breast Cancer Trialists' Collaborative Group (2) meta-analysis of randomized clinical trials of adjuvant polychemotherapy reported a small but statistically significant benefit from anthracycline-based regimens compared with CMF regimens, with an estimated 3.2% absolute disease-free survival (DFS) benefit (P = .006) and a 2.7% absolute survival benefit (P = .02) at 5 years after randomization. Nevertheless, the CMF regimen continues to be widely used; in a recent review of practice patterns of oncologists in the United States (4), 45.7% of 5819 cases were treated with CMF. The choice between AC and CMF is often made on the basis of the different toxicity profiles of the two regimens or on the basis of treatment duration (4).

Since selection between the two regimens has been based largely on differences in toxicity or ease of administration rather than on relative efficacy, markers that predict response or resistance to these regimens would be useful in clinical practice. Recently, some clinicians (57) have advocated use of HER2 (erbB-2) overexpression as such a predictive marker. This choice is based, in part, on data from retrospective analyses of two adjuvant studies: Cancer and Leukemia Group B (CALGB) 8869 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-11. Data from these studies suggest that patients whose tumors overexpress HER2 may derive a preferential benefit from treatment with doxorubicin (810). In addition, at least one report (11) indicates that HER2-overexpressing patients may be relatively resistant to treatment with CMF. However, recent reports (12,13) comparing the efficacy of CMF relative to observation in HER2-positive and HER2-negative patients have not supported this finding.

In this article, we report the results of a retrospective analysis of HER2-positive and HER2-negative patients enrolled in NSABP protocol B-15, an adjuvant study that compared the efficacy of four cycles of AC therapy with that of six cycles of CMF therapy. The findings from this trial, which were first reported in 1990 (3), indicated that the two treatments were not demonstrably different in terms of overall efficacy. On the basis of the results from CALGB 8869 and NSABP B-11 cited above, we hypothesized that the AC regimen might improve outcomes relative to CMF among the HER2-positive patients but not among those patients whose tumors did not overexpress HER2. In contrast to the B-11 study, in which the experimental arm differed from the control arm only by the addition of doxorubicin, the analyses reported here were not intended to serve as a "proof-of-principle" study concerning the existence of HER2–doxorubicin interaction. Rather, these analyses were designed to provide clinically relevant comparisons relating directly to treatment decisions involving two widely used regimens for treating invasive breast cancer.


    SUBJECTS AND METHODS
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Subjects

This study (Institutional Review Board approval number RC-2136) was conducted with the approval from the Institutional Review Board of Allegheny General Hospital, Pittsburgh, PA, where the NSABP Pathology Section Laboratory is located. We examined primary tumor specimens from patients enrolled in NSABP protocol B-15. In this trial, patients with operable breast cancer were randomly assigned to receive adjuvant therapy consisting of either AC, CMF, or AC followed by interval reinduction with CMF (3). Total accrual to the trial from October 1, 1984, to October 14, 1988, was 2338 patients, 2295 of whom were eligible with follow-up. Informed written consent for participation in protocol B-15 was obtained from all patients.

Patient population. Patients were required to have at least one histologically positive axillary lymph node and to be no older than 49 years at the time of surgery or no older than 59 years with negative progesterone receptor (PgR) status (<10 fmol/mg cytosol protein). Randomization was stratified by lymph node status (1–3, 4–9, or >=10 positive lymph nodes), by PgR status (<10 or >=10 fmol/mg), and by type of surgery (lumpectomy or mastectomy).

Treatment regimens. Patients were randomly assigned to receive either AC (doxorubicin [Adriamycin] at a dose of 60 mg/m2 intravenously [IV] and cyclophosphamide at a dose of 600 mg/m2 IV every 21 days for four cycles), conventional CMF (cyclophosphamide at a dose of 100 mg/m2 orally on days 1–14 every 28 days for six cycles, methotrexate at a dose of 40 mg/m2 IV on days 1 and 8 every 28 days for six cycles, and 5-fluorouracil at a dose of 600 mg/m2 IV on days 1 and 8 every 28 days for six cycles), or AC followed by IV CMF (AC->CMF); 6 months after the last course of AC chemotherapy, patients were given cyclophosphamide at a dose of 750 mg/m2 IV every 28 days for three cycles, methotrexate at a dose of 40 mg/m2 IV on days 1 and 8 every 28 days for three cycles, and 5-fluorouracil at a dose of 600 mg/m2 IV on days 1 and 8 every 28 days for three cycles. The median delivered dose of AC was almost 100% of the full protocol-defined dose. The median delivered dose of conventional CMF was about 90% of the full protocol-defined dose. The use of tamoxifen or other hormonal therapy was prohibited prior to first recurrence or second primary cancer.

