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Journal of Clinical Oncology, Vol 21, Issue 10 (May), 2003: 1967-1972
© 2003 American Society for Clinical Oncology

Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen

A. Lipton, S.M. Ali, K. Leitzel, L. Demers, H.A. Harvey, H.A. Chaudri-Ross, C. Brady, P. Wyld, W. Carney

From the Milton S. Hershey Medical Center, Hershey, PA; Veterans Affairs Medical Center, Lebanon, PA; Novartis Pharmaceutical Corporation, East Hanover, NJ; Bayer Corporation, Tarrytown, New York; and Novartis Pharma AG, Basel, Switzerland.

Address reprint requests to Allan Lipton, MD, Penn State Milton S. Hershey Medical Center, Department of Medicine, Division of Hematology/Oncology HO46, 500 University Dr, PO Box 850, Hershey, PA 17033; email: alipton{at}psu.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To determine the effect of elevated serum HER-2/neu on the response of metastatic breast cancer patients to an aromatase inhibitor versus an antiestrogen.

Patients and Methods: Five hundred sixty-two estrogen receptor–positive metastatic breast cancer patients were randomized to first-line hormone therapy with either letrozole or tamoxifen. An automated enzyme-linked immunosorbent assay was used to detect serum HER-2/neu.

Results: For patients with normal serum HER-2/neu (70.5%), objective response rate (ORR; 39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P = .008), clinical benefit (CB; 57% v 45%; P = .016), time to progression (TTP; median, 12.2 v 8.5 months; P = .0019), and time to treatment failure (TTF; median, 11.6 v 6.2 months; P = .0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group (29.5%), there was no significant difference in ORR (17% in letrozole-treated patients v 13% in tamoxifen-treated patients; P = .45) or CB (33% v 26%; P = .31), but there was a strong trend in favor of a longer TTP with letrozole (median, 6.1 v 3.3 months; P = .0596) and a significantly longer TTF with letrozole (median, 6.0 v 3.2 months; P = .0418). Multivariate analysis revealed that elevated serum HER-2/neu was a negative predictor for ORR and TTP.

Conclusion: Patients with normal serum HER-2/neu receiving letrozole demonstrated a significantly greater ORR and CB and longer TTP and TTF than patients receiving tamoxifen. Although in patients with elevated serum HER-2/neu there was no significant difference between letrozole and tamoxifen in ORR or CB, there was a strong trend favoring longer TTP and significantly longer TTF with letrozole.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE PREDICTION of which patients have the highest chance of responding to endocrine therapy was changed from using clinical parameters to measurement of the estrogen receptor (ER) in the 1960s. Despite the presence of the ER, only half of the patients will respond to endocrine therapy. A possible explanation for the failure of this group of patients with ER-positive tumors to respond is that these cancers have developed other autocrine or paracrine pathways to facilitate their growth.

The HER-2/neu (c-erbB-2) proto-oncogene encodes a 185-kd transmembrane glycoprotein growth factor receptor (p185-HER-2/neu) that contains an extracellular ligand-binding domain and intracellular tyrosine kinase activity.1 HER-2/neu gene amplification or protein overexpression is present in 20% to 30% of primary human breast cancers.2–4 As with other cell-surface transmembrane receptors, HER-2/neu is shed and can be detected in the serum of a proportion of patients with metastatic breast cancer.5–7

Wright et al8 first reported that coexpression of HER-2/neu in ER-positive patients was associated with a reduced response rate to first-line hormone therapy of metastatic breast cancer from 48% to 20%. We have recently reported that patients with ER-positive and serum HER-2/neu–positive metastatic breast cancer are less likely to respond to second-line hormone treatment and have a shorter duration of response and survival than ER-positive and serum HER-2/neu–negative patients.9

The aromatase enzyme catalyzes the synthesis of estrogens from androgens derived from the adrenal gland. Several potent and selective inhibitors of aromatase have been developed for the treatment of hormone-dependent breast cancer. Letrozole (Femara; Novartis Pharma AG, Basel, Switzerland), an imidazole derivative, is a potent, oral, nonsteroidal inhibitor of the enzyme aromatase. Letrozole has recently been shown to be superior to tamoxifen for the first-line treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer.10 The purpose of this study was to compare the response rate of the aromatase inhibitor letrozole to the antiestrogen tamoxifen in metastatic breast cancer patients with elevated serum HER-2/neu compared with patients with normal serum HER-2/neu.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Nine hundred seven patients were randomly assigned to either letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). The patient inclusion-exclusion criteria and clinical, radiologic, and efficacy assessments are briefly described below.10 In our current study, pretreatment serum samples obtained within 14 days before initiation of therapy were available from 566 patients (mainly European sites). This project was approved by the Institutional Review Board of the Hershey Medical Center of the Pennsylvania State University (Hershey, PA).

Inclusion Criteria
Briefly, postmenopausal women with histologically or cytologically confirmed breast cancer and with locally advanced (stage IIIB by American Joint Committee on Cancer criteria, 1992) or locoregionally recurrent disease not amenable to treatment by surgery or radiotherapy or women with metastatic disease were eligible for the study. Patients were required to have tumors with ER–positive and/or progesterone receptor (PgR)–positive status or with both receptors unknown. Patients previously treated with one regimen of chemotherapy for advanced disease were allowed in the study provided that they had objective evidence of progression within the 3 months before study enrollment.

Exclusion Criteria
Patients were excluded from the study if they had evidence of CNS metastasis, bilateral diffuse lymphangitic carcinomatosis of the lung with more than 50% lung involvement, metastasis estimated as more than one third of the liver, inflammatory breast cancer, or concurrent or previous malignant diseases. Patients whose disease relapsed or recurred during adjuvant antiestrogen therapy or within 12 months of completing such therapy were excluded. Adjuvant endocrine therapy other than antiestrogens, prior systemic endocrine treatment for advanced disease, systemic investigational drugs within the past 30 days, or topical investigational drugs within the past 30 days precluded enrollment onto the study.

Clinical and Radiologic Assessments
A complete tumor assessment was performed at baseline and areas found positive for disease at baseline were monitored every 3 months for response assessment according to the International Union Against Cancer criteria.11 All patients were monitored for survival at least every 6 months after termination of study treatment.

Primary Efficacy Assessments
The primary efficacy end point was time to progression (TTP). TTP was defined as the interval between the date of random assignment to treatment and the earliest date of disease progression. An increase of 25% or more in measurable lesions (single lesion or sum of products of all measurable lesions), an estimated increase of 25% or more in existing assessable or nonmeasurable-nonassessable disease, or the appearance of new lesions was considered as progression. Discontinuation of treatment with documented evidence of clinical deterioration as a result of breast cancer, death caused by breast cancer, or death of unknown cause (with documented evidence of clinical deterioration as a result of breast cancer) while receiving treatment or within 6 weeks of discontinuation of treatment also constituted disease progression.

Secondary Efficacy Assessments
Secondary end points included overall objective tumor response rate (ORR), duration of overall response, rate of clinical benefit (CB), duration of CB, time to treatment failure (TTF), and overall survival. ORR was defined as the proportion of patients who achieved a complete response (CR) or a partial response (PR) as confirmed by a second evaluation at least 1 month but generally 3 months later. Overall response was evaluated at 3-month intervals after initiation of therapy. Duration of overall objective response was defined for those patients with a confirmed response (CR or PR) as the interval between the date of random treatment assignment and the earliest date of disease progression (International Union Against Cancer method). The rate of CB was defined as the proportion of patients who achieved a confirmed objective response (CR or PR) or who had stabilization or no change in disease lasting for 24 weeks or more. Duration of CB was defined for these patients as the interval between the date of random treatment assignment and the earliest date of disease progression.

TTF was defined as the interval between the date of random treatment assignment and the earliest date of disease progression, withdrawal of study treatment for any reason, withdrawal of consent, loss to follow-up, or death from any cause. Overall survival was defined as the time from the date of random treatment assignment to death. Patients lost to follow-up were assumed to have died.

