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HER-2/neu and p53 Expression Versus Tamoxifen Resistance in Estrogen Receptor–Positive, Node-Positive Breast Cancer

From The University of Texas M.D. Anderson Cancer Center, Houston, TX; Statistical Office, Cancer and Leukemia Group B, Duke University, Durham; University of North Carolina, Chapel Hill, NC; Vermont Cancer Center, Burlington, VT; Evanston Hospital, Evanston, IL; Division of Clinical Sciences, National Cancer Institute, and Georgetown University Medical Center, Washington, DC; North Shore University Hospital, Manhasset; Roswell Park Cancer Center, Buffalo; Memorial Sloan-Kettering Cancer Center, New York, NY; and University of California at San Francisco, San Francisco, CA.

Address reprint requests to Donald A. Berry, PhD, Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 213, Houston, TX 77030; email dberry{at}odin.mdacc.tmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: An association between the overexpression of proto-oncogene HER-2/neu and resistance to tamoxifen in estrogen receptor (ER)–positive primary and metastatic breast cancer has been suggested. We examine a possible interaction between HER-2/neu or p53 expression and tamoxifen effectiveness in patients with ER-positive, node-positive disease treated with cyclophosphamide, doxorubicin, and fluorouracil in a large adjuvant chemotherapy trial (Cancer and Leukemia Group B [CALGB] 8541). Tamoxifen assignment was not randomized—physician discretion was used for premenopausal and postmenopausal women. Trial protocol then specified assignment to postmenopausal women with ER-positive tumors, although not all took tamoxifen.

PATIENTS AND METHODS: CALGB 8541 assessed HER-2/neu expression in patients with ER-positive disease by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) and amplification by differential polymerase chain reaction (PCR). IHC assessed expression of p53. Univariate and multivariate proportional hazards models assessed tamoxifen–HER-2/neu status interactions and tamoxifen-p53 status interactions.

RESULTS: HER-2/neu status was available for 651 patients with ER-positive disease; 650, 608, and 353 patients were assessed by IHC, PCR, and FISH, respectively. Approximately one half received tamoxifen. Reduction in risk of disease recurrence or death resulting from tamoxifen was approximately 37% (32% with overexpression and 39% with normal expression of HER-2/neu; n = 155 by IHC). The tamoxifen–HER-2/neu status interaction was not significant in multivariate analysis of all three HER-2/neu assessment methods. Tamoxifen-p53 interaction did not significantly predict outcome.

CONCLUSION: Disease-free and overall survival benefit of tamoxifen in patients with ER-positive, node-positive breast cancer does not depend on HER-2/neu or p53 status. Our data suggest that neither HER-2/neu nor p53 expression should be used to determine assignment of tamoxifen.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE PROTO-ONCOGENE HER-2/neu (erbB-2) encodes a 185-kd transmembrane glycoprotein and is a member of the epidermal growth factor receptor family.¹ Amplification or overexpression has been reported in 10% to 40% of primary breast cancers. Preclinical studies have suggested that estrogen-dependent cultured human breast cancer cell lines are rendered hormone independent after transfection with multiple copies of the stably expressed HER-2/neu gene.^1-4 Retrospective metastatic and adjuvant clinical studies in estrogen receptor (ER)–positive breast cancers have addressed this issue. Some have suggested that HER-2/neu overexpression is associated with hormone resistance,^5-13 whereas others have found no such association.^14-16

Elledge et al¹⁶ suggest that earlier findings of association may result from failure to rigorously exclude ER-negative tumors, which are unlikely to respond to tamoxifen and which are more likely to overexpress HER-2/neu. Other explanations are possible.¹⁷ The differing conclusions may also result from the method of assessing overexpression: different antibodies and different laboratory procedures are used, and some investigators have quantified circulating extracellular domain of HER-2/neu in patients’ serum. Perhaps most importantly, many of these studies were small, especially considering that patients whose tumors overexpressed HER-2/neu have been in the minority.

The issue is of clinical importance. If tamoxifen has no impact on tumors that overexpress HER-2/neu, then these patients could be spared its use.