Selection of the study subset. Hematoxylin–eosin (H & E)-stained sections that had been collected as part of the quality-assurance program for B-15 were used for this study. A total of 2034 (89%) of 2295 eligible patients were available for the HER2 assay. In the remaining 261 cases, the assay could not be performed because the accruing institution failed to submit appropriate slides or the submitted slides lacked sections containing invasive tumor.

The primary purpose of this study was to determine whether the assessment of HER2 status is useful in selecting between the use of AC or CMF chemotherapy. Therefore, the 1355 eligible patients having assay results in these two treatment arms comprised the study subset for the primary analysis, which determined the degree to which the efficacy of AC relative to that of CMF was modulated by HER2 overexpression (treatment-by-HER2 interaction). In secondary analyses, the clinical outcomes of the 679 patients assigned to the AC->CMF arm were also assessed for purposes of comparison. The entire population of assayed cases (n = 2034) was used to ascertain the degree to which HER2 status was correlated with patient and tumor characteristics.

Immunohistochemistry for HER2

All immunohistochemical analyses were performed at the NSABP Pathology Section Laboratory. The HER2 antigen was detected by use of a mixture of the monoclonal mouse antibody TAB250/MAb-1 at a 1 : 40 dilution and the polyclonal rabbit anti-c-erbB-2 antibody pAb-1 at a 1 : 150 dilution (both obtained from Zymed Laboratories Inc., South San Francisco, CA) by use of an Optimax 1.5 automated immunostainer (BioGenex Laboratories, San Ramon, CA) as described previously (8). Slides were incubated with primary antibodies for 14–18 hours at 7 °C. The rest of the procedure was performed at room temperature.

Data Analysis and Statistical Methods

Scoring HER2 expression. Slides were scored as positive for HER2 overexpression if any tumor cell showed definite membrane staining, resulting in a so-called fishnet appearance. Slides were scored as negative for HER2 overexpression if cells displayed ambiguous staining with cytoplasmic background or if the noninvasive carcinoma components stained positive but the invasive component did not. All slides were scored by one of the authors (S. Paik), who was blinded to both treatment assignment and clinical outcome.

Patient outcome endpoints. The role of HER2 as a predictor of treatment effect was investigated with respect to three endpoints: survival, DFS, and recurrence-free survival (RFS). Survival was defined as time from surgery to death from any cause. DFS was defined as the time from surgery until the recurrence of breast cancer, the occurrence of contralateral breast cancer or other second primary cancer, or death without any evidence of disease. RFS was defined as the time from surgery to the first local, regional, or distant tumor recurrence, with second primary cancers, contralateral breast cancer, and deaths without evidence of disease being treated as censoring events. RFS was included in this analysis because it may be a more biologically relevant endpoint than DFS for assessing the efficacy of chemotherapy on the index tumor.

Inclusion of data. All reported analyses were based on the cohort of eligible patients for which HER2 assay data were available (n = 2034). Patients were analyzed according to their randomly assigned treatment group. The findings presented in this article are based on follow-up information received as of March 31, 1999, at which point the average time on study was 12.4 years. Ten-year DFS status is known for 1908 (94%) of the 2034 patients; i.e., 1908 patients are known to have had an event prior to 10 years or have been followed event free for at least 10 years.

Association of HER2 overexpression with other patient characteristics. The frequency of HER2 overexpression was associated with the following patient and tumor characteristics: age at surgery (<=39, 40–49, or >=50 years), self-reported menopausal status (premenopausal or perimenopausal versus postmenopausal), clinical tumor size (<=2.0, 2.1–4.0, or >=4.1 cm), pathologic lymph node status (1–3, 4–9, or >=10), and estrogen receptor and PgR status (<10 fmol/mg versus >=10 fmol/mg cytosolic protein). The association of HER2 overexpression with each of these covariates was tested individually by use of the chi-square test. Logistic regression was used to model the frequency of overexpression with each of these variables simultaneously. All statistical tests were two-sided.