Serum Preparation
Blood was drawn by forearm venipuncture 14 days before initiation of first-line hormone therapy. The blood was then centrifuged at 500 x g for 10 minutes at room temperature. The serum supernatant was then collected, aliquoted, and stored at -70°C.

HER-2/neu Enzyme-Linked Immunosorbent Assay
Serum HER-2/neu levels were measured using an automated HER-2/neu assay (Immuno 1, Bayer Corporation, Tarrytown, NY) for research use. All patient samples were analyzed in blinded fashion; that is, without knowledge of clinical outcome of the individual patient or of assigned treatment.

Immunoassay of HER-2/neu
The Immuno 1 HER-2/neu assay is a magnetic particle separation immunoassay designed for the random access automated Immuno 1 immunochemistry analyzer. The assay uses two monoclonal antibodies (mAbs) developed by Oncogene Science Diagnostics, Inc (Cambridge, MA). These mAbs, designated NB-3 and TA-1, bind to independent binding sites on the HER-2/neu ECD. Reagent 1 of the assay contains the mAb NB-3, which is conjugated to fluorescein; reagent 2 contains the Fab’ fragment of mAb TA-1, which is conjugated to alkaline phosphatase. Reagents (65 µL) are incubated at 37°C on the system for 20 minutes. Magnetic particles covalently coated with antifluorescein mAb (20 µL) are then added to capture the sandwich immunocomplexes. After 28 minutes, the magnetic particles are washed, a colorimetric substrate reagent containing p-nitrophenyl phosphate is added, and the rate of increase in absorbance at 405 and 450 nm is measured. A cubic-through-zero curve-fitting algorithm is used to construct the calibration curve.

Calibration and Controls
The Immuno 1 assay uses six calibrators containing 0, 10, 25, 60, 125, or 250 µg/L of HER-2/neu ECD. The calibrator matrix is delipidated bovine serum supplemented with detergent and sodium azide. The HER-2/neu ECD used to make the calibrators is a recombinant protein secreted by transfected mouse NIH 3T3 cells and was developed by Oncogene Science. The original cloned DNA containing the sequence for the complete HER-2/neu protein was isolated from the human breast carcinoma cells, SK-BR-3. An additional modification was used to generate a truncated version coding for the ECD fragment of the HER-2/neu protein, which was inserted in the mouse cell designated as 3–30 (p105). The cells were grown in roller bottles using 100 mL/L of bovine calf serum in DMEM. The supernatant was concentrated to give an ECD concentration of approximately 8,000 µg/L and was diluted into the calibrator matrix to give the required final ECD concentrations.

Statistical Methods
A cutoff of 15 ng/mL (mean + 2 SD) for serum HER-2/neu was derived from the sera of 242 healthy women; this cut point is identical to that used in a previous publication.12 Time-to-event data, such as TTP and TTF, were analyzed applying Cox proportional hazards regression models to estimate differences between treatments in the subsets of patients with serum HER-2/neu measurements (patients with normal levels and patients with elevated levels) and to estimate differences between expression (elevated compared with normal) regardless of treatment. Statistics of the survivor function were estimated by the Kaplan-Meier product-limit method. Overall tumor response and overall CB were analyzed applying logistic regression models for the same subsets of patients. All analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC) on the Novartis UNIX platform (Novartis Pharma AG).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
This trial was a multinational, multicenter, double-blind, double-dummy, randomized, two-arm, phase III trial comparing the efficacy of letrozole to the efficacy of tamoxifen as first-line treatment of postmenopausal women with advanced breast cancer. Nine hundred seven patients (intent-to-treat [ITT] population) were randomly assigned to either letrozole 2.5 mg once daily (453 patients), or tamoxifen 20 mg once daily (454 patients). The recently published results have established the superiority of letrozole in this trial.10 The ORR was significantly higher for letrozole compared with tamoxifen (32% v 21%, respectively; P = .0002), and the rate of CB was also higher (50% v 38%, respectively; P = .0004). TTP was also significantly longer for letrozole than for tamoxifen (median, 9.4 v 6.0 months, respectively). Treatment with letrozole reduced the risk of progression by 28% (hazard ratio = 0.72; 95% confidence interval, 0.62 to 0.83; P < .0001).

