This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lipton, A. Articles by Allard, J. Search for Related Content PubMed PubMed Citation Articles by Lipton, A. Articles by Allard, J. Social Bookmarking                            What's this?

Elevated Serum HER-2/neu Level Predicts Decreased Response to Hormone Therapy in Metastatic Breast Cancer

From the Department of Hematology and Oncology, Penn State Milton S. Hershey Medical Center, Hershey, and Veterans Affairs Medical Center, Lebanon, PA; Novartis Pharmaceutical Corporation, East Hanover, NJ; and Bayer Corp, Tarrytown, NY.

Address reprint requests to Allan Lipton, MD, Department of Medicine, Division of Hematology and Oncology HO46, Penn State Milton S. Hershey Medical Center, 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 elevation of serum HER-2/neu on response to hormone therapy.

PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor–positive (ER⁺), progesterone receptor–positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels.

RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with nonelevated and 23% in 217 patients with elevated serum HER-2/neu levels (P < .0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with nonelevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P < .0001).

CONCLUSION: Patients with ER⁺ and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER⁺ and serum HER-2/neu–negative patients. Their survival duration is also shorter.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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 Amplification of the HER-2/neu gene and overexpression of its protein was discovered in a human breast cancer cell line.² Sequencing of the HER-2/neu gene revealed a distinct gene with strong homology to the epidermal growth factor receptor.³ Since that time, numerous reports have shown that HER-2/neu gene amplification or protein overexpression is evident in 10% to 40% of primary human breast cancers,^4,5 with an overall average of 20% from a combined total of almost 3,000 patients.⁶

Many cell-surface transmembrane receptors are shed. Soluble forms of the insulin, epidermal growth factor receptor, interleukin-2, and tissue necrosis factor receptors have been demonstrated in cell culture supernatants, human serum, and urine. A soluble immunoreactive form of the HER-2/neu receptor has also been detected in the sera of nude mice that bear SK-0V-3 ovarian cancer or MDA-MB-361 breast cancer xenografts.⁷ These antigen levels correlated with both overexpression of the HER-2/neu protein and increased tumor volume. Subsequently, several investigators reported elevations of soluble HER-2/neu in the plasma of 20% to 25% of patients with metastatic breast cancer.^8-10

Breast cancers are either estrogen dependent or estrogen independent. Despite the presence of estrogen receptors (ERs), a proportion of patients will not respond to endocrine treatment. Wright et al¹¹ first reported that coexpression of HER-2/neu was associated with a reduced response rate of ER–positive (ER⁺) patients to first-line hormone therapy of metastatic breast cancer from 48% to 20%. This study used immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumor tissue of the primary breast cancer to detect overexpression of the HER-2/neu oncoprotein, and only 30 ER⁺ tumors were studied. Two follow-up studies using IHC yielded conflicting results.^12,13 We previously reported that elevated (> 15 ng/mL) pretreatment serum levels of circulating HER-2/neu extracellular domain (ECD) was associated with a lower response rate, decreased time to progression (TTP), and shortened survival in 300 patients receiving second-line hormone therapy for metastatic breast cancer.¹⁴ A second study correlating serum HER-2/neu with response to an antiestrogen droloxifene as first-line endocrine therapy obtained a similar result; however, specimens from only 94 (25%) of 369 patients who were enrolled onto the therapeutic study were available for the HER-2/neu analysis.¹⁵ A different result was obtained by Willsher et al¹⁶ using a serum enzyme-linked immunosorbent assay (ELISA) in 77 patients with stage III or IV breast cancer. No significant correlation was observed between pretreatment serum HER-2/neu levels and response to first-line tamoxifen therapy. In this report, we correlate the presence of elevated levels of serum HER-2/neu detected by an automated ELISA in a much larger group of patients with ER⁺ or ER status unknown metastatic breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Serum was obtained from 719 patients with metastatic breast cancer on the day of the entry onto three independent clinical trials of second-line hormone therapy for metastatic breast cancer. All three trials compared an aromatase inhibitor with megestrol acetate. The first two trials (299 and 267 patients) compared the second-generation aromatase inhibitor fadrozole with megestrol acetate. The third study (153 patients) compared the third-generation aromatase inhibitor letrozole (Femara; Novartis Pharmaceutical Corp, East Hanover, NJ) with megestrol acetate.