We undertook the present study to assess the role of HER-2/neu expression in mitigating the effectiveness of tamoxifen in primary breast cancer, particularly in ER-positive, node-positive disease. The Cancer and Leukemia Group B (CALGB) Protocol 8541 was a randomized trial^18,19 that addressed the effectiveness of increasing dose and dose-intensity of cyclophosphamide, doxorubicin, and fluorouracil (CAF) in women with primary node-positive breast cancer. Patient accrual occurred from 1985 to 1991. The trial was conducted at 28 main member CALGB institutions and their affiliates in the United States and Canada. The trial had three treatment arms, each with a different dosing schedule: high dose was 600/60/600 mg/m² of C/A/F over four cycles of 28 days each; middle dose was the same total dose as high dose but given over six cycles (400/40/400 mg/m² per cycle); and low dose was one half that of high dose (300/30/300 mg/m²), also given over four cycles. In a companion trial, CALGB 8869, HER-2/neu overexpression showed a dose-response interaction with CAF.^20,21 Namely, patients with tumors that overexpressed HER-2/neu benefited from increased dose-intensity, whereas normal expressors did not. A similar interaction was shown with p53 positivity.²¹

Some of the ER-positive patients in CALGB 8541 received tamoxifen, but others did not. Tamoxifen assignment was not randomized. When the trial was opened, participating clinicians assigned patients to tamoxifen according to their own preferences. At approximately halfway through the accrual period, preliminary announcements from the Early Breast Cancer Collaborative Group²² suggested that tamoxifen improved disease-free survival (DFS) and overall survival (OS) in postmenopausal patients with ER-positive tumors. In 1988, the study protocol was amended to specify that postmenopausal patients with ER-positive tumors should receive tamoxifen therapy. Although not all of these patients received this therapy, the use of tamoxifen in this subset increased over the course of the trial, from 28% in the first third of the patients accrued to 73% in the second third and, then, to 89% in the last third. Also, the proportion of postmenopausal patients in the trial increased from 54% to 55% to 61%, and the proportion of all patients with ER-positive tumors who received tamoxifen increased from 21% to 52% to 63%.

In this investigation, we have addressed the interaction of tamoxifen and HER-2/neu overexpression with outcome. We considered HER-2/neu as assessed by three different laboratories using three different methods: expression by immunohistochemistry (IHC) (author, A.D.T.), fluorescent in situ hybridization (FISH) (author, L.D.), and amplification by differential polymerase chain reaction (PCR) (author, E.L.). Assessments were carried out independently, and technicians were blinded regarding the results of the other methods and the patients’ clinical characteristics and survival. For each method, we assessed whether tamoxifen has a differential effect depending on HER-2/neu status. In view of the likely interaction between the dose of CAF and p53 expression,²¹ we also addressed the interaction of tamoxifen and p53 expression, assessed by IHC (author, A.D.T.).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
The population consisted of patients who were enrolled onto CALGB 8541, whose tumors were ER-positive, and whose tumors had been assessed for HER-2/neu expression by at least one method. Tumor blocks were requested of all patients in the trial, but not all were received by our central pathology office: of the 999 patients in CALGB 8541 whose tumors were ER-positive, we were able to assess HER-2/neu expression for blocks from 651 patients (65%) using at least one method. Clinical characteristics of these patients are presented in Table 1. Patients in the tamoxifen group were those who were assigned to receive tamoxifen by their physicians, but the durations of tamoxifen treatment are unknown.

Assessment of HER-2/neu by FISH
We used the Vysis PathVysion HER-2/neu FISH kit (Vysis, Inc, Downers Grove, IL), which incorporates two directly labeled probes: an orange probe directed against the HER-2/neu gene (17q11.2-q12) and a green probe directed against the pericentromeric region of chromosome 17 (17p11.1-q11.1), the chromosome where the HER-2/neu gene resides. Briefly, following the manufacturer’s instructions, we performed acid pretreatment and protease digestion followed by denaturation with a solution of sodium chloride and sodium citrate (SSC) mixed with formamide (72°C, 5 minutes). After dehydration, the HER-2/neu–CEP17 probe cocktail was added, coverslips were sealed with rubber cement, and slides were incubated in a humidity changer overnight for 18 hours at 37°C. On the following day, slides were washed in stringency buffer (SSC, NP40), dried on a slide warming tray, and incubated with DAPI. Slides were stored in the dark at -20°C. Nonamplified and amplified control slides provided in the PathVysion kit (fixed cell lines, MDA-MB-231, and HS578T, respectively) were run with each assay.

All FISH scoring was performed within 1 week of assay, most within 48 hours. Slides were scored with a Zeiss Axioplan Epifluorescent microscope (Carl Zeiss, Inc, Thornwood, NY) equipped with a 100-W mercury arc lamp, using a multifilter cube supplied by Vysis, Inc, for visualization of DAPI, and orange and green probes. To identify malignant cells for scoring, our study pathologist had previously demarcated the underside of the slide. Sixty nonoverlapping invasive cancer nuclei per case were scored for HER-2/neu (orange) and CEP17 (green) signals. Only cancer nuclei showing at least one orange and one green signal were counted. The ratio of orange (HER-2/neu) to green (chromosome 17 centromere) signals was calculated to normalize amplification of HER-2/neu signal. A case was considered amplified if the ratio was 2.