In our current study, pretreatment serum HER-2/neu was evaluated as a predictive factor for response to hormone therapy. Pretreatment serum samples were available from 562 of the 907 patients. Serum was available for 62% of the patients in the letrozole arm (283 of 453 patients) and 61% of the patients in the tamoxifen arm (279 of 454 patients). There were no significant differences in clinical characteristics of all ITT patients (N = 907) when compared with patients with available serum (n = 562). ORR, CB rate, TTP, and TTF were similar in the subset of patients with available pretreatment serum. Compared with tamoxifen, letrozole reduced the hazard ratio for TTP in patients with available serum to 0.73 (Fig 1Go), which was very similar to the letrozole hazard ratio reduction of 0.72 for the whole ITT study group (data not shown). We concluded that the response to therapy was similar in the subset of 562 patients with available serum compared with the whole ITT population of 907 patients.



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  		Fig 1. Time to progression by treatment arm, irrespective of serum HER-2/neu status. (——) Letrozole first; (- - - -) tamoxifen first; CI, confidence interval.

 
Patient Characteristics
The patient characteristics and extent and severity of disease were similar in the subset of patients with available serum for HER-2/neu measurement compared with the whole ITT study population. Treatment groups were generally well balanced. Slightly more patients in the tamoxifen arm had adjuvant chemotherapy than in the letrozole arm, and slightly more patients had visceral metastases in the tamoxifen arm than in the letrozole arm, which was attributable to more patients with pulmonary involvement. Slightly more patients had liver metastases in the letrozole arm than in the tamoxifen arm. Bone-dominant disease was present slightly more often in the letrozole arm than in the tamoxifen arm (Tables 1 to 5GoGoGoGoGo).


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  		Table 1. Patient Characteristics
 

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  		Table 2. Receptor Status
 

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  		Table 3. Disease Characteristics
 

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  		Table 4. Extent of Disease
 

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  		Table 5. Measurability of Disease
 
Serum HER-2/neu
Serum HER-2/neu was defined as elevated if the pretreatment level was 15 ng/mL or greater, a cut point also used in a previous report using the serum HER-2/neu Immuno l assay.12 The cut point value of 15 ng/mL was the mean + 2 SD (9.18 + 5.5 ng/mL) obtained from measurement of serum HER-2/neu in 242 healthy female volunteers. There was no significant difference in serum HER-2/neu between healthy premenopausal (n = 121) and postmenopausal (n = 121) females (range, 3.13 to 29.13 ng/mL). Of the 562 patients in this study, 164 (29%) had elevated serum levels of HER-2/neu. Of the 283 patients who received letrozole and of the 279 patients treated with tamoxifen, 87 (31%) and 77 (28%) had elevated serum HER-2/neu before initiation of therapy, respectively.

Response According to HER-2/neu Status
ORR (sum of CR + PR) and CB rate (sum of CR + PR + stable disease for at least 24 weeks) were analyzed in the elevated versus normal serum HER-2/neu groups regardless of treatment and separately by treatment arm. The ORR (15% in elevated patients v 32% in normal patients; P < .0001) and CB rate (30% in elevated patients v 51% in normal patients; P < .0001) were significantly lower in patients with an elevated baseline serum HER-2/neu level. In addition, the duration of objective response (for patients who responded; CR + PR) was significantly shorter in patients with an elevated baseline serum HER-2/neu compared with patients with normal HER-2/neu (median, 18.5 v 25.3 months, respectively; P = .0140). The median duration of CB (CR + PR + stable disease) was also significantly shorter in patients with an elevated baseline serum HER-2/neu compared with normal serum HER-2/neu patients (median, 16.9 v 20.9 months, respectively; P = .0067); TTP (median, 5.7 v 9.4 months, respectively; P < .0001) and TTF (median, 4.2 v 9.1 months, respectively; P < .0001) were also significantly shorter (Fig 2Go for TTP; TTF is not shown). Multivariate analyses revealed that elevated serum HER-2/neu was an independent negative predictive factor for ORR, CB rate, TTP, and TTF after adjusting for the other variables (Table 6Go). These results were unchanged when the analyses were conducted within the subgroup of patients with ER-positive and/or PR-positive disease only (n = 374; receptor-unknown patients omitted). Overall survival was significantly reduced for patients with elevated serum HER-2/neu (20.8 months), compared with patients with normal serum HER-2/neu levels (36.5 months; P < .0001).



