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American Journal of Surgical Pathology:
doi: 10.1097/PAS.0b013e3181d65639
Original Articles

Accurately Assessing HER-2/neu Status in Needle Core Biopsies of Breast Cancer Patients in the Era of Neoadjuvant Therapy: Emerging Questions and Considerations Addressed

D'Alfonso, Timothy MD*; Liu, Yi-Fang BSc*; Monni, Stefano PhD; Rosen, Paul Peter MD*; Shin, Sandra J. MD*

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Department of *Pathology and Laboratory Medicine-Starr 1002

Department of Public Health, Division of Biostatistics and Epidemiology, Weill Cornell Medical Center, New York, NY

Correspondence: Sandra J. Shin, MD, Department of Pathology and Laboratory Medicine-Starr 1002, Weill Cornell Medical Center, 1300 York Avenue, New York, NY 10065 (e-mail: sjshin@med.cornell.edu).

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Abstract

Background: Emerging data show that patients with operable, HER-2/neu overexpressed/amplified breast carcinomas have significantly better responses (more frequently obtaining pathologic complete response and greater percent disease-free survival) when treated with trastuzumab (Herceptin) simultaneously with neoadjuvant chemotherapy than with chemotherapy alone. With the increasing use of neoadjuvant therapies, clinicians require information on biomarkers including HER-2/neu status at the time of needle core biopsy. Concordance rates between fluorescence in situ hybridization (FISH)-determined HER-2/neu status on needle core biopsies and on subsequent excisional biopsies of the same tumor have not been well studied. Moreover, the practice of automatically performing (“reflexing”) 2+ immunohistochemical (IHC) staining needle core biopsies for FISH analysis on the same sample needs to be validated. In this study, we set out to (1) determine the accuracy of HER-2/neu status as determined by FISH on needle core biopsy material compared with FISH on the subsequent excisional biopsy of the same tumor with special consideration of IHC 2+staining cases and (2) determine the constancy of HER-2/neu status in pre-neoadjuvant and post-neoadjuvant chemotherapy-treated tumor in the form of needle core biopsy and excisional biopsy samples, respectively.

Design: 100 patients whose needle core biopsies and subsequent excisional biopsy samples were pathologically evaluated at our institution were studied. For each patient, unstained sections from both specimens were prepared and used for IHC or FISH. IHC was carried out using the HercepTest kit (DAKO, Carpinteria, CA). Parallel unstained slides were used to carry out FISH (dual probe, Vysis). Statistical analyses were carried out on the resulting data generated after interpretation.

Results: The concordance rate between FISH results determined on the needle core biopsy and subsequent excisional biopsy of the same tumor was 86% (κ=0.56, P=2×10−8). If equivocal FISH cases (≥1.8 to ≤2.2 amplification ratio) in a needle core biopsy or excisional biopsy specimen or both, were excluded, the concordance rate increased to 95% (κ coefficient=0.86, P=2×10−15). Fourteen of 100 (14%) cases showed 2+ IHC staining in the needle core biopsy specimen with good concordance of FISH-determined HER-2/neu status between the needle core biopsy and excisional biopsy specimens (79% agreement and κ=0.512, P=0.05). Nine, 3, and 2 cases of the 14 cases were amplified, equivocal, and negative on the excisional biopsy specimens, respectively. Of the 15 patients who received neoadjuvant chemotherapy, 93% and 87% had no change in HER-2/neu status as determined by IHC or FISH, respectively, in the excisional biopsy specimen when compared with that determined on the prior core biopsy sample.

Conclusions: Excellent overall concordance was achieved between FISH-determined HER-2/neu status on the needle core biopsy and that determined on the subsequent excisional biopsy of the same tumor. These results suggest that intratumoral heterogeneity of HER-2/neu assessed by FISH is not a significant confounding factor when analyzing smaller sized samples. Furthermore, 79% of 2+IHC staining needle core biopsy cases showed concordant FISH results in the needle core biopsy and subsequent excisional biopsy specimens. Our results show good concordance, however, larger cohorts need to be studied to verify this finding. HER-2/neu status remains unchanged in the majority of cases when comparing pre-neoadjuvant and post-neoadjuvant chemotherapy-treated specimens.

Until recently, neoadjuvant chemotherapy to treat breast cancer was only offered to patients with locally advanced disease. Currently, this treatment approach has been extended to include patients with operable breast cancer. There are emerging data that show that the inclusion of trastuzumab (Herceptin) as part of a neoadjuvant chemotherapy regimen for women with HER-2/neu-positive breast cancer yields a higher pathologic complete response (pCR) rate and greater percentage of patients disease-free than with neoadjuvant chemotherapy alone.6,7,8,10 The increasing number of breast cancer patients being treated in the neoadjuvant setting gives rise to the need to accurately assess biomarkers on the needle core biopsy material that often is the only tissue available before treatment in these patients.

Accurately assessing HER-2/neu status is critically important because this pathologic determination will be one of the most compelling if not the sole reason to decide the eligibility of individual breast cancer patients for trastuzumab treatment. Currently, HER-2/neu status is assessed by 2 methodologies, IHC and FISH. There is an abundance of published studies that report the accuracy of determining HER-2/neu status by these methodologies and the high concordance rate achieved when these methodologies are compared. The current protocol as outlined in the 2007 ASCO/CAP guidelines states that HER-2/neu status is initially assessed by IHC and all 2+staining cases are to be “reflexed” to FISH in determining HER-2/neu status in breast cancer patients suggesting that status determined by FISH is more accurate than IHC.

There are reports of concordance rates using a single methodology and other reports comparing results between different types of biopsy material (ie, needle core biopsy versus excisional biopsy). However, these studies compared HER-2/neu status as determined by IHC in needle core biopsy samples to that of IHC or FISH in the excisional biopsy material. Surprisingly, there is a dearth of studies investigating the concordance rate of FISH-determined HER-2/neu status between needle core biopsy and subsequent excisional biopsy specimens in the same tumor. This is only now becoming apparent owing to the current evolving trend to treat patients with HER-2/neu-positive breast cancer in the neoadjuvant setting in which status is determined exclusively on needle core biopsy material. Studies are needed to confirm that FISH-determined HER-2/neu status on the needle core biopsy sample in 2+IHC cases is equally reliable as the same analysis carried out on the excisional biopsy specimen. The question of whether neoadjuvant chemotherapy alters HER-2/neu status as it does tumor morphology needs to be explored.

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MATERIALS AND METHODS

Sample Selection

One hundred patients with invasive breast carcinoma, whose needle core biopsy and subsequent excisional biopsy specimