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Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial

From the Duke University Comprehensive Cancer Center, Durham, NC; Lombardi Cancer Center, Washington DC; Institut Bergonié, Bordeaux Cedex, France; Instituto Valenciano de Oncologia, Valencia, Spain; Universitaets Frauen-und Poliklinik UKE, Hamburg, Germany; Breast Research Unit, Western General Hospital, Edinburgh, United Kingdom; Novartis Pharma AG, Basel, Switzerland; and Novartis Pharmaceuticals, East Hanover, NJ.

Address reprint requests to Matthew Ellis, MB, PhD, FRCP, Duke University Breast Cancer Program, Box 3446, The Morris Building, Rm 25149F, Duke University Medical Center, Durham, NC 27710; email: ellis053{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Expression of ErbB-1 and ErbB-2 (epidermal growth factor receptor and HER2/neu) in breast cancer may cause tamoxifen resistance, but not all studies concur. Additionally, the relationship between ErbB-1 and ErbB-2 expression and response to selective aromatase inhibitors is unknown. A neoadjuvant study for primary breast cancer that randomized treatment between letrozole and tamoxifen provided a context within which these issues could be addressed prospectively.

PATIENTS AND METHODS: Postmenopausal patients with estrogen– and/or progesterone receptor–positive (ER+ and/or PgR+) primary breast cancer ineligible for breast-conserving surgery were randomly assigned to 4 months of neoadjuvant letrozole 2.5 mg daily or tamoxifen 20 mg daily in a double-blinded study. Immunohistochemistry (IHC) for ER and PgR was conducted on pretreatment biopsies and assessed by the Allred score. ErbB-1 and ErbB-2 IHC were assessed by intensity and completeness of membranous staining according to published criteria.

RESULTS: For study biopsy-confirmed ER+ and/or PgR+ cases that received letrozole, 60% responded and 48% underwent successful breast-conserving surgery. The response to tamoxifen was inferior (41%, P = .004), and fewer patients underwent breast conservation (36%, P = .036). Differences in response rates between letrozole and tamoxifen were most marked for tumors that were positive for ErbB-1 and/or ErbB-2 and ER (88% v 21%, P = .0004).

CONCLUSION: ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. This suggests that ErbB-1 and ErbB-2 signaling through ER is ligand-dependent and that the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer can be inhibited by potent estrogen deprivation therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN PRINCIPLE, A reduction in tumor size with 3 to 6 months of neoadjuvant tamoxifen is a logical and well-tolerated approach to improve surgical outcomes for postmenopausal women with estrogen receptor–positive (ER+) primary breast cancer. However, neoadjuvant tamoxifen is infrequently used, even in selected populations of older patients, because cytotoxic chemotherapy is considered to be a more active and better documented neoadjuvant regimen, although it is clearly more toxic. Several experimental approaches might improve the response rate and, therefore, the utility of neoadjuvant endocrine therapy. These include better patient selection to exclude nonresponsive tumors and the identification of alternatives to tamoxifen that more effectively induce primary tumor regression.¹

Selective aromatase inhibitors may prove more active than tamoxifen. These agents are currently under investigation as adjuvant treatment for postmenopausal women with ER+ breast cancer. In the metastatic setting, aromatase inhibitors are at least as effective as tamoxifen,^2-4 and letrozole has been shown to be more effective than tamoxifen in terms of response rates and time to disease progression.⁵ Rather than disrupt ER function though a ligand-receptor interaction, selective aromatase inhibitors block the conversion of adrenal androgens to estrogens, which leaves the ER in target tissues deprived of ligand and hence inactive.⁶ In contrast, tamoxifen binds to the ER and induces receptor dimerization and DNA binding. Transcription is then either activated or inhibited, depending on the target gene and cellular context.⁷