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  		Fig 2. Time to progression by serum HER-2/neu status, irrespective of treatment arm. (——) Normal serum HER-2/neu; (- - - -) elevated serum HER-2/neu; CI, confidence interval.

 

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  		Table 6. Multivariate Analysis of Objective Response
 
Normal Serum HER-2/neu Subgroup
There were 398 patients with a normal baseline serum HER-2/neu (196 letrozole patients and 202 tamoxifen patients). For patients with normal serum HER-2/neu, ORR (39% in letrozole-treated patients v 26% in tamoxifen-treated patients; P = .0078), CB rate (57% v 45%; P = .0162), TTP (median, 12.2 v 8.5 months; P = .0019; Fig 3Go), and TTF (median, 11.6 months v 6.2 months; P = .0066) were significantly better in patients treated with letrozole versus patients treated with tamoxifen.



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  		Fig 3. Time to progression in patients with normal serum HER-2/neu. (——) Letrozole first; (- - - -) tamoxifen first; CI, confidence interval.

 
Elevated Serum HER-2/neu Subgroup
There were 164 patients with an elevated baseline serum HER-2/neu (87 letrozole patients and 77 tamoxifen patients). For patients with elevated serum HER-2/neu, there were no significant differences between the letrozole and tamoxifen groups for ORR (17% v 13%, respectively; P = .4507) or CB rate (33% v 26%, respectively; P = .3051). There was a strong trend favoring letrozole versus tamoxifen toward longer TTP (median, 6.1 v 3.3 months, respectively; P = .0596; Fig 4Go), and TTF was significantly longer with letrozole than with tamoxifen (median, 6.0 v 3.2 months, respectively; P = .0418).



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  		Fig 4. Time to progression in patients with elevated serum HER-2/neu. (——) Letrozole first; (- - - -) tamoxifen first; CI, confidence interval.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Endocrine therapy is usually used as initial treatment of metastatic breast cancer that is either ER-or PR-positive. The goal of therapy is to either reduce estrogen synthesis (aromatase inhibition) or, alternatively, block the ER (antiestrogen) in those tumors that are hormone sensitive. Even in ER-positive breast cancer, the response rate (CR + PR + stable disease) to endocrine therapy is only 50% to 60%. One third to one half of patients will not benefit from treatment that blocks the ER or inhibits estrogen biosynthesis. A possible explanation for this failure to respond is that these cancers have developed other autocrine or paracrine pathways to facilitate their growth.2

The mechanism of hormone resistance in HER-2/neu–overexpressing breast cancer cells has been the subject of intensive laboratory investigation. Transfection of multiple copies and/or overexpression of the HER-2/neu receptor results in tamoxifen resistance in ER-positive, estrogen-dependent, human breast cancer cell lines.13–15 Furthermore, the growth of MCF-7 xenografts in ovariectomized athymic mice is inhibited by tamoxifen, whereas HER-2/neu–transfected MCF-7 xenografts are less sensitive to tamoxifen.13–15 However, there is little available information on the efficacy of aromatase inhibitors on HER-2/neu–positive breast cancer.

