Assessment of Her-2/neu Overexpression in Primary Breast Cancers and Their Metastatic Lesions: An Immunohistochemical Study

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1 Annals o f Clinical & Laboratory Science, vol. 30, no. 3, Assessment of Her-2/neu Overexpression in Primary Breast Cancers and Their Metastatic Lesions: An Immunohistochemical Study Shahla Masood and Marilyn M. Bui Department of Pathology and Laboratory Medicine, University of Florida Health Science Center, Shands Jacksonville Hospital, Jacksonville, Florida Abstract. Since the development of novel immunotherapy using Herceptin as the first agent specifically indicated for HER-2/neu overexpression in metastatic breast cancer, there has been interest in using HercepTest as a predictor of response to such therapy. There is debate whether it is justifiable to perform HercepTest on every newly diagnosed breast cancer, since only approximately 43% of the cases will have related metastatic disease, and Herceptin is indicated only for breast cancer with metastatic disease. It may be more cost-effective to limit HercepTest to the related metastatic lesions. Therefore, it is important to assess whether the pattern of HERrllneu overexpression of metastatic breast cancer is also present in the primary lesion. HercepTest was performed on formalin-fixed, paraffin-embedded tissue sections of 56 primary breast cancers and their corresponding metastatic lesions. The protocol and scoring guidelines recommended by the manufacturer were followed. Tissue sections (5 lm) of a primary and the metastatic lesion from the same case were placed parallel on a single glass slide. The pattern and intensity of YŒK-Hneu overexpression (32%) in the primary and metastatic lesions were found to be nearly identical. Heterogeneity was observed in only one case. The score of primary cancer was 3+, and the metastatic lesion was 2+. Both were reported as positive. Intratumor heterogeneity (1+ to 3+) was also noted in two (4%) cases. However, the same pattern was found in both the primary and related metastatic lesions. The nearly identical HercepTest results in the primary and metastatic lesions suggest the potentiality of limiting the HercepTest to breast cancer-related métastasés. Currently, any superficial and most deep-seated metastatic lesions can be easily sampled by fine needle aspiration biopsy or core biopsy, providing adequate samples for HercepTest. Eliminating unnecessary use of the HercepTest may provide a cost-effective alternative approach to the management of breast cancer patients. Keywords: HER-2/««, overexpression, HercepTest, immunohistochemistry, breast cancer Introduction In the last few years there has been significant interest in the assessment of the H ER-21 neu oncogene amplification and overexpression in breast cancer. The HER-2/neu oncogene, also known as c-erb B2, encodes a 185 kd transmembrane protein, which is related to the epiderm al grow th factor receptor [1-3]. Address correspondence to Shahla Masood, M.D., Department o f Pathology, University o f Florida Health Science Center/ Jacksonville, 655 West 8th Street, Jacksonville, FL , USA; tel: ; fax: ; e-m ail: shahla.masood@jax.ufl.edu. Amplification and overexpression of HER-2/we«have been observed in 25-30% of the human breast cancers [4-5]. As a previous study indicated, HER-2/neu overexpression is m ainly (95%) achieved by gene amplification (increased number of copies of the normal HER-21 neu gene), resulting in increased gene transcription, increased HER-2/neu receptors on the cell membrane (overexpression), and increased cell proliferation [4]. HER-2/«^m positivity has been correlated with a shorter disease-free interval and a shorter overall survival in node-positive and nodenegative breast cancers [6-9]. Patients with HER-2/ neu amplification/overexpression are less responsive to /00/ $1.75; 2000 by the Association of Clinical Scientists, Inc.