As part of the ongoing effort to compare aromatase inhibitors with tamoxifen, a double-blinded, randomized phase III neoadjuvant endocrine therapy trial was conducted to compare 4 months of letrozole 2.5 mg daily with tamoxifen 20 mg daily for postmenopausal women with hormone receptor–positive breast cancer who are ineligible for breast-conserving surgery. The clinical objectives of the study were to compare response rates and surgical outcomes on the two treatment arms. In addition, this study also provided an important opportunity to explore the biologic basis for the response of breast cancer to endocrine therapies. This article reports on a prospective analysis plan that had three initial objectives. The first objective was to confirm tumor ER and progesterone receptor (PgR) expression, with a central analysis of hormone receptor status. These data were used to validate the tumor bank and to conduct a supportive analysis of trial outcomes for patients with study biopsy-proven ER+ and/or PgR+ tumors. The second objective was to explore relationships between ER and PgR expression levels and response to establish expression values associated with optimal clinical outcomes. The third objective was to examine the relationship between ErbB-2 (HER2/neu) expression and primary tumor regression, because this protein kinase receptor may be a marker of tamoxifen resistance,^8-13 although not all studies concur with this conclusion.^14,15 Epidermal growth factor receptor (ErbB-1) expression has also been linked to endocrine therapy resistance, so ErbB-1 analysis was included in the study design.¹⁶

The predictive properties of these four proteins exhibited remarkable differences in the two arms of the study. These findings suggest several molecular explanations for the superiority of letrozole over tamoxifen and underscore the importance of an analysis of predictive biomarkers in ongoing trials that are comparing tamoxifen with selective aromatase inhibitors in the adjuvant setting.

	PATIENTS AND METHODS

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Patient and Tumor Bank Description
Between March 1998 and August 1999, patients were enrolled from 55 centers in 16 countries. The baseline characteristics of both treatment groups were well balanced for stage, age, surgical intention, and histologic grade. A detailed description of patient characteristics and clinical outcomes has been described elsewhere.¹⁷ All patients provided written informed consent, and institutional review board approvals were obtained at each center for both the clinical and the correlative science protocols. Efficacy analysis was conducted on a total of 324 patients: 154 study subjects received letrozole and 170 tamoxifen. Biopsies that were suitable for analysis in this study were received from 136 patients treated with letrozole and 142 treated with tamoxifen. When no specimen was available, it was either because none was provided, the biopsy did not contain invasive cancer, or the sample could not be identified because of inadequate labeling. Eligible patients were postmenopausal women with untreated primary breast cancer, confirmed by core needle biopsy, with 10% nuclear staining for ER and/or PgR, determined by immunohistochemistry (IHC) at the local study site. At baseline, tumors were considered not amenable to breast conserving surgery. Adequate hematologic, renal, and liver function and a life expectancy of at least 6 months were also required. Exclusion criteria included prior exposure to aromatase inhibitors or tamoxifen, uncontrolled endocrine or cardiac disease, bilateral or inflammatory breast cancer, distant metastasis, and other malignant diseases (except treated in situ cervical carcinoma or adequately treated basal or squamous cell carcinoma of the skin). Administration of other cancer treatments was not allowed, and hormone replacement therapy must have been discontinued.

Study Treatment
Using a double-dummy technique, patients were randomly assigned treatment to letrozole (Femara, Novartis Pharma AG, Basel, Switzerland) 2.5 mg daily or tamoxifen 20 mg daily using permuted blocks so that treatments were balanced within each country. Treatment was continued for 4 months unless the patient was withdrawn because of progressive disease (PD), an adverse event, or a request from the patient or investigator. Surgery was scheduled for 4 months after the date the patient received her first treatment to ensure there was no interval between the last study treatment day and the patient’s operation. A 5-year follow-up program to examine recurrence and survival is ongoing.

Study Assessment
Initial evaluation included clinical measurement of the primary breast lesion and regional lymph nodes, pathologic diagnosis by core needle biopsy, and ER and PgR analysis by IHC. Mammogram and ultrasound-based tumor measurements were also obtained, as well as two core biopsies for correlative science analysis. After initiating the study treatment, patients were assessed monthly for clinical response, adverse events, and concomitant medications/therapies, and, at months 2 and 3, by breast ultrasound. At 4 months, a surgical assessment was conducted, a final ultrasound and mammogram were obtained, and subsequently surgical outcomes were recorded. The primary efficacy end point was overall objective response, determined by breast palpation (clinical response), expressed as the percentage of patients in each treatment arm with a complete response (CR) or a partial response (PR). Response categories were defined according to World Health Organization criteria as CR, PR, no change, PD, and not assessable. Palpable ipsilateral axillary lymph node involvement downgraded a clinical CR. The secondary efficacy end points were the percentage of patients who underwent breast-conserving surgery, the response rate (CR + PR) determined by mammography at 4 months, and the response rate (CR + PR) determined by ultrasound at 4 months.