Assessing the role of HER2 as a predictive marker of response to therapy. Because the primary purpose of this study was to determine whether the effectiveness of AC relative to CMF differed on the basis of HER2 overexpression, the primary analysis of HER2 expression as a predictive marker was restricted to these two treatment arms. We used the Kaplan–Meier method to estimate curves for survival, DFS, and RFS for HER2-negative and HER2-positive patients who had received the AC and CMF treatment regimens. We estimated treatment relative risks (RRs) and tested treatments for equality within the HER2-negative and HER2-positive cohorts by Cox proportional hazards regression analysis. HER2-negative and HER2-positive cohorts were examined with regard to differences in the magnitude of treatment effect on patient outcome by comparing survival curves, RRs, and P values. The treatment RRs for patients whose tumors were HER2 negative and for those whose tumors were HER2 positive were tested for equality by adding an interaction term to a Cox proportional hazards model and by testing its significance by use of the Wald test. Treatment RRs were estimated and tested for equality both before and after adjusting for other patient characteristics that were prognostic for outcome, including patient age at surgery, clinical tumor size, number of pathologically positive lymph nodes, and estrogen receptor and PgR status. All statistical tests were two-sided.

Although the basic aim of the study dictated a comparison of the AC and CMF arms separately for the HER2-negative and HER2-positive patient populations, as a secondary analysis, we also determined survival, DFS, and RFS by HER2 status for patients assigned to receive AC->CMF to compare their outcomes with those of the patients in the other two arms.


    RESULTS
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Characteristics of the Study Cohort

Characteristics of the cohort of eligible patients for which HER2 assays were available (n = 2034) are shown in Table 1Go. These Characteristics were well balanced across the three treatment arms.


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Table 1. Patient and tumor characteristics: eligible patients with follow-up and HER2 assay
 
Association of HER2 Overexpression With Other Patient and Tumor Characteristics

Tumor sections from 599 patients (29% of 2034) scored positive for HER2 overexpression. This proportion of overexpression was well balanced across the three treatment arms (Table 1Go). Four patients showed strong positive staining in the in situ component but not in the invasive component. These patients were scored as negative for HER2 overexpression. Sections of lymph node metastases from these patients also stained negative.

The association of HER2 overexpression with age at surgery, menopausal status, clinical tumor size, pathologic lymph node status, and estrogen receptor and PgR status is summarized in Table 2Go. On a univariate basis, older age (P<.001), postmenopausal status (P = .005), larger tumor size (P = .003), and number of positive lymph nodes (P = .004) were positively associated with HER2 overexpression, whereas estrogen receptor expression and PgR expression were negatively associated with HER2 overexpression (P<.001 for both) . The univariate association of HER2 overexpression with older age at surgery and postmenopausal status is an artifact created by the protocol eligibility criteria, which required that older women (aged 50–59 years) could be accrued to the study only if they were PgR negative (<10 fmol/mg). When logistic regression was used to simultaneously control for multiple patient and tumor characteristics, age at surgery (P = .92) and menopausal status (P = .32) became statistically nonsignificant. In contrast, PgR status (P<.001), estrogen receptor status (P = .02), tumor size (P = .039), and number of positive lymph nodes (P = .044) remained statistically significantly associated with HER2 overexpression.


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Table 2. Association of patient and tumor characteristics with HER2 overexpression in eligible patients with follow-up*
 
HER2 as a Predictor of Response to Doxorubicin

We compared the outcomes of the 1355 patients in the AC and CMF treatment arms of protocol B-15 separately within the HER2-negative (n = 951) and HER2-positive (n = 404) cohorts. Fig. 1Go shows Kaplan–Meier plots for DFS, survival, and RFS, while Table 3Go summarizes estimates of 2-, 5-, and 10-year DFS, survival, and RFS by treatment arm and HER2 status. For each HER2 cohort, treatment RRs were estimated by fitting Cox proportional hazards models, and treatments were tested for equality. The results of these analyses are shown in Table 4Go and Fig. 2Go. To assess whether the modulation of the doxorubicin effect by HER2 was independent of other variables, Table 4Go includes RRs that were estimated before and after adjusting for age at surgery, clinical tumor size, pathologic lymph node status, and estrogen receptor and PgR status (Cox model). Adjusted and unadjusted RRs were similar; in the text below, we will refer to the adjusted estimates.