End Points
The primary end point was DFS. An event was any recurrence of the patient’s primary breast cancer, local or distant, or death resulting from any cause. Second primary cancers, including breast cancers, were not considered events. The secondary end point was OS, for which an event was death resulting from any cause.

Statistical Methods
Comparisons were made of sensitivity, specificity, and overall agreement among the three measures of HER-2/neu. For dichotomized measures, sensitivity and specificity were estimated for FISH assessment in predicting both IHC overexpression and gene amplification by PCR and for IHC in predicting PCR. Kappa statistics (with SEs) were used to quantify the level of agreement within each pair.²³ Population proportions were compared using a ² test.

The principal method of analysis was multivariate Cox proportional hazards regression. Variables considered were (square root of) the number of positive lymph nodes, (square root of) tumor size, dose regimen of CAF, menopausal status, tamoxifen, HER-2/neu status, and interaction of tamoxifen and HER-2/neu. (We took square roots of the number of positive lymph nodes and tumor size because the risk of recurrence associated with these variables is not linear: risk is approximately doubled for a patient who has four positive lymph nodes compared with one who has one positive lymph node, and it is doubled again for a patient having 16 positive lymph nodes.) Our primary focus was on the coefficient of the interaction term and, in particular, whether it was statistically significant (P < .05). A statistically significant interaction term would suggest a differential benefit for tamoxifen depending on the patient’s HER-2/neu status. An interaction term that is not significant would suggest that tamoxifen benefits all ER-positive tumors equally.

To show the degree of interaction between tamoxifen and the expression of HER-2/neu, Kaplan-Meier curves of DFS and OS were plotted for the four relevant subgroups: HER-2/neu–positive tumors with and without tamoxifen and HER-2/neu–negative tumors with and without tamoxifen. Additionally, univariate proportional hazards regression models were carried out separately within the HER-2/neu–positive and HER-2/neu–negative subgroups, and the estimates of the effect of tamoxifen within these two subgroups were compared.

Because of the preferential use of tamoxifen for postmenopausal patients in the trial, we considered postmenopausal patients separately and compared the DFS curves in the four categories of HER-2/neu status and tamoxifen use for this subpopulation. In addition, because of the possibility that a HER-2/neu-by-tamoxifen interaction may have been influenced by dose of CAF chemotherapy, we assessed whether there was an interaction within each dose group.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HER-2/neu status was assessed by IHC, PCR, and FISH for 650, 608, and 353 ER-positive patients from CALGB 8541, respectively. The median duration of follow-up for living ER-positive patients in this trial was 10.5 years. Table 1 shows the characteristics of those patients who received tamoxifen and of those who did not, for each method of assessing HER-2/neu status and also for p53 expression by IHC. The total number of patients considered was 651, with only one patient assessed for HER-2/neu status by FISH and not by IHC.

The three methods of assessing HER-2/neu status are compared in Fig 1. As expected, because both assess amplification, the greatest concordance was between FISH and PCR. The various methods were clearly correlated with each other, but none was strongly correlated with the others.

View larger version (24K): [in this window] [in a new window]   Fig 1. HER-2/neu status of patients with ER-positive tumors. IHC+ means 50% positive cells. Sensitivity is proportion positive by first method based on second method. Specificity is proportion negative by first method based on second method. Kappa measures agreement between methods.19 Abbreviations: Spec, specificity; Sens, sensitivity.

View larger version (39K): [in this window] [in a new window]   Fig 2. Effectiveness of tamoxifen for HER-2/neu–negative and –positive tumors; all ER-positive patients. (a) DFS; assessment by IHC. (b) OS; assessment by IHC. (c) DFS; assessment by PCR. (d) DFS; assessment by FISH. Abbreviation: Tam, tamoxifen.

Among the ER-positive patients under consideration, the proportion of postmenopausal patients in the tamoxifen-treated group was substantially greater than in the group that did not receive tamoxifen (Table 1). Because this was a potential source of bias, we considered postmenopausal patients as a separate group. The survival curves corresponding to Fig 2(a) and (b) for this subgroup are shown in Fig 3 (a) and (b). The qualitative interaction—or lack thereof—was the same in this subgroup as it was in all ER-positive patients.

View larger version (26K): [in this window] [in a new window]   Fig 3. Effectiveness of tamoxifen for HER-2/neu–negative and –positive tumors, restricted to those ER-positive patients who were postmenopausal. (a) DFS; assessment by IHC. (b) OS; assessment by IHC. (These correspond to Fig 2(a) and (b), which includes premenopausal as well as postmenopausal ER-positive patients.)