2 260 Annals o f Clinical & Laboratory Science cyclophosphamide, methotrexate, 5-fluorouracilcontaining adjuvant therapy, and resistant to tamoxifen treatment, but more responsive to dose-intensified doxorubicin-based therapy [7,10-11]. A recently developed, FDA approved immunotherapy using Herceptin is the first therapy specifically indicated for H ER-2/««overexpressing metastatic breast cancer [12-14]. It is indicated for use as a single agent for the treatment of patients who have received one or more chemotherapy regimens for metastatic disease, or in combination with paclitaxel for treatment of patients who have not received chemotherapy for metastatic disease. There are three principal reasons for deter mination of the status of HER-2/neu in breast cancer patients: (1) to assess the prognosis of the breast cancer, (2) to predict the outcome of adjuvant chemotherapy and endocrine therapy, and (3) to select patients for Herceptin immunotherapy. Since the FDA s approval of HercepTest as a predictor of response to Herceptin immunotherapy, many physicians order the HercepTest assay for patients with newly diagnosed breast cancer. It is debatable whether this practice is justifiable. Considering that only cases that are metastatic (43%) and HercepTest positive (25-30%) will benefit from Herceptin, it may be more cost-effective to limit HercepTest to breast cancer-related metastatic lesions. To assess whether the pattern of HER-2/wew overexpression of metastatic breast cancer is also present in the primary lesion, we performed parallel HercepTest assays on formalin-fixed paraffin-embedded tissue sections of 56 primary breast cancers and their corresponding metastatic lesions. Materials and Methods Cases were selected from our Surgical Pathology database by SNOMED code searching for metastatic breast cancer. After reviewing the archived slides, the most representative sections of the primary tumor and its metastatic lesion were identified. The corresponding tissue blocks of these cases were sectioned. For each block, two consecutive 5- lm sections were obtained for H&E stain and HercepTest, respectively. The H&E slides were reviewed again by a pathologist to confirm the diagnosis prior to immunohistochemical staining. By this process, 56 cases of primary breast cancers and their metastatic lesions were selected for this study. Fig. 1. Tissue sections from both a primary cancer and its metastatic lesion were placed parallel on a single glass slide, (a) and (b): H & E stains of a primary breast cancer and involved lymph node; (c) and (d): HercepTest result of the same case. (Note the brown staining indicating positive immunoreactivity to HercepTest.) HER-2/neu testing. HER-2/««/ overexpression was assayed manually using the HercepTest Kit (DAKO Corp., Carpinteria, CA), following the manufacturer s protocol and scoring guidelines. Tissue sections (5 U r n ) of each primary tumor and its metastatic lesion were placed parallel on a single glass slide (Fig. 1). In brief, the HercepTest procedure involves the following seven steps: (1) deparaffinization in three 10m in changes o f xylene, followed by rehydration through alcohols to distilled water; (2) antigen recovery with Epitope Retrieval Reagent at 95 C for 40 min; (3) hydrogen peroxide blocking for 5 min; (4) primary antibody application for 30 min; (5) application of labeled secondary antibody ( Visualization Reagent ) for 30 min; (6) application of diaminobenzidine chromogen; and finally (7) counterstaining with hematoxylin.

3 Her-2/neu overexpression in breast cancers and métastasés 261 Fig. 2. Scoring and interpretation of HercepTest. (a, top left) and (b, right): 1+ score is faintly perceptible staining of partial membrane of a primary infdtrating ductal carcinoma (40X) and the related lymph node métastasés (x20). (c, middle left) and (d, right): 2+ score is weak staining of the entire membrane of a primary lesion (x40) and its métastasés (x20). (e, bottom left) and (f, right): 3+ score is moderate or strong staining of the entire membrane evidenced by brown color in a primary lesion (x20) and its métastasés (x20).

4 262 Annals o f Clinical & Laboratory Science Each run included a positive control slide of a breast cancer case, selected from our hospital s series, that was known to express HER-2/neu, and a kit control slide of three pelleted breast cell lines with staining intensity scores of zero, 1+, and3+. According to the HercepTest kit s scoring guidelines, the pattern and intensity of membrane staining were both considered for scoring. Scores of 0 and 1+ were interpreted and reported as negative for HER-2/»«/ overexpression; scores of 2+ and 3+ were positive... - Table 1. H E R -2/««/ overexpression by immunohistochemical detection using the HercepTest kit. Score Interpretation negative negative weak positive strong positive No. of cases (and %) (53.6) (14.3) (10.7) (21.4) -f- V X -"! -I v i 7:.. A A i y. > - Results HER-2/neu overexpression. Among the 56 cases, 18 (32%) were interpreted as positive (scores of 2+ and 3+), and 38 (68%) were interpreted as negative (scores of 0 and 1+) (Fig. 2 and Table 1). Two independent observers were in complete agreement about the results. The pattern and intensity of HER-21neu over expression were identical in the primary tumor and its metastatic lesions in all cases but one. In that case, the score of the primary cancer was 3+, while the metastatic lesion was 2+. Since these results were both reported as positive, the discordance was not clinically relevant. Two (4%) of the cases demonstrated significant heterogeneity of staining (1+ to 3+) within the same tum or (Fig. 3). However, a similar pattern was consistently found in both the primary and related metastatic lesions. ", V f Patient data and pathologicalfeatures o f carcinomas. The patients ages ranged from yr (mean 50.5 yr). The pathologic diagnosis in all of the 56 cases was infiltrating ductal carcinoma of the breast. The cases were all lymph node-positive. In eleven cases there were also metastases to other sites, such as skin, liver, spleen, lung, and bone. - y ", - t \ % C» i- yr y. t ^ \ i ^ v V ijp fls p r,;< [ -,. «:.,«} 1 " > #, y s, & r~( v " \.x tv.^ S» v,? «- -." ; r -V- V» J. -», >..-.,.» J Fig. 3. Intratum or heterogeneity. Membrane staining varying from 1+ to 3+ in a metastatic lymph node (x20). In two cases that had coexisting DCIS, one had the same positive pattern of HER-2/neu overexpression between the DCIS and invasive component; the other demonstrated negativity in the invasive component, but strong positivity (3+ score) in the in situ component of the primary tumor. Non-neoplastic epithelium adjacent to the tumor was not reactive to HercepTest (Fig. 4). Discussion As the importance of HercepTest becomes recognized by clinicians, pathology laboratories are receiving an increasing number of requests for testing of breast cancer specimens. Currently, there are no accepted guidelines for when and how this test should be applied in routine clinical practice. Although there are valid

5 Her-2/neu overexpression in breast cancers and, métastasés Fig. 4. No normal epithelium staining. The component of infiltrating tumor was strongly positive by HercepTest, while the adjacent normal epithelium was clearly negative (20x). reasons for HercepTest, such testing should be limited to circumstances where the test results will influence the course of therapy. The American Cancer Society estimates that there will be about 175,000 new cases of invasive breast cancer this year among women in the United States. Because of improvement of patient education and early detection, more than half (56.2%) of all cases of breast cancer reported in 1995 were diagnosed as stage 0 and stage I disease, which have a favorable prognosis [15]. However, in the remaining patients, especially those with metastases, the 10-year relative survival rates were poor (ie, stage III, 36%; and stage IV, 7%). Among the estimated 175,000 new cases of invasive breast cancer per year, more than 43% have related metastatic lesions. Potentially 25-30% of these cases will overexpress HER-2tneu oncogene, 263 w hich will test positive by H ercept est. T he management of this large number of cases each year is a financial challenge. We propose that for a breast cancer patient who presents with a metastatic lesion, the clinician, instead of assessing HER-2/«<?m status of the primary breast cancer, might adopt the alternative approach of assessing HER-2 tneu status of the metastatic lesion. Currently, any superficial and most deep-seated metastatic lesions (excluding those in the brain, spine, and spinal cord, etc.) can be easily sampled by fine needle aspiration biopsy or core biopsy [1617]. Cellular material and tumor tissue obtained via non-surgical sampling of metastatic lesions frequently provide adequate samples to determine the status of HER-2Ineu by HercepTest, as well as to assess other prognostic factors [15]. This has value in guiding the therapy for breast cancer with metastatic lesions. Eliminating unnecessary use of the HercepTest may provide a cost-effective alternative approach to the management of breast cancer patients. Therefore, it is important to know if there is heterogeneity between the prim ary breast cancer and its corresponding m etastatic lesion in regard to HER-2 Ineu over expression. In the present study, HER-2 Ineu was over expressed in 32% of the primary breast cancers and their metastatic sites, which is in agreement with published data [4-5]. Moreover, the pattern of HER2Ineu overexpression was nearly identical in the primary and metastatic lesions. In one case, the score of the primary cancer was 3+ and that of the metastatic lesion was 2+. Both were reported as positive. To our knowledge, this is the first study of this kind. The results are encouraging for those who seek an alternative approach for management of breast cancer patients with metastases. Heterogeneity of HER-2/neu overexpression has been observed in other studies. Diverse sensitivity and specificity of the antibodies were potentially responsible factors [18-20]. The methods of tissue fixation and antigen recovery also contributed to the discordance. Intratum oral heterogeneity of HER-2 Ineu ampli fication and overexpression has been reported [22], but the extent of such heterogeneity is unknown. To minimize factors that might contribute to the diversity of the results, the HercepTest was used following the recommended procedures and scoring guidelines. The