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Fig. 1. Kaplan–Meier plots for doxorubicin and cyclophosphamide (AC) and cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) treatment arms in HER2-negative and HER2-positive cohorts. Disease-free survival (DFS; top panel), survival (middle panel), and recurrence-free survival (RFS; bottom panel) are estimated by the Kaplan–Meier method for patients whose tumors are HER2 negative and for patients whose tumors overexpress HER2. Bars indicate individual 95% confidence intervals at selected time points. Relative risk (RR) of failure and P values shown on each plot are adjusted (by use of the Cox model) for a patient's age at surgery, clinical tumor size, pathologic lymph node status, estrogen receptor status, and progesterone receptor status. All P values are two-sided.

 

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Table 3. Number of events and clinical outcome estimates according to HER2 status and treatment arm (AC versus CMF)*
 

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Table 4. Risks to patients treated with AC relative to those treated with CMF by HER2 status*
 


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Fig. 2. Risks to patients treated with doxorubicin and cyclophosphamide (AC) relative to risks of patients treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) according to HER2 status (positive [pos] and negative [neg]). Relative risks of failure and P values shown for each plot are adjusted (by use of the Cox model) for a patient's age at surgery, clinical tumor size, pathologic lymph node status, estrogen receptor status, and progesterone receptor status. Bars indicate 95% confidence intervals. All P values are two-sided. DFS = disease-free survival; RFS = recurrence-free survival; OS = overall survival.

 
In HER2-negative patients, there was little indication that either treatment is superior to the other. There was little separation between the Kaplan–Meier curves for any of the three outcome end points (Fig. 1Go). Absolute differences in DFS, survival, and RFS at a follow-up of 10 years were approximately 1%–2%, favoring the CMF treatment arm. These treatment differences did not approach statistical significance for any of the three end points (Table 4Go). The RRs for DFS, survival, and RFS were 1.02 (95% confidence interval [CI] = 0.86–1.20; P = .84), 1.07 (95% CI = 0.88–1.30; P = .51), and 1.07 (95% CI = 0.89–1.28; P = .47), respectively. Since we defined RR as the failure rate following treatment with AC divided by the failure rate following treatment with CMF, RRs greater than 1 favor the CMF treatment regimen, while those less than 1 favor the AC regimen. In contrast, for HER2-positive patients, there was more of a trend toward superiority for AC, although again the differences did not achieve statistical significance for any of the three end points (Fig. 1Go). For this cohort, RRs for DFS, survival, and RFS were 0.84 (95% CI = 0.65–1.07; P = .15), 0.82 (95% CI = 0.63–1.06; P = .14), and 0.80 (95% CI = 0.62–1.04; P = .10), respectively (Table 4Go). Absolute differences in DFS, survival, and RFS at a follow-up of 10 years were approximately 4%–6% and favored the AC treatment arm.

The central hypothesis of this investigation was that AC would be more efficacious relative to CMF in the HER2-positive patients than in the HER2-negative patients, i.e., that treatment effect (AC versus CMF) would interact with HER2 status (negative versus positive). Qualitatively, our data are consistent with this hypothesis because, for each endpoint that we investigated, the RR (AC versus CMF) in the HER2-negative cohort exceeded 1, while in the HER2-positive cohort, it was less than 1. However, statistical tests for the equality of the treatment RRs associated with HER2-negative and HER2-positive patients were not statistically significant for DFS (P = .19), survival (P = .11), or RFS (P = .08). Thus, these results are consistent with previous observations demonstrating a preferential benefit for doxorubicin-based regimens or doxorubicin intensification in HER2-positive patients (810) but are not in isolation sufficient to demonstrate such an interaction.

DFS, survival, and RFS curves were also computed for HER2-negative (n = 484) and HER2-positive (n = 195) patients who were randomly assigned to the AC->CMF reinduction arm. For all three endpoints, results in both patient cohorts in this treatment arm were similar to those seen in the AC-only arm. Fig. 3Go illustrates this similarity for the DFS end point.



