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Clinical Cancer Research Vol. 9, 601-605, February 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

High and Differential Expression of HER-2/neu Extracellular Domain in Bilateral Ductal Fluids from Women with Unilateral Invasive Breast Cancer1

Henry M. Kuerer2, Patricia A. Thompson3, Savitri Krishnamurthy, Herbert A. Fritsche, Sylvie M. Marcy, Gildy V. Babiera, S. Eva Singletary, Massimo Cristofanilli, Nour Sneige and Kelly K. Hunt

Departments of Surgical Oncology [H. M. K., S. M. M., G. V. B., S. E. S., K. K. H.], Epidemiology [P. A. T.], Laboratory Medicine [H. A. F.], Pathology [S. K., N. S.], and Breast Medical Oncology [M. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Patients and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: Overexpression of HER-2/neu is associated with aggressive diseaseand perhaps with increased risk of breast cancer when presentin benign breast tissue. Breast ductal fluid can be obtained from women by simple nipple aspiration and may be useful for analyzing the microenvironment of the breast.

Experimental Design: After obtaining informed consent, we prospectively compared the volume of fluid collected, protein concentration, and level of HER-2/neu expression in nipple aspiration fluid (NAF) samples from both breasts and serum samples in 65 patients with unilateral primary invasive breast cancer (median age, 54 years). HER-2/neu concentrations were determined by immunoassay, with a sensitivity of 0.1 ng/ml.

Results: The mean NAF volume obtained and the mean NAF protein concentration were no different in the normal versus the affected breast (62.4 versus 60.4 µl and 140.9 versus 107.8 mg/ml, respectively). Mean serum HER-2/neu level was 4.36 ng/ml (range, 0–16.8 ng/ml), ~50 times less than the mean NAF HER-2/neu level from all patients and all breasts (209.2 ng/ml; range, 1.0–3480.0). NAF HER-2/neu levels were significantly correlated between breasts for each individual patient (r = 0.302; P = 0.038). HER-2/neu-overexpressing tumors produced significantly more HER-2/neu in the affected breast (653.6 ng/ml) than in the unaffected breast (101.7 ng/ml) or serum (3.46 ng/ml; P = 0.016).

Conclusions: Nipple aspiration is a noninvasive method for detecting tumor-specific relevant molecular changes from ductal fluid. The presence of high HER-2/neu levels in the ductal systems of breast cancer patients may have clinical implications for monoclonal antibody directed therapy.


   Introduction
Top
 ABSTRACT
 Introduction
Patients and Methods
 Results
 Discussion
 REFERENCES
 
Analysis of the biochemical and cellular contents of breast ductal fluid has recently gained attention for its potential to noninvasively study the local microenvironment associated with the development and progression of breast carcinoma (1, 2, 3, 4) . Breast cancers arise from the ductal or lobular units of the breast. These units secrete into an average of six to nine ducts, and the secretions are easily accessible as they exit each breast through separate orifices at the nipple. Interest in nipple aspiration has become renewed partly because a simple hand-held, externally placed suction cup can be used to quickly and noninvasively obtain a concentrated fluid fraction of breast secretions in most women (5) . Although much of the earlier groundbreaking work was performed either with healthy volunteers or women with benign breast disease (2 , 6) , we believe that comparing the ductal fluid characteristics of a breast containing a known carcinoma to the healthy contralateral breast may be a practical method to identify clinically relevant tumor markers that may be useful in risk stratification, diagnosis, treatment monitoring, and detection of cancer recurrence. To investigate this hypothesis, we initiated a prospective trial and enrolled 65 patients with primary invasive breast cancer and measured soluble HER-2/neu in NAF4 samples from the breast with cancer and the normal contralateral breast and in the serum. We chose to measure the extracellular domain of the HER-2/neu tyrosine kinase growth factor receptor because the identification and characterization of this molecule seems to be one of the most significant and clinically relevant developments in our understanding of breast cancer biology and treatment (7, 8, 9, 10) .


   Patients and Methods
Top
 ABSTRACT
 Introduction
 Patients and Methods
Results
 Discussion
 REFERENCES
 
Patients.
Patients who presented to The University of Texas M. D. Anderson Cancer Center Nellie B. Connally Breast Center were eligible to participate in this Institutional Review Board-approved prospective investigation if they had biopsy-proven unilateral primary invasive breast cancer and signed written consent to undergo bilateral nipple aspiration and concomitantly provide a blood sample for serum evaluation. Patients were excluded from participation if they had had prior subareolar surgery that might have disrupted the terminal ductal system.