Patients in all three studies were between 35 and 92 years of age and had a Karnofsky performance rating of at least 60% or an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3. All patients were required to be postmenopausal as defined according to one of the following criteria: women 50 years old who had not menstruated during the preceding 12 months or had castrate follicle-stimulating hormone levels (> 40 IU/L), those younger than 50 years who had castrate follicle-stimulating hormone levels, or those who had undergone a bilateral oophorectomy. All patients had received unsuccessful antiestrogen therapy for metastatic disease. Patients could have received one adjuvant chemotherapy or one adjuvant hormonal therapy before the start of the study.

Study Design
All three studies were multicenter, randomized, parallel-group, double-blinded trials. Drugs were supplied using the double-dummy technique. Patients who met admission criteria were randomized to receive the following: on study 1, megestrol acetate 40 mg orally (PO) qid plus placebo (matching fadrozole) or fadrozole 1 mg PO bid plus placebo (matching megestrol acetate). Study 2 was identical to study 1. On study 3, patients received megestrol acetate 40 mg PO qid plus placebo (matching letrozole) or letrozole 2.5 mg PO once a day plus placebo (matching megestrol acetate).

Efficacy Assessments
Tumor response in each study was assessed by appropriate measurements or x-rays every 3 months. Complete response (CR) required the complete disappearance of all disease for at least 4 weeks. Partial response (PR) was defined as a 50% decrease in the sum of the product of two diameters of all measurable lesions and at least stabilization of all nonmeasurable disease maintained for a minimum of 4 weeks. Stable disease (SD) consisted of a less than 50% decrease in the sum of the products of two diameters of all measurable lesions that was maintained for at least 6 months. Progressive disease was defined as a greater than 25% increase in the sum of the product of two diameters of one or more measurable tumors or an unequivocal increase of nonmeasurable disease or the appearance of new lesions. Patients with clinical benefit were defined as those responding (CR + PR) plus those with SD for at least 6 months.

TTP, time to treatment failure (TTF), duration of response, and survival were calculated from the date of randomization. TTP represented the time to objective disease progression or death. TTF was the time to the earliest occurrence of progression, death, or withdrawal from randomized trial treatment. Duration of response in patients who achieved CR, PR, or SD for 6 months or more was also defined as the time from randomization to the time of first detection of objective progression. Survival was the time from the date of randomization to death.

Serum Preparation
Blood was drawn by forearm venipuncture 14 days before initiation of second-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 ELISA
Serum HER-2/neu levels were measured using an automated HER-2/neu assay (Bayer Immuno 1; Bayer Co, Tarrytown, NY) for research use. All patient samples were analyzed in blinded fashion, ie, without knowledge of clinical outcome of the individual patient.

Automated Immunoassay for HER-2/neu
The Bayer Immuno 1 HER-2/neu assay is a magnetic particle separation immunoassay designed for the random access automated Bayer 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 contains the mAb NB-3, which is conjugated to fluorescein, and 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 or 450 nm is measured. A cubic-through-zero curve-fitting algorithm is used to construct a calibration curve.

Calibrations and Controls
The Bayer Immuno 1 assay uses six calibrators containing 0, 10, 25, 60, 125, or 250 µg/L 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 cell line SK-BR-3. A further 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 bovine calf serum in DMEM. The supernatant was concentrated to give an ECD concentration of 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 cutoff point is identical to that used in a previous publication.¹⁷ Two-way frequency tables were constructed to describe the categoric variables such as elevated serum HER-2/neu and response status. The ² test was applied to ascertain statistically significant differences. More sophisticated analysis of categoric variables consisted of logistic regression that modeled the probability of CR, PR, or SD with regressors HER-2/neu (nanograms per milliliters) or elevated HER-2/neu, age, race, disease-free interval, ECOG performance status, and ER or progesterone receptor (PgR) status.