Predictive Marker Analysis
Samples were shipped at ambient temperature to the Lombardi Cancer Center in 10% (vol/vol) buffered formalin and were paraffin-embedded on receipt. All study analyses were conducted blinded with respect to clinical outcomes, patient identity, and drug assignment. Specimens that contained invasive breast cancer were immunostained for ER, PgR, ErbB-2, and ErbB-1 according to manufacturer’s instructions, using an automated immunostainer and ready-to-use reagents (Biogenex, San Ramon, CA). Briefly, the IHC assay was based on the avidin-biotin-complex method.¹⁸ Five-micron sections were mounted on coated slides (Probe on Plus, Fisher Scientific, Unionville, Ontario, Canada) and baked for 1 hour at 60°C, then deparaffinized and rehydrated. For ER, PgR, and ErbB-2 IHC, epitope retrieval was performed by boiling the slides in 10 mmol/L citrate buffer (pH 6.0) for 10 minutes and allowing the slides to cool in solution for a further 20 minutes. Epitope retrieval for ErbB-1 was achieved by incubation in 5% protease solution (P5147, Sigma, St Louis, MO) at 37°C for 3 minutes. After a 5-minute treatment with 3% H2O2, slides were washed in phosphate-buffered saline (PBS) and blocked with normal goat serum (Biogenex) for 5 minutes. The sections were then incubated with the appropriate monoclonal antibodies diluted in antibody diluent (Biogenex) for either 45 minutes (ER and PgR) or 30 minutes (ErbB-1 and ErbB-2). The antibodies and dilutions were as follows: ER (clone ER1D5, dilution 1:50, Immunotec/Coulter, Marseille, France), PgR (clone PR1A6, dilution 1:25, Immunotec/Coulter) ErbB-2, (clone 3B5, dilution 1:30, Immunotec/Coulter),^19,20 and ErbB-1 or epidermal growth factor receptor (clone 31G7, dilution 1:50, Zymed Lab, Inc, San Francisco, CA). After two washes in PBS, samples were incubated with biotinylated multilink complex (Biogenex) for 20 minutes, washed twice with PBS, and incubated in horseradish-peroxidase-streptavidin label for 20 minutes. After two washes in PBS, sections were exposed to 3,3' diamino benzidine tetrahydrochloride dehydrate (Biogenex) for 10 minutes for color development and lightly counterstained in 6% Mayers solution, washed, dehydrated, and coverslipped. ER and PgR were recorded as positive if 10% or more of the nuclei in the invasive component of the tumor stained positive for the receptor. To further assess the level of receptor expression, a histopathologic score, developed by Allred et al,²¹ was applied that records both the frequency and intensity of staining. ErbB-1 and ErbB-2 were scored by widely accepted criteria that assess the intensity and completeness of membrane staining.²² A score of 0/+ was considered negative and ++/+++ as positive or overexpressed. Controls without primary antibody and positive control tissues were included in all experiments to ensure the quality of staining for each assay run (human breast for ER and PgR, SKBR3 cell pellet for ErbB-2, and human placenta for epidermal growth factor receptor). The rate of assay failure (usually because of the absence of invasive cancer on the slide in question because the lesion was sectioned through) was low and ranged from 0% to 2.2% for each marker. This accounted for minor discrepancies in the denominators in each of the predictive biomarker categories defined in the results.

Statistical Methodology
The trial was designed to detect a difference in response rate between letrozole and tamoxifen based on clinical measurements. On the basis of a review of the literature,¹ a response rate of 65% was anticipated on the tamoxifen arm. A sample size of 302 patients was therefore considered adequate to detect a difference of 15% between letrozole and tamoxifen at a 5% significance level (two-sided) and 80% power. All the statistical analyses for predictive marker analysis were considered exploratory. All P values reported were two-sided; values .05 were considered to be statistically significant. No adjustment for multiple testing was performed. The comparability of the population with marker determinations to the entire study population was assessed by repeating analyses performed for both clinical response (CR and PR) and breast-conserving surgery (yes, no). The Mantel-Haenszel ² test was used for this analysis, stratified by treatment, baseline tumor size (T2, > T2), and nodal involvement (N0, > N0). Logistic regression was again used to analyze trial outcomes and was also adjusted to take into account the influence of baseline tumor size, nodal involvement, and age (< 70, 70 years). The Wald test was applied to generate P values. If a patient discontinued study treatment earlier than 4 months (+/- 2 weeks) and had a last assessment of PD, the earlier diagnosis of PD was counted. If a patient discontinued study treatment earlier than 4 months (+/- 2 weeks) for any other reason, then her final response was considered not assessable for the analysis. ER, PgR, ErbB-1, and ErbB-2 were taken as categorical variables as described above. Unadjusted logistic regression analysis was conducted to examine the predictive value of the markers on clinical response. The logistic models included the markers or treatment group individually as set out in the tables. To assess the relationship between ER and PgR, Allred scores and response logistic regression were also used.