This study was performed using serum from 562 patients with metastatic breast cancer receiving first-line hormone therapy with either the aromatase inhibitor letrozole or the antiestrogen tamoxifen. All patients were ER-positive and/or PR-positive or had both receptors unknown. Sera were analyzed for HER-2/neu using the Immuno 1 assay. A previous study of 378 patients in the pivotal trastuzumab (Herceptin, Genentech, San Francisco, CA) metastatic breast cancer trials showed a significant overall correlation of 74% for patients with elevated serum HER-2/neu and positive HER-2/neu immunohistochemistry [IHC] of the primary tumor (84% correlation with IHC 3+ and 44% correlation with IHC 2+).16 With a cutoff of 15 ng/mL as the upper limit of normal, 29.5% of patients had an elevated serum HER-2/neu level. ORR, CB rate, duration of response, TTP, TTF, and survival were lower in patients with an elevated serum HER-2/neu level. This result is similar to that observed in patients receiving second-line hormone therapy for metastatic breast cancer.9

We next examined the effect of HER-2/neu status on response to each hormonal therapy (letrozole v tamoxifen). For patients with normal serum HER-2/neu, ORR (39% v 25%, respectively; P = .0078), CB rate (57% v 45%, respectively; P = .0162), TTP (median, 12.2 v 8.5 months, respectively; P = .0019), and TTF (median, 11.6 v 6.2 months, respectively; P = .0066) were significantly better in patients treated with letrozole. In the elevated HER-2/neu group, there were no significant differences in ORR or CB rate for patients treated with letrozole versus tamoxifen. There was a strong trend for longer TTP with letrozole treatment than with tamoxifen (P = .0596). TTF was significantly longer with letrozole treatment than with tamoxifen (P = .0418). Despite the limited statistical power of treatment-effect analysis in the relatively small number of patients with elevated serum HER-2/neu, this is the largest randomized clinical study that has examined this issue to date. The results were unchanged when the analyses were conducted within the subgroup of patients with ER-positive and/or PR-positive disease only (receptor-unknown patients omitted).

A recent study by Ellis et al17 concluded that ER-positive, HER-2/neu–positive, primary breast cancer responded well to letrozole, but responses to tamoxifen were infrequent. There are several differences between the Ellis study and ours. Their study was a neoadjuvant study, and HER-2/neu status was determined by IHC. In addition, the total number of patients in the study by Ellis who were both ER-positive and HER-2/neu–positive was relatively small.17 The clinical end points also are different; Ellis et al measured shrinkage of the primary tumor, whereas our study end points are clinical assessments of the response of metastatic disease to hormone therapy. Finally, the accelerated acquisition of additional genetic changes during tumor evolution from primary tumor to the metastatic phase may endow HER-2/neu–expressing tumor cells with additional mechanisms of resistance to hormone therapy.

Much data exist to indicate cross-talk between the HER-2/neu and ER signal transduction pathways. Treatment of HER-2/neu–overexpressing cells with estrogen decreases HER-2/neu mRNA as well as downregulates the HER-2/neu product.18 Conversely, treatment of ER-positive cells with heregulin leads to decreased ER expression.19 Ligand-independent ER activation in cancers that are both ER-positive and serum HER-2/neu–elevated could explain resistance to both aromatase inhibitors and antiestrogen.20,21

In summary, the advantage of letrozole over tamoxifen is mostly in cancers that are serum HER-2/neu–normal. Cancers that have elevated serum levels of HER-2/neu are relatively resistant to both types of hormone therapy. A logical therapeutic approach for patients whose cancer is both ER-positive and serum HER-2/neu–elevated may be to simultaneously block both the ER and HER-2/neu pathways. BT474 is an ER-positive breast cancer cell line that also overexpresses HER-2/neu. Simultaneously interrupting the ER pathway with tamoxifen and the HER-2/neu pathway with the 4D5 anti–HER-2/neu antibody leads to greater growth inhibition than that achieved by either agent alone.22 Metastatic breast cancer patients with ER-positive, serum HER-2/neu–elevated breast cancer might benefit from combined hormonal and HER-2/neu blockade.