Kaplan-Meier survival curves were graphed to compare visually time-to-event variables such as TTP, duration of response, and survival time for the elevated and nonelevated groups. The log-rank test and proportional hazards regression were used to compare these survival curves. All calculations were performed using PROC FREQ, PROC LOGISTIC, PROC LIFETEST, and PROC PHREG in version 8.0 of SAS (SAS Institute, Berkeley, CA).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Serum HER-2/neu was defined as elevated if the pretreatment level exceeded 15 ng/mL, a cutoff point also used in a previous report using the serum HER-2/neu Bayer Immuno 1 assay.¹⁷ The cutoff point value of 15 ng/mL was the mean + 2 SD (9.18 + 2.75 ng/mL) obtained from measuring 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) women (range, 3.13 to 29.13 ng/mL).

Two hundred nineteen patients (30%) with metastatic breast cancer had an elevated serum HER-2/neu, and 500 patients (70%) had a value within the normal range. A similar percentage of elevated serum HER-2/neu was found in each of the three individual studies. There were no significant differences between the elevated and normal serum HER-2/neu groups according to age, race (white v nonwhite), disease-free interval, ECOG performance status, and ER or PgR status. A greater percentage of patients with elevated serum HER-2/neu (129 [59%] of 219) had dominant visceral metastases than those with nonelevated HER-2/neu (197 [39%] of 500), and fewer patients had soft tissue and bone metastases (Table 1; P .0001).

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of TTP as a function of pretreatment serum HER-2/neu level. HER-2/neu not elevated is less than 15 ng/mL (n = 500), and HER-2/neu elevated is > 15 ng/mL (n = 219).

View larger version (15K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of TTF as a function of pretreatment serum HER-2/neu level.

View larger version (17K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot of duration of response to hormone therapy as a function of pretreatment serum HER-2/neu.

View larger version (16K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plot of survival from start of second-line hormone therapy as a function of pretreatment serum HER-2/neu level.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Prediction of which patients have the highest chance of responding to endocrine therapy was changed from using clinical parameters, such as disease-free interval, to the laboratory with the discovery of the ER in the 1960s. The response rate (CR + PR + SD) to endocrine therapy in patients with ER⁺ breast cancer is 50% to 60%. One third to one half of patients will not benefit from treatments that block the ER or inhibit estrogen biosynthesis. A possible explanation for the failure of this group of ER⁺ tumors to respond is that these cancers have developed other autocrine or paracrine pathways to facilitate their growth.⁴

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 overexpression of the HER-2/neu receptor results in tamoxifen resistance in ER⁺ estrogen-dependent, human breast cancer cell lines.^18-20 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.^18-20

Much data exist to suggest 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.²¹ Conversely, treatment of ER⁺ cells with HER-2/neu ligand leads to decreased ER expression.^4,20,22 HER-2/neu overexpression results in activation of the Ras/MAPK signaling pathway in breast tumor cell lines and carcinomas. HER-2/neu overexpression is also associated with enhanced phosphorylation of both serine and tyrosine residues in the ER.^20,23,24 Both alterations may be significant for ligand-independent ER activation with loss of the inhibitory effect of tamoxifen on ER-mediated transcription, providing a viable mechanism to explain the association of HER-2/neu with tamoxifen resistance.