Ductal Fluid Collection.
Ductal fluid was collected by using a hand-held suction cup similar to a nonpowered breast pump used to express milk from lactating women. This simple device consists of a plastic cup that is connected to a section of polymer tubing. The tubing is attached to a standard syringe that is used to create a gentle vacuum to express breast ductal fluid from the nipple. This device was originally used and described by Sartorius et al. (5) and purchased for this study from Product Health, Inc. (Menlo Park, CA).

Nipple Aspiration Technique.
At the time of definitive surgery, general anesthesia was administered, and the nipple was cleansed with a small amount of Omniprep paste (D. O. Weaver and Co., Aurora, CO) to remove any keratin plugs and then cleansed with an alcohol pad. A small amount of lotion was placed on the breast, and the breast was gently massaged from the chest wall toward the nipple for 1 min. The suction cup was then placed over the nipple, and the plunger of the syringe was withdrawn to the 5–10-ml level until ductal fluid was visualized. The fluid droplets were collected into a 10-µl graduated micropipette (Drummond Scientific Co., Broomall, PA). NAF samples were obtained from both breasts, and the presence and volumes of NAF obtained were recorded for each patient and each breast.

Specimen Preparation and Evaluation.
Immediately after collection, the NAF samples were rinsed into centrifuge tubs containing sterile RPMI or PBS supplemented with protease inhibitors [4-(2-aminoethyl) benzenesulfonylfluoride, HCl] (0.2 mM), leupeptin (50 µg/ml), aprotinin (2 µg/ml), and 1,4-dithio-DL-threitol (0.5 mM). The samples were then centrifuged at 1500 rpm for 10 min, and the supernatant was collected, aliquoted, and stored at -80°C until biochemical analysis.

Total Protein Determination in NAF Samples.
Total protein concentration in NAF samples was determined by using the Micro BCA Protein Assay Reagent (Pierce, Rockford, IL) in triplicate. Protein concentration standards were diluted in the NAF diluent containing protease inhibitors described above.

Determination of HER-2/neu Concentration in NAF and Serum Samples.
The HER-2/neu extracellular domain was measured in NAF and serum samples by using the Bayer Immuno 1 System (Bayer Diagnostics, Tarrytown, NY) as previously described and validated (11) . This assay, currently used in our clinical laboratory, uses two monoclonal antibodies designated NB-3 and TA-1 that bind to two independent binding sites on the HER-2/neu extracellular domain (Oncogene Science, Cambridge, MA). Instruments were calibrated with control samples containing recombinant HER-2/neu protein before the test runs to determine the dynamic range of the assay and to construct a calibration curve. The sensitivity of this assay was determined to be 0.1 ng/ml.

Determination of HER-2/neu Status in the Primary Tumor.
The HER-2/neu status of the primary tumor was determined by immunohistochemical staining of 4-µm sections cut from a representative paraffin block of invasive carcinoma as follows. The slides were incubated with the anti-HER-2/neu monoclonal antibody e2-4001 (1:100 dilution) on a Dako autostainer (Dako Corp., Carpinteria, CA) with the LSAB-2 peroxidase kit (Dako Corp.) using 3,3'-diaminobenzidine. The percentage of cells displaying complete membrane staining and the intensity of the staining were evaluated on a semiquantitative scale of 0–3+. In all cases exhibiting any positivity (1+–3+), we confirmed the immunoreactivity by fluorescence in situ hybridization analysis of the Her-2/neu gene copy number. We used the Path Vysion HER-2/neu kit (Vysis, Downers Grove, IL), which uses two directly labeled fluorescent DNA probes, one specific for the HER-2/neu gene locus and the second for the alpha satellite DNA sequence at the centromeric region of chromosome 17. Signals are counted for 60 tumor cells by using an epifluorescence microscope, and the ratio of HER-2/neu to chromosome 17 is calculated. A ratio > 2.0 is considered to represent HER-2/neu gene amplification and is considered a positive test result.

Statistical Analysis.
For statistical comparisons between groups, individual values were normalized by natural logarithm transformations and the means, SE, and range were reported for each measured variable. Groups were compared with two-tailed paired (Pearson correlation distribution) and the Student’s t test, and differences between groups were considered significant when the Ps were <0.05.


   Results
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 ABSTRACT
 Introduction
 Patients and Methods
 Results
Discussion
 REFERENCES
 
Patient and tumor characteristics from the 65 patients who participated in this prospective protocol are presented in Table 1Citation . The patients median age was 54 years, and 60% were postmenopausal. Most patients were white (77%), had invasive ductal carcinoma (83%), and had stage I or II disease (94%). HER-2/neu gene amplification was found in 18% of breast tumors in this series.


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  		Table 1 Patient and tumor characteristics

 
Ductal fluid characteristics are shown in Table 2Citation . NAF samples could be obtained from 88% of breasts without cancer (n = 57) compared with 82% of breasts with cancer (n = 53; P = 0.721). NAF samples could not be obtained from either breast in 7 patients (11%). The mean volume of ductal fluid obtained from the normal breasts versus that from the breasts with cancer was not significantly different (62.4 versus 60.4 µl, respectively; P = 0.779). Ductal fluid samples from either breast were found to contain large amounts of protein. Although the mean protein concentration from the breasts without cancer was somewhat higher than the breasts with cancer, the difference was not statistically significant (140.9 versus 107.8 mg/ml; P = 0.823).


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  		Table 2 Bilateral ductal fluid and serum characteristics from women with unilateral invasive breast cancer

 
High levels of the HER-2/neu extracellular domain were found in NAF samples compared with simultaneously obtained serum samples (Table 2)Citation . The mean HER-2/neu level in the serum of patients from the entire series (n = 65) was 4.36 ng/ml (range, 0–16.8 ng/ml). In patients with HER-2/neu-overexpressing tumors, the mean serum HER-2/neu concentration was 3.46 ng/ml (range, 0–11.2 ng/ml). The mean HER-2/neu level in NAF samples for the entire series (from breasts with and those without cancer) was ~50 times that in the serum. The mean HER-2/neu level in NAF samples from the entire series was 209.2 ng/ml (n = 110 samples; range, 1.0–3480.0). No correlation between NAF and serum HER-2/neu levels was observed. However, a highly significant correlation was noted between the NAF HER-2/neu level in the breast with cancer versus that in the contralateral breast (r = 0.302, P = 0.038; Fig. 1Citation ). In individual patients, the NAF HER-2/neu level was very similar in both breasts regardless of the presence of carcinoma. However, when the analysis was restricted to patients with HER-2/neu-overexpressing tumors, a clear difference in NAF HER-2/neu level was evident between the normal and affected breast, with the affected breast having a significantly elevated HER-2/neu level (653.6 versus 101.7 ng/ml, P = 0.016; Table 2Citation , Fig. 2Citation ).



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  		Fig. 1. HER-2/neu levels in the NAF samples obtained from a patient’s normal breast and the patient’s breast with cancer are highly correlated (r = 0.302; P = 0.038). Data shown represent the mean log HER-2/neu values () with the 95% confidence intervals ( ) from 48 patients from whom NAF samples could be obtained from both the normal breast and the breast with carcinoma.

 


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  		Fig. 2. Box plots of log-transformed HER-2/neu levels in NAF samples from the normal breast and the breast with cancer in patients with known HER-2/neu-overexpressing breast cancers. The {blacksquare} represents the mean HER-2/neu level, the {square} is bounded above and below by the SE, and the upper and lower error bars indicate 95% confidence limits.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Patients and Methods
 Results
 Discussion
REFERENCES
 
Overexpression of HER-2/neu may be involved in the initiation of breast carcinogenesis. It occurs in up to one-third of invasive breast cancers and has been associated with aggressive disease, resistance to certain types of cytotoxic chemotherapy, and poor prognosis (8 , 9) . In this study, our results demonstrate that soluble HER-2/neu was present in high concentrations in the breast ductal fluid of women with breast cancer in comparison to the serum. In addition, the HER-2/neu level between breasts was highly positively correlated in individual women, and differential expression of HER-2/neu was found in NAF samples obtained from breasts with HER-2/neu-overexpressing/amplified tumors in comparison to the healthy contralateral breast. These results establish that biologically pertinent molecules can be detected and measured in NAF samples and suggest that further study of these fluids may be useful in identification of other locally concentrated and potentially relevant molecules.

Breast ductal fluid has been shown to contain a variety of chemical substances and many different proteins (12) . Substances of exogenous origin found in breast ductal fluids include nicotine, caffeine, technetium, pesticides, p.o.-ingested drugs, and Ames test-positive substances that are indicative of mutagenic agents of undetermined origin (6 , 12) , thus indicating that the breast ductal epithelium is in contact with exogenously derived substances. Many endogenously derived proteins have also been found in NAF samples, including immunoglobulins, estrogen and progesterone, androgens, prolactin, prostate-specific antigen, and carcinoembryonic antigen (3 , 6 , 12 , 13) . Perhaps one of the most interesting groups of molecules detected in breast ductal fluid are members of the epidermal growth factor family, which are secreted and act locally and have potent mitogenic effects on human breast cancer cells (14) . Both epidermal growth factor and transforming growth factor {alpha} have been found in NAF samples from healthy premenopausal women, and ErbB-2 (HER-2/neu) has been detected in nipple discharge samples from patients (15) . The extremely high amounts of HER-2/neu extracellular domain detected in bilateral NAF samples from patients with unilateral breast cancer in the current study was unexpected. This finding may have important clinical ramifications in light of recent studies regarding expression of this molecule in patients with benign breast disease and in the use of monoclonal antibody therapy for HER-2/neu-overexpressing breast cancer.