   ACKNOWLEDGMENTS
 
We thank Eileen Kenney for her excellent help in the preparation of this manuscript.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Maguire HC, Greene MI: The neu (c-erbB-2) oncogene. Semin Oncol 16:148–155, 1989[Medline]

2. Lupu R, Lippman ME: The role of erbB-2 signal transduction pathways in human breast cancer. Breast Cancer Res Treat 27:83–93, 1993[CrossRef][Medline]

3. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712, 1989[Abstract/Free Full Text]

4. Clark GM, McGuire WL: Follow-up study of HER-2/neu amplification in primary breast cancer. Cancer Res 51:944–948, 1991[Abstract/Free Full Text]

5. Mori S, Mori Y, Mukaiyama T, et al: In vitro and in vivo release of soluble erbB-2 protein from human carcinoma cells. Jpn J Cancer Res 81:489–494, 1990[CrossRef][Medline]

6. Carney WP, Hamer PJ, Petit D, et al: Detection and quantitation of the human neu oncoprotein. J Tumor Marker Oncol 6:53–72, 1991

7. Langton BC, Crenshaw MC, Chao LA, et al: An antigen immunologically related to the external domain of gp 185 is shed from nude mouse tumors overexpressing the c-erbB-2 (HER-2/neu) oncogene. Cancer Res 51:2593–2598, 1991[Abstract/Free Full Text]

8. Wright C, Angus B, Nicholson S, et al: Expression of c-erbB-2 oncoprotein: A prognostic indicator in human breast cancer. Cancer Res 49:2087–2090, 1989[Abstract/Free Full Text]

9. Lipton A, Ali SM, Leitzel K, et al: Elevated serum HER-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20:1467–1472, 2002[Abstract/Free Full Text]

10. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596–2606, 2001[Abstract/Free Full Text]

11. International Union Against Cancer: Manual of adult and pediatric medical oncology, in Monfardini S, Brunner K, Crowther D, et al (eds): Evaluation of the Cancer Patient and the Response to Treatment. Berlin, Germany, Springer, 1987, pp 22–38

12. Schwartz MK, Smith C, Schwartz DC, et al: Monitoring therapy by serum HER-2/neu. Int J Biol Markers 5:324–329, 2000

13. Benz CC, Scott GK, Sarup JC, et al: Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24:85–95, 1993

14. Liu Y, el-Ashry D, Chen D, et al: MCF-7 breast cancer cells overexpressing transfected c-erbB-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo. Breast Cancer Res Treat 34:97–117, 1995[CrossRef][Medline]

15. Pietras R. Arboleda J, Reese D, et al: HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10:2435–2446, 1995[Medline]

16. Wong WL, Bajamonde A, Nelson B, et al: Baseline serum HER2 (sHER2) levels in pivotal herceptin breast cancer trials: A comparison of 2 ELISA methods. Proc Am Soc Clin Oncol 19:77a, 2000 (abstr 297)

17. Ellis M, Coop A, Singh B, et al: 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. J Clin Oncol 19:3808–3816, 2001[Abstract/Free Full Text]

18. Read LD, Keith D Jr, Slamon DJ, et al: Hormonal modulation of HER-2/neu proto-oncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cells lines. Cancer Res 50:3947–3951, 1990[Abstract/Free Full Text]

19. Colomer R, Saceda M, Martin BM, et al: Cross-regulation of erbB2 oncoprotein and estrogen receptor by estrogen and the erbB2 ligands (gp30/p75). Proc Am Assoc Cancer Res 33:82, 1992 (abstr 494)

20. Kato S, Endoh H, Masuhiro Y, et al: Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494, 1995[Abstract/Free Full Text]

21. Bunone G, Briand PA, Miksicek RJ, et al: Activation of the unliganded estrogen receptor by EGF involves the MAPKinase pathway and direct phosphorylation. EMBO J 15:2174–2183, 1996[Medline]

22. Witters L, Kumar R, Chinchilli V, et al: Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2/neu antibody. Breast Cancer Res Treat 42:1–5, 1997[CrossRef][Medline]

Submitted September 19, 2002; accepted February 20, 2003.




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