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Fig. 3. Kaplan–Meier plots for doxorubicin and cyclophosphamide (AC), cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and AC followed by CMF (AC->CMF) treatment arms in HER2-negative and HER2-positive cohorts. Disease-free survival (DFS) is estimated by the Kaplan–Meier method for patients whose tumors are HER2 negative and for patients whose tumors overexpress HER2. Bars indicate individual 95% confidence intervals at selected time points.

 

    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
During the past decade, investigations regarding the role of HER2 as a predictor of response to chemotherapy have taken two directions that are directly relevant to examining the potential worth of HER2 overexpression in choosing between an anthracycline-based regimen or CMF. The first line of investigation relates to the role of HER2 as a predictor of response to doxorubicin, while the second line has assessed the degree to which HER2 overexpression is associated with resistance to CMF.

In the adjuvant setting, the first indication that HER2 overexpression may be associated with improved response to anthracyclines was based on data from CALGB 8869, a study that investigated dose escalation of the cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) combination. In both the original study and the subsequent confirmatory study, benefit from the highest dose of CAF was confined to the HER2-positive cohort (9,10). However, the question of whether there is a specific interaction between the efficacy of doxorubicin and HER2 overexpression could not be definitively addressed in this study because all three drugs were dose intensified. NSABP protocol B-11 provided the opportunity for a more direct test of the interaction hypothesis because patients in that study were randomly assigned to receive either a combination of L-phenylalanine mustard and 5-fluorouracil (PF) or a combination of L-phenylalanine mustard, 5-fluorouracil, and doxorubicin (PAF) (8). Thus, the two arms of this study differed only in the administration of doxorubicin. When the tumor tissues of 638 of the 682 eligible patients in NSABP B-11 were assayed for HER2 expression, it was observed that those patients who overexpressed HER2 and who were treated with PAF experienced a 40% reduction in failure rate (RR = 0.60; 95% CI = 0.44–0.83; P = .001) and a 34% decrease in mortality (RR = 0.66; 95% CI = 0.47–0.92; P = .01) relative to those patients who received PF. However, no statistically significant difference in treatment effectiveness (PAF versus PF) was demonstrated among those patients who did not overexpress HER2 (RR = 0.96 for DFS [95% CI = 0.75–1.23; P = .74] and RR = 0.90 for survival [95% CI = 0.69–1.19; P = .47]). Formal tests of the interaction hypothesis were statistically significant for DFS (P = .02) but only suggestive for survival (P = .15).

Results from studies testing the interaction between HER2 status and response to CMF are less clear. According to a retrospective analysis (11) of data from International Breast Cancer Study Group (IBCSG) trial V, the benefit from CMF over a single course of CMF perioperative therapy was more pronounced in HER2-negative patients than in HER2-positive patients. Although these data have been frequently cited as evidence for resistance to CMF among HER2-positive patients, there was a trend for benefit of CMF even within the HER2-positive cohort (RR = 0.77 for DFS), although to a lesser degree compared with the HER2-negative cohort (RR = 0.57 for DFS). The authors of that study did not report a statistical test for interaction. On the other hand, Miles et al. (12) reported a clear trend for benefit from CMF regardless of HER2 status in a retrospective analysis of 274 lymph node-positive patients enrolled in the Guy's/Manchester Trial comparing 12 months of CMF with observation, with no evidence of treatment-by-HER2 interaction. Similarly, in an analysis of 337 patients enrolled in the first Milan trial comparing 12 months of CMF with observation, Menard et al. (13) reported a trend for even greater benefit in the HER2-positive cohort (RR = 0.484 for DFS; 95% CI = 0.283–0.827) than in the HER2-negative cohort (RR = 0.641 for DFS; 95% CI = 0.481–0.853). Therefore, there is evidence that HER2-positive patients derive a significant clinical benefit from the CMF regimen compared with no treatment.