	RESULTS

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Supportive Analysis of Trial Outcomes Based on Study Biopsy Assignment of ER and PgR Status
In view of the discrepancies between the study institution and the central laboratory designation of ER and PgR status, a supportive analysis was conducted that restricted the analysis of trial outcomes to study biopsy-confirmed ER and/or PgR+ cases (Table 2). The response rate to neoadjuvant letrozole therapy in this subgroup analysis was 60%, and 48% of patients underwent breast-conserving surgery. The response rate to tamoxifen was 41%, which was significantly inferior to that to letrozole treatment (P = .004). Tamoxifen was also inferior in terms of rates of breast-conserving surgery (36%, P = .036). These data emphasize the critical importance of accurate ER and PgR analysis for the safe application of neoadjuvant endocrine treatment, because patients with ER-, PgR- tumors do not respond to this form of treatment. However, with 10% as a cutoff value for positive ER and PgR status, a remarkable improvement in surgical outcomes was documented with neoadjuvant letrozole therapy.

View larger version (26K): [in this window] [in a new window]   Fig 1. Clinical response rate versus ER Allred score for letrozole and tamoxifen. The P value for a linear logistic model was .0013 for letrozole and .0061 for tamoxifen according the Wald test. In this analysis, ER-, PgR+ cases (determined by conventional cut points) were excluded.

View larger version (37K): [in this window] [in a new window]   Fig 2. Clinical response rate v PgR Allred score for letrozole and tamoxifen. Logistic models were linear assuming a peak response rate associated with a score of 5 for letrozole and 4 for tamoxifen. The P values for these models were .0015 and .0165, respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The linear relationship between the ER Allred expression score and log odds of response to both tamoxifen and letrozole in logistic regression models contributes to the validation of this scoring methodology. The observation that tumors with low positive levels of ER expression were responsive to letrozole (Allred scores 3, 4, and 5) validates the concern expressed by Allred et al²¹ that a 10% cutoff for ER may be too high and could exclude patients unnecessarily from the benefits of endocrine therapy. A substantial number of patients with tumor ER Allred expression categories in the 3 to 5 range (generally involving 1% to 10% positive cells) might derive benefit from aromatase inhibitor treatment in this and potentially in other treatment settings. These observations further emphasize the need for a concerted effort to re-evaluate the predictive value of ER IHC in the context of the ongoing selective aromatase inhibitor adjuvant studies.

The inverse V–shaped relationship between PgR expression and response was unexpectedly complex and was not anticipated from prior information on the predictive properties of PgR in breast cancer.²³ It is generally accepted that expression of PgR is a marker for estrogen-dependent cancers with a functional ER because PgR requires activated ER for expression.²⁴ Furthermore, it is also assumed that the relationship between PgR level and response is linear, as with ER, with the most responsive tumors exhibiting the highest levels of expression. Although this conventional model explains the initial increase in response rates associated with PgR Allred scores of 0 to 5, ie, the initial rise in response rates associated with the appearance of PgR expression, it does not predict the subsequent decline in response rates associated with PgR Allred scores of 6, 7, and 8. These data underscore the uncertain value of PgR analysis as a predictive biomarker. For example, in the Oxford overview analysis, PgR was not shown to be a useful predictor for the adjuvant benefit of tamoxifen.²⁵ The degree of statistical significance associated with the inverse V–shaped relationship between PgR expression levels and response to letrozole (P = .0015) suggests that new hypotheses and models for the predictive relationship between PgR and the effectiveness of aromatase inhibitors should be considered. Perhaps PgR-rich tumors are associated with sufficiently high levels of aromatase activity or hypersensitivity to estrogen to blunt the efficacy of estrogen deprivation therapy with aromatase inhibitors. In paired samples taken before and after treatment, expression of PgR was strongly downregulated by letrozole but not by tamoxifen.²⁶ These data show how the predictive properties of PgR may differ between these two classes of endocrine agents.