Investigators at the Mayo Clinic and University of North Carolina at Chapel Hill recently explored the relationship between HER-2/neu overexpression in benign breast disease and the risk of subsequent breast cancer in 99 patients (8) . In that study, women whose breast biopsy samples were judged benign but showed both HER-2/neu amplification and benign proliferative findings on histopathology had seven times the risk of developing breast cancer as those whose biopsy samples did show these characteristics. In women with a prior history of breast cancer, the risk of developing contralateral breast cancer is estimated to be 0.7–1%/year. The high levels of HER-2/neu in the contralateral breast of women with a current diagnosis of breast cancer in our study may well be a molecular marker for the known increase in risk of subsequent contralateral breast cancer. In this regard, the finding that the HER-2/neu levels were highly correlated between breasts in individual patients may suggest that endogenous individualized factors associated with HER-2/neu expression are global and that each breast may not act as an independent organ until breast cancer develops. Our observation that HER-2/neu levels were similar in NAF samples obtained from both breasts of individual patients also supports previous reports that expression of this molecule is regulated by multiple circulating factors that may have similar effects on both breasts in an individual patient (16 , 17) .

Trastuzumab, a recombinant monoclonal antibody against HER-2/neu, was recently tested in a Phase III clinical trial for women with metastatic breast cancer that overexpressed HER-2/neu and was found to decrease recurrence and prolong survival compared with patients treated with chemotherapy alone (10) . Trastuzmab is currently being tested in a randomized trial at our institution and in other national trials for women with earlier stage HER-2/neu-overexpressing breast cancer. The high HER-2/neu expression levels found in NAF samples may have important clinical implications regarding the dosage of and response to trastuzumab in patients with and without prior mastectomy, and measurement of HER-2/neu in NAF samples during neoadjuvant trastuzmab therapy might provide important information regarding breast tumor end-organ response.

In summary, the breast is a unique organ in that its microenvironment can be readily accessed and evaluated by aspiration of fluid from the nipple. Ductal fluids contain large amounts of protein. As the breasts are a paired organ system, significant differences may be discovered by conducting systematic comparisons of the NAF between them when cancer develops in one breast. The local molecular microenvironment is markedly different from that of the serum as evidenced by the ~50-fold increase in HER-2/neu in the ductal fluid compared with that in a concomitantly obtained serum sample. Moreover, in women with HER-2/neu-overexpressing tumors, a distinct elevation of HER-2/neu is detectable in NAF samples from the breast with the tumor versus the breast without breast carcinoma. Taken together, these results strongly suggest that analysis of paired NAF samples and serum samples from women with breast cancer may be useful as a high-throughput global discovery mechanism for other highly relevant proteins that may be involved in carcinogenesis, progression of in situ disease to invasive carcinoma, monitoring treatment response of breast cancer in the neoadjuvant setting, and serum marker development. Toward this end, our group has used this strategy to identify 1300 separate protein species by two-dimensional electrophoresis in NAF samples that have unique expression profiles in the breast with the carcinoma relative to the breast without the carcinoma and the serum. We are currently characterizing these expression profiles, and it is hoped that the results of those experiments will allow identification of other useful markers for the prevention and treatment of breast cancer.


   ACKNOWLEDGMENTS
 
We thank Dr. Donald Berry, Dr. Nadeem Mirza, and Deborah Cohen for their assistance in statistical analyses of the data presented in this article.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This investigation was supported, in part, by the Institutional Research Grant Program for Clinical, Translational, and Population-based Projects funded through The University of Texas M. D. Anderson Cancer Center. Back

2 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, Department of Surgical Oncology, 1515 Holcombe Boulevard, Box 444, Houston, TX 77030. Phone: (713) 745-5043; Fax: (713) 792-4689. Back

3 Present Address: Department of Pathology, University of Arizona Cancer Center, Tucson, AZ 85724. Back

4 The abbreviation used is: NAF, nipple aspiration fluid. Back

Received 5/16/02; revised 9/ 9/02; accepted 9/11/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Patients and Methods
 Results
 Discussion
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