6 264 Annals o f Clinical & Laboratory Science archived materials were fixed, embedded, stored, and sectioned in the same fashion. These tests were performed in batches by the same operator. More important, sections of the primary cancer and its metastases were placed parallel on the same slide. We observed intratumoral heterogeneity (1+ to 3+) only in 2 cases (4%). However, the same pattern was found in the primary and related metastatic lesions, which did not make any clinical difference. Since the approval of HercepTest for HER-2/««/ testing by the FDA, tincreasing numbers of laboratories are using this test. There have been reports of a high percentage of positive results (>50%) and of staining of non-neoplastic epithelium adjacent to the tumor [23]. It has been suggested that such obscuring staining should be deducted when interpreting the results of HercepTest. In our experience, HER-2/neu positivity is rarely encountered in normal epithelium by HercepTest. In the present study, no staining of nonneoplastic epithelium adjacent to the tumor was observed. In summary, the consistency of the HercepTest results for primary and metastatic breast cancer in our study may be of clinical importance. This information provides a level of reassurance if a clinician decides to treat a metastatic breast cancer with Herceptin on the basis of a HercepTest performed on a primary breast carcinoma. Alternatively, it becomes more cost-effective to defer performing the HercepTest on early stage primary breast carcinomas. Metastatic lesions, when they occur, can be sampled by non-surgical procedures, and evaluated by HercepTest for assessment of HER- 2Ineu overexpression. Acknowledgment The authors thank Karen McCaulley, BS, H T (ASCP), a histotechnologist at the Tumor Analysis Laboratory of Shands Jacksonville, for performing the HercepTest. DAKO Corp. supported this project by providing HercepTest kits. References 1. Schecter AL, Stern DF, Vaidyanathan L, et al. The neu oncogene: an ir -B related gene encoding a 185, 000- M r tumor antigen. Nature 1984;312: AkiyamaT, Sudo C, Ogawara H, et al. The product of the hum an c-erb B-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science 1986; 232: Coussens L, Yang-Feng TL, Liao Y-C, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230: Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/wi«oncogene. Science 1987;235: Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244: Lovekin C, Ellis IO, Locker A, et al. c-erb B-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 1991;63: Gusterson BA, Gelber RD, Goldhirsch A, et al, for the International (Ludwig) Breast Cancer Study Group. Prognostic importance of c-erb B2 expression in breast cancer. J Clin Oncol 1992;10: Seshadri R, Firgaira FA, Horsfall DJ, et al. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study G roup. J C lin O ncol 1993; 11: Quenel N, Wafflart J, Bonichon F, et al. The prognostic value of c-erb B2 in primary breast carcinomas: a study on 942 cases. Breast Cancer Res Treat 1995;35: Muss HB, Thor AD, Berry DA, et al. c-erb B2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994; 330: Carlomagno C, Perrone F, Gallo C, et al. c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol 1996;14: Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-pl85her2 monoclonal antibody in patients with HER2/«f«-overexpression metastatic breast cancer. J Clin Oncol 1996;14: Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Pton V, Shak S, Laeberman DG, Slamon D. Efficacy and safety of Herceptin (humanized anti-her-2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 1998; 17:376.

7 Her-2/neu overexpression in breast cancers and métastasés Slamon D, Leyland-Jones B, Shak S, et al. Addition of Herceptin (humanized anti-her-2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anticancer activity: A randomized, multinational controlled Phase III trial. Proc Am Soc Clin Oncol 1998;17: Fremgen AM, Bland KI, McGinnis LMS Jr, et al. Clinical highlights from the National Cancer Data Base, CA Cancer J Clin 1999;49: Masood S. Prognostic factors in breast cancer: use of cytologic preparations. Diagn Cytopathol 1995;13: Clin MJ, Battifora J, Yokota J. Proto-oncogene abnormalities in human breast cancer: correlations with anatomic features and clinical course of disease. J Clin Oncol 1987;5: Press MF, Hung G, Godolphin W, et al. Sensitivity of HER-2Ineu antibodies in archival tissue samples: potential sources of error in immunohistochemical studies of oncogene expression. Cancer Res 1994;54: Busmanis I, Feleppa F, Jones A, et al. Analysis of c-erb B2 expression using a panel of commercially available antibodies. Pathology 1994;26: Szollosi J, Balazs M, Feuerstein BG, et al. ERB B-2 (HER2!neu) gene copy number, pl85h ER-2 overexpression, and intratumor heterogenerity in human breast cancer. Cancer Res 1995;15;55: Pennault-Llorca F, Adelaide J, Houvenaeghel G, et al. Optimization of immunohistochemical detection of erb >2 in human breast cancer: Impact of fixation. J Pathol 1994;173: Pertschuk LP, Axiotis CA, Feldman JG, et al. Marked intratumoral heterogeneity of the protooncogene HER- 2Ineu determined by three different detection systems. Breast J (in press) 23. Jacobs TW, Gown AM, Yaxiji H, et al. Specificity of HercepTest in determining HF>R-2/«i«status of breast cancers using the United States Food and Drug Administration approved scoring system. J Clin Oncol 1999;17:

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