Tumors that expressed ER and ErbB-1 and/or ErbB-2 exhibited a significantly higher response rate to letrozole than tumors that expressed ER+, but not ErbB-1 or ErbB-2 (P = .02). This remarkable observation suggests that the ErbB-1/2–activated second messenger pathway mediates estrogen-dependent growth through ER, presumably via ER phosphorylation. Although ErbB-1+ and/or ErbB-2+ tumors treated with tamoxifen exhibited the opposite outcome, ie, a lower response rate when compared with ErbB-1- and ErbB-2- cases, the data were not statistically significant once ER- cases had been censored from the data (P = .12). This study did not, therefore, definitively resolve the issue of whether ER+, ErbB-1+, and/or ErbB-2+ tumors are tamoxifen-resistant, presumably because the analysis of small subsets of tumors defined by ER, ErbB-1, and ErbB-2 lacked sufficient statistical power to be conclusive in this regard. However, a statistically robust conclusion can be drawn with respect to the relative activity of letrozole and tamoxifen in the ER+, ErbB-1+, and/or ErbB-2+ tumor subset. Letrozole was considerably more effective than tamoxifen for these tumors (P = .0004). If correct, this conclusion has important biologic and clinical implications.

Preclinical modeling is consistent with the conclusion that ER+ and ErbB-2+ tumors are highly estrogen-dependent. Benz et al²⁷ demonstrated that MCF-7 breast cancer cells transfected with an ErbB-2 expression vector grew rapidly as xenografts in nude mice supplemented with estrogen. No ErbB-2+ tumors formed in the absence of estrogen, indicating that estrogen dependence was maintained despite ErbB-2 overexpression. When estrogen supplementation was stopped and tamoxifen started, control ErbB-2- cells stopped growing and regressed, yet ErbB-2 transfected cells continued to grow in the presence of tamoxifen with no signs of regression, even after weeks of treatment.²⁷ A molecular explanation for these findings is suggested by the recent observation that a downstream mediator of ErbB-1/2 signaling, MEKK1, activates ER and stimulates the agonist activity of tamoxifen.²⁸ The ErbB-1/2 tamoxifen resistance pathway may be circumvented by letrozole because, by removing estrogen, the ER becomes monomeric and unable to bind DNA. Under these circumstances, we speculate that ER is incapable of transcription and is not, therefore, a productive target for ErbB-1/2–activated protein kinases (Fig 3).

View larger version (14K): [in this window] [in a new window]   Fig 3. A simple model to explain the superior efficacy of letrozole when ER is coexpressed with ErbB-1 and/or ErbB-2. These tumors are estrogen-dependent and therefore sensitive to estrogen deprivation. However, ErbB-1/2–dependent ER phosphorylation (P) prevents tamoxifen (T) from acting as an antagonist, compromising effectiveness.

Recent data suggest that gene amplification studies for ErbB-2 are more predictive for the benefits of trastuzumab than assignment of ErbB-2 status by IHC.²⁹ A retrospective analysis of the samples in this study for evidence of ErbB-1 and ErbB-2 gene amplification has therefore been planned. However, it should not be presumed that gene amplification assays are necessarily the best way to investigate the interaction between ErbB-1 and ErbB-2 and effectiveness of endocrine agents. The biologic basis for the effect of ErbB-1 and ErbB-2 on ER function is quite distinct from the therapeutic application of an ErbB-2–targeted monoclonal antibody, and resistance to tamoxifen (or sensitivity to aromatase inhibitors) may occur in cases in which ErbB-1 and/or ErbB-2 is expressed but not amplified.

This article underscores the potential of neoadjuvant endocrine therapy trials for the investigation of new endocrine agents for breast cancer. Clinical outcomes are available after a short period of treatment, and biopsy material for scientific investigation is readily available. From the clinical perspective, neoadjuvant letrozole treatment offers a new clinical approach to improve surgical outcomes for older women with breast cancer. However, the predictive biomarker analysis described in this article demonstrates that the significance of this approach extends beyond a surgical context. Neoadjuvant aromatase inhibitor therapy offers an in vivo estrogen-dependence test that can be used to identify and validate predictive biomarkers for endocrine therapy.

	ACKNOWLEDGMENTS

 
Supported by a research grant from Novartis Pharma, Summit, NJ (M.J.E.).

We thank the clinical researchers and patients who participated in this trial.

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Submitted March 7, 2001; accepted May 30, 2001.

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