In this article, we have described the results of an analysis of patients enrolled in NSABP trial B-15 that directly examined the worth of HER2 as a potential tool to choose between the AC and CMF regimens, both of which have been considered as standard treatment in North America. In this study, immunohistochemistry for HER2 was performed on H & E-stained tumor sections from 2034 (89%) of 2295 eligible patients from B-15. Therefore, the study cohort was representative of the original study population enrolled in B-15. The general trends seen in the data were consistent with the study hypothesis derived from the NSABP B-11 and CALGB 8869 trials, in that HER2-positive patients who were treated with the AC regimen had better outcomes than those who were treated with CMF, while among HER2-negative patients, there was no indication that the AC regimen was superior and, in fact, was marginally worse. These trends did not achieve statistical significance, either in terms of tests of interaction or within-cohort tests of treatment effect, and, therefore, do not stand as an independent confirmation of the hypothesis that HER2 status is a predictive marker of relative efficacy of AC versus CMF regimens. While these results demonstrate that HER2 overexpression is not an ideal marker for differentiating the use of these therapies, the magnitude of the observed treatment differences may nevertheless be of clinical relevance, at least in the HER2-positive cohort, in which a 16% reduction in failure rate (RR = 0.84 for DFS; 95% CI = 0.69–1.12; P = .15) and an 18% reduction in mortality (RR = 0.82 for survival; 95% CI = 0.63–1.06; P = .14) were noted, translating to roughly a 4% improvement in DFS and a 6% improvement in survival at 10 years.

When viewed in the context of previous literature, there are three reasons for our believing that the best interpretation of our data is that anthracycline-based regimens are generally preferred in HER2-positive patients. First, meta-analyses compiled by the Early Breast Cancer Trialists' Collaborative Group have indicated a small but statistically significant overall advantage, consisting of a 3% absolute improvement in survival and DFS at 5 years, for anthracycline-based regimens relative to CMF. Second, two previous studies (CALGB 8869 and NSABP B-11) demonstrated statistically significant interactions by testing for the preferential benefit of doxorubicin in HER2-positive patients. Third, the pattern evidenced in the NSABP B-15 data is completely consistent with previously reported trends, even if not statistically significant.

In a secondary analysis, we also found that the clinical outcomes (DFS, survival, and RFS) of patients assigned to the AC->CMF arm of protocol B-15 were indistinguishable from those of patients who had received AC alone, regardless of their HER2 status (Fig. 3Go). These results are also consistent with the hypothesis that treatment with an anthracycline-based regimen is preferred for HER2-positive patients.

In protocol B-11, two dissimilar explanations have been proposed to explain the phenomenon of preferential benefit from PAF over PF in HER2-positive patients (8). According to the first explanation, the interaction of treatment and HER2 status may be secondary to a selective sensitivity to doxorubicin in the HER2-positive cohort. Alternatively, the interaction could be because of a general resistance to chemotherapy that is overcome by use of the more dose-intense regimen, PAF. If the latter explanation is the case, then in the current B-15 analysis, the benefit of AC over CMF for HER2-positive patients (RR = 0.84 for DFS), in contrast to the more dramatic benefit of PAF over PF observed in B-11 (RR = 0.60 for DFS), may be due to the possibility that CMF is a more "treatment-intense" regimen than PF. Likewise, the discrepant results of IBCSG trial V and two subsequent studies looking at the CMF response could be explained by the differences in the cumulative dose and duration of the CMF regimens used, i.e., six cycles versus 12 cycles (1113). This hypothesis of a HER2-treatment intensity interaction predicts that benefit from further intensification by the addition of paclitaxel (Taxol) to AC will also be restricted to the HER2-positive cohort. The recently completed intergroup (CALGB 9834) and NSABP B-28 trials should provide valuable materials to test this hypothesis.

Whereas CMF is not an inactive regimen regardless of HER2 status, the results presented in this article suggest a preferential benefit from the AC regimen relative to CMF in HER2-positive patients, particularly in view of the overview results and results from NSABP B-11 and CALGB 8869. They further suggest that both AC and CMF regimens may be considered for patients with HER2-negative tumors.


    NOTES
 
Supported by Public Health Service grants U10CA12027, U10CA69651, U10CA37377, and U10CA69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human.

We thank William King and Lamar Eaton for their technical assistance and database management and Christine Ruddock for her graphics.


    REFERENCES
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 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

1 The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Adjuvant systemic therapy for women with node-positive breast cancer. CMAJ 1998;158(Suppl 3):S52–64.[Medline]

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Manuscript received April 13, 2000; revised October 2, 2000; accepted October 5, 2000.


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