This analysis was performed using serum from 719 patients with metastatic breast cancer randomized in three comparable second-line hormonal treatment studies that included patients with similar entry criteria. Sera were analyzed for HER-2/neu using the Bayer Immuno 1 assay. A previous study of 378 patients in the pivotal trastuzumab metastatic breast cancer trials showed a significant overall correlation of 74% of patients with elevated serum HER-2/neu who had positive HER-2/neu IHC of the primary tumor (84% correlation with IHC 3⁺ and 44% correlation with IHC 2⁺).²⁵ In our study, patients in all three trials were randomized to receive either megestrol acetate or an aromatase inhibitor (fadrozole in two studies and letrozole in the third). Entry criteria were identical in all three studies, which allowed for pooling of the data. All patients were ER⁺, PgR⁺, or both or both receptors were unknown. In nearly every case, the results were the same as in the pooled analysis. Overall, the chance of a patient achieving clinical benefit from second-line endocrine therapy (CR + PR + SD) was approximately half (23% v 45%) if her serum HER-2/neu was elevated (> 15 ng/mL). In addition, the median duration of response was significantly shorter in the patient group with elevated serum HER-2/neu (11.7 v 17.4 months; P < .0001). The TTP and TTF for all patients were significantly shorter in the patient cohort with elevated serum HER-2/neu (3 v 6 months; P < .0001). In this study, in addition to decreased response to endocrine therapy, the survival of patients from the initiation of second-line hormonal therapy was shorter if they had elevated serum HER-2/neu. Our results support the recent conclusion of Hamilton and Piccart²⁶ that HER-2/neu is the most promising molecular marker for predicting decreased response to hormonal therapy in breast cancer.

A previous article using IHC for HER-2/neu concluded that HER-2/neu is not significantly associated with a poorer response to tamoxifen or a more aggressive clinical course.¹² However, as the authors of this article state "IHC is a semisubjective method, so that study results can vary somewhat by observer." In addition, the serum HER-2/neu levels quantified in our much larger study were obtained from the immediate pretreatment blood drawn at the time of patient entry onto the trial, not from formalin-fixed paraffin tumor blocks that are often stored many years before a patient relapses with metastatic disease.

A logical therapeutic approach for patients whose cancer is both ER⁺ and overexpresses HER-2/neu may be to simultaneously block both the ER and HER-2/neu pathways. BT474 is an ER⁺ breast cancer cell line that overexpresses HER-2/neu. Simultaneously interrupting the ER pathway with the antiestrogen 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.²⁷ Clinical trials in metastatic breast cancer comparing treatment with an aromatase inhibitor alone versus an aromatase inhibitor combined with trastuzumab will shortly commence.

	ACKNOWLEDGMENTS

 
We thank Eileen Kenney for her excellent help in the preparation of the 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. King CR, Kraus MH, Aaronson SA: Amplification of a novel v-erbB-2 related gene in a human mammary carcinoma. Science 229: 974-976, 1985[Abstract/Free Full Text]

3. Schechter AL, Hung MC, Vaidyanathan L, et al: The neu gene: An erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor. Science 229: 976-978, 1985[Abstract/Free Full Text]

4. 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]

5. 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]

6. 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]

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. 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]

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

10. Leitzel K, Teramoto Y, Sampson E, et al: Elevated soluble c-erbB-2 antigen levels in the serum and effusions of a proportion of breast cancer patients. J Clin Oncol 10: 1436-1443, 1992[Abstract/Free Full Text]

11. 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]

12. Elledge RM, Green S, Ciocca D, et al: HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: A Southwest Oncology Group study. Clin Cancer Res 4: 7-12, 1998[Abstract]

13. Houston SJ, Plunket TA, Barnes DM, et al: Overexpression of c-erbB-2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79: 1220-1226, 1999[CrossRef][Medline]

14. Leitzel K, Teramoto Y, Konrad K, et al: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13: 1129-1135, 1995[Abstract]

15. Yamauchi H, O’Neill A, Gelman R, et al: Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of HER-2/neu protein. J Clin Oncol 15: 2518-2524, 1997[Abstract/Free Full Text]

16. Willsher PC, Beaver J, Pinder S, et al: Prognostic significance of serum c-erbB-2 protein in breast cancer patients. Breast Cancer Res Treat 40: 251-255, 1996[CrossRef][Medline]