Table 4 shows the risk reduction in DFS resulting from tamoxifen within the p53-negative and -positive subgroups considered separately. Just as in the case of HER-2/neu, the estimated reductions of risk were nearly the same: 36% in the former and 44% in the latter. Table 5 shows that the risk reduction resulting from tamoxifen was approximately 41% overall when accounting for the covariates shown in the Table. The interaction between p53 positivity and tamoxifen is not significant. The lack of interaction is shown by the survival curves in Fig 4 (a): there was a similar benefit resulting from tamoxifen for both patients with p53-negative and -positive tumors. The conclusions for OS were qualitatively similar to those for DFS, as is evident in Fig 4(b) (modeling results not shown).

View larger version (26K): [in this window] [in a new window]   Fig 4. Effectiveness of tamoxifen for p53-negative and -positive tumors; all ER-positive patients. (a) DFS. (b) OS.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

ER-positive patients in CALGB 8541 received tamoxifen in an arbitrary fashion, in a way that imitates randomness at least to some extent. Attitudes toward tamoxifen varied considerably among oncologists during the time in which patients were accrued to this trial, and these attitudes changed during the accrual period. Few of the patients received tamoxifen if they were admitted early in the trial. On the other hand, most of these same patients would have received the drug had they been admitted late in the trial, merely because they presented with breast cancer at a different time. Whether patients of a given menopausal status with ER-positive tumors received tamoxifen at a given stage of the trial likely depended more on the attitudes of the treating physicians than on the patients’ prognostic factors. At any given time during the trial, there was heterogeneity in physician attitudes, which resulted in heterogeneity of treatment. If assignment to tamoxifen depended on measurable characteristics such as age, number of positive lymph nodes, size of tumor, and so on, this information was available for each patient and we took it into account in our multivariate analyses. However, our analyses cannot account for biases in treatment assignment that depended on characteristics of the patient that could not be or were not measured. And they cannot account for the possibility that a patient’s attitude toward receiving tamoxifen was related to her response to the drug. The great virtue of randomization is that it eliminates or minimizes these biases. Our analysis is more credible if such biases are deemed unlikely to exist or to have little consequence.

The available evidence concerning the possibility that patients with breast cancer with HER-2/neu–positive tumors do not respond to tamoxifen is equivocal.^5-16 However, the preponderance of the published evidence suggests a differential response to tamoxifen depending on HER-2/neu status. It is possible that findings of association may result from failure to rigorously exclude ER-negative tumors.¹⁶ It is also possible that investigators who failed to find an association used antibodies or procedures that gave less than adequate assessment of HER-2/neu status. The opposite is unlikely: if investigators who found an association used inadequate HER-2/neu assessment procedures, then this would add noise to the process, and adding noise is unlikely to convert a null result into a positive finding. Other possibilities include heterogeneity in the patient population, the source of the specimen assessed, the assay used, and the scoring system applied.^7,17

Finally, most of the studies that found an association were small—especially small when considering that a minority of tumors overexpress HER-2/neu. Although these studies taken together suggest an association, circumstances such as this are ripe for publication biases. A small study that has little power to detect an association and does not detect an association is unlikely to be submitted for publication, and it would be unlikely to be accepted for publication if it were submitted. Hence, positive results tend to go unchallenged, except by studies with large numbers of patients.

Our study was comparatively large: 651 node-positive, ER-positive patients, approximately one half of whom received tamoxifen. We addressed the question of HER-2/neu–by–tamoxifen interaction in these patients. We find no suggestion of an interaction. In particular, the effect of tamoxifen is almost identical in patients with HER-2/neu-negative and HER-2/neu-positive tumors. Moreover, this observation does not depend on which of the methods is used to assess HER-2/neu status. Our observation does depend on which doses of CAF chemotherapy the patients received.

Our study was large enough that it likely would have detected an interaction of the magnitude suggested by earlier, smaller studies. For example, using simulation we find that a study with our patient numbers in the four possible categories of tamoxifen and HER-2/neu status has greater than 99% power to detect an interaction of the magnitude observed by Carlomagno et al.⁹

In addition, our study suggests that the effect of tamoxifen is the same in patients with p53-negative and in those with p53-positive tumors. We conclude that response to tamoxifen among patients with node-positive breast cancer with ER-positive tumors does not depend on either HER-2/neu status or p53 status.

On the basis of our study, using HER-2/neu status to determine whether patients with ER-positive, early-stage breast cancer should receive adjuvant tamoxifen cannot be justified. The same is true for p53 status.

	ACKNOWLEDGMENTS

 
Supported in part by research grant no. CA31946 from the National Cancer Institute to the Cancer and Leukemia Group B, Richard L. Schilsky, Chairman, and the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research, New York, NY.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted December 17, 1999; accepted June 16, 2000.

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