17. Schwartz MK, Smith C, Schwartz DC, et al: Monitoring therapy by serum HER-2/neu. Int J Biol Markers 15: 324-329, 2000[Medline]

18. 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, 1992[CrossRef][Medline]

19. 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]

20. 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]

21. 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]

22. 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: 494, 1992 (abstr)

23. 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]

24. 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]

25. 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)

26. Hamilton A, Piccart M: The contribution of molecular markers to the prediction of response in the treatment of breast cancer: A review of the literature of HER-2, p53 and BC1-2. Ann Oncol 11: 647-663, 2000[Abstract/Free Full Text]

27. Witters LM, Kumar R, Chinchilli VM, 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 May 22, 2001; accepted December 5, 2001.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. U. Buzdar Role of biologic therapy and chemotherapy in hormone receptor- and HER2-positive breast cancer Ann. Onc., June 1, 2009; 20(6): 993 - 999. [Abstract] [Full Text] [PDF]

				A. F. Leary, W. M. Hanna, M. J. van de Vijver, F. Penault-Llorca, J. Ruschoff, R. Y. Osamura, M. Bilous, and M. Dowsett Value and Limitations of Measuring HER-2 Extracellular Domain in the Serum of Breast Cancer Patients J. Clin. Oncol., April 1, 2009; 27(10): 1694 - 1705. [Abstract] [Full Text] [PDF]

				J. S. Ross, E. A. Slodkowska, W. F. Symmans, L. Pusztai, P. M. Ravdin, and G. N. Hortobagyi The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine Oncologist, April 1, 2009; 14(4): 320 - 368. [Abstract] [Full Text] [PDF]

				L. Witters, P. Scherle, S. Friedman, J. Fridman, E. Caulder, R. Newton, and A. Lipton Synergistic Inhibition with a Dual Epidermal Growth Factor Receptor/HER-2/neu Tyrosine Kinase Inhibitor and a Disintegrin and Metalloprotease Inhibitor Cancer Res., September 1, 2008; 68(17): 7083 - 7089. [Abstract] [Full Text] [PDF]

				V. Ludovini, S. Gori, M. Colozza, L. Pistola, E. Rulli, I. Floriani, E. Pacifico, F. R. Tofanetti, A. Sidoni, C. Basurto, et al. Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival Ann. Onc., May 1, 2008; 19(5): 883 - 890. [Abstract] [Full Text] [PDF]

				L. Harris, H. Fritsche, R. Mennel, L. Norton, P. Ravdin, S. Taube, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer J. Clin. Oncol., November 20, 2007; 25(33): 5287 - 5312. [Abstract] [Full Text] [PDF]

				V. Kulasingam and E. P. Diamandis Proteomics Analysis of Conditioned Media from Three Breast Cancer Cell Lines: A Mine for Biomarkers and Therapeutic Targets Mol. Cell. Proteomics, November 1, 2007; 6(11): 1997 - 2011. [Abstract] [Full Text] [PDF]

				R. J. Pietras and D. C. Marquez-Garban Membrane-Associated Estrogen Receptor Signaling Pathways in Human Cancers Clin. Cancer Res., August 15, 2007; 13(16): 4672 - 4676. [Full Text] [PDF]

				R. Bartsch, C. Wenzel, G. Altorjai, U. Pluschnig, R. M. Mader, M. Gnant, R. Jakesz, M. Rudas, C. C. Zielinski, and G. G. Steger Her2 and Progesterone Receptor Status Are Not Predictive of Response to Fulvestrant Treatment Clin. Cancer Res., August 1, 2007; 13(15): 4435 - 4439. [Abstract] [Full Text] [PDF]

				M. Colozza, E. de Azambuja, N. Personeni, F. Lebrun, M. J. Piccart, and F. Cardoso Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer Oncologist, March 1, 2007; 12(3): 253 - 270. [Abstract] [Full Text] [PDF]

				F. R. Luo, Z. Yang, A. Camuso, R. Smykla, K. McGlinchey, K. Fager, C. Flefleh, S. Castaneda, I. Inigo, D. Kan, et al. Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure Clin. Cancer Res., December 1, 2006; 12(23): 7180 - 7186. [Abstract] [Full Text] [PDF]

				A. M. Gonzalez-Angulo, G. N. Hortobagyi, and F. J. Esteva Adjuvant Therapy with Trastuzumab for HER-2/neu-Positive Breast Cancer Oncologist, September 1, 2006; 11(8): 857 - 867. [Abstract] [Full Text] [PDF]

				C. Jackisch HER-2-Positive Metastatic Breast Cancer: Optimizing Trastuzumab-Based Therapy Oncologist, September 1, 2006; 11(suppl_1): 34 - 41. [Abstract] [Full Text] [PDF]

				S.-Y. Kong, B.-H. Nam, K. S. Lee, Y. Kwon, E. S. Lee, M.-W. Seong, D. H. Lee, and J. Ro Predicting Tissue HER2 Status Using Serum HER2 Levels in Patients with Metastatic Breast Cancer Clin. Chem., August 1, 2006; 52(8): 1510 - 1515. [Abstract] [Full Text] [PDF]

				R. J. Pietras Biologic Basis of Sequential and Combination Therapies for Hormone-Responsive Breast Cancer Oncologist, July 1, 2006; 11(7): 704 - 717. [Abstract] [Full Text] [PDF]

				S-Y Kong, J H Kang, Y Kwon, H-S Kang, K-W Chung, S H Kang, D H Lee, J Ro, and E S Lee Serum HER-2 concentration in patients with primary breast cancer J. Clin. Pathol., April 1, 2006; 59(4): 373 - 736. [Abstract] [Full Text] [PDF]

				M. De Laurentiis, G. Arpino, E. Massarelli, A. Ruggiero, C. Carlomagno, F. Ciardiello, G. Tortora, D. D'Agostino, F. Caputo, G. Cancello, et al. A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer Clin. Cancer Res., July 1, 2005; 11(13): 4741 - 4748. [Abstract] [Full Text] [PDF]

				H J Huang, P Neven, M Drijkoningen, R Paridaens, H Wildiers, E Van Limbergen, P Berteloot, F Amant, I Vergote, and M R Christiaens Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer J. Clin. Pathol., June 1, 2005; 58(6): 611 - 616. [Abstract] [Full Text] [PDF]

				M. N. Fornier, A. D. Seidman, M. K. Schwartz, F. Ghani, R. Thiel, L. Norton, and C. Hudis Serum HER2 extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ hybridization and with response rate Ann. Onc., February 1, 2005; 16(2): 234 - 239. [Abstract] [Full Text] [PDF]

				M. Ellis Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition Oncologist, June 3, 2004; 9(suppl_3): 20 - 26. [Abstract] [Full Text] [PDF]

				J. W. Park, R. S. Kerbel, G. J. Kelloff, J. C. Barrett, B. A. Chabner, D. R. Parkinson, J. Peck, R. W. Ruddon, C. C. Sigman, and D. J. Slamon Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development Clin. Cancer Res., June 1, 2004; 10(11): 3885 - 3896. [Full Text] [PDF]

				J. S. Ross, J. A. Fletcher, K. J. Bloom, G. P. Linette, J. Stec, W. F. Symmans, L. Pusztai, and G. N. Hortobagyi Targeted Therapy in Breast Cancer: The HER-2/neu Gene and Protein Mol. Cell. Proteomics, April 1, 2004; 3(4): 379 - 398. [Abstract] [Full Text] [PDF]

				W. J. Kostler, B. Schwab, C. F. Singer, R. Neumann, E. Rucklinger, T. Brodowicz, S. Tomek, M. Niedermayr, M. Hejna, G. G. Steger, et al. Monitoring of Serum Her-2/neu Predicts Response and Progression-Free Survival to Trastuzumab-Based Treatment in Patients with Metastatic Breast Cancer Clin. Cancer Res., March 1, 2004; 10(5): 1618 - 1624. [Abstract] [Full Text] [PDF]

				R. Colomer, A. Llombart-Cussac, A. Lluch, A. Barnadas, B. Ojeda, V. Caranana, Y. Fernandez, J. Garcia-Conde, S. Alonso, S. Montero, et al. Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER2 extracellular domain Ann. Onc., February 1, 2004; 15(2): 201 - 206. [Abstract] [Full Text] [PDF]

				A. Jones Combining trastuzumab (Herceptin(R)) with hormonal therapy in breast cancer: what can be expected and why? Ann. Onc., December 1, 2003; 14(12): 1697 - 1704. [Abstract] [Full Text] [PDF]

				W. P. Carney, R. Neumann, A. Lipton, K. Leitzel, S. Ali, and C. P. Price Potential Clinical Utility of Serum HER-2/neu Oncoprotein Concentrations in Patients with Breast Cancer Clin. Chem., October 1, 2003; 49(10): 1579 - 1598. [Abstract] [Full Text] [PDF]

				J. S. Ross, J. A. Fletcher, G. P. Linette, J. Stec, E. Clark, M. Ayers, W. F. Symmans, L. Pusztai, and K. J. Bloom The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy Oncologist, August 1, 2003; 8(4): 307 - 325. [Abstract] [Full Text] [PDF]

				A. Lipton, S.M. Ali, K. Leitzel, L. Demers, H.A. Harvey, H.A. Chaudri-Ross, C. Brady, P. Wyld, and W. Carney Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen J. Clin. Oncol., May 15, 2003; 21(10): 1967 - 1972. [Abstract] [Full Text] [PDF]

				M. Ozdogan, M. Samur, H. S. Bozcuk, E. Sagtas, M. Yildiz, M. Artac, and B. Savas Durable Remission of Leptomeningeal Metastasis of Breast Cancer with Letrozole: a Case Report and Implications of Biomarkers on Treatment Selection Jpn. J. Clin. Oncol., May 1, 2003; 33(5): 229 - 231. [Abstract] [Full Text] [PDF]

				S. De Placido, M. De Laurentiis, C. Carlomagno, C. Gallo, F. Perrone, S. Pepe, A. Ruggiero, A. Marinelli, C. Pagliarulo, L. Panico, et al. Twenty-year Results of the Naples GUN Randomized Trial: Predictive Factors of Adjuvant Tamoxifen Efficacy in Early Breast Cancer Clin. Cancer Res., March 1, 2003; 9(3): 1039 - 1046. [Abstract] [Full Text] [PDF]

				G. Konecny, G. Pauletti, M. Pegram, M. Untch, S. Dandekar, Z. Aguilar, C. Wilson, H.-M. Rong, I. Bauerfeind, M. Felber, et al. Quantitative Association Between HER-2/neu and Steroid Hormone Receptors in Hormone Receptor-Positive Primary Breast Cancer J Natl Cancer Inst, January 15, 2003; 95(2): 142 - 153. [Abstract] [Full Text] [PDF]

				M. Beltran, R. Colomer, A Lipton, S.M. Ali, and K. Leitzel Does HER-2 Status Predict Only a Decreased Response to Hormone Therapy in Advanced Breast Cancer, or Does It Also Predict the Extent of Metastatic Disease? J. Clin. Oncol., December 1, 2002; 20(23): 4605 - 4606. [Full Text] [PDF]

				L. C. Panasci, A. Lipton, S.M. Ali, K. Leitzel, L. Engle, and V. Chinchilli HER-2/neu Serum Levels Vis-a-Vis Hormonal Response in Metastatic Breast Cancer J. Clin. Oncol., August 1, 2002; 20(15): 3357 - 3357. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lipton, A. Articles by Allard, J. Search for Related Content PubMed PubMed Citation Articles by Lipton, A. Articles by Allard, J. Social Bookmarking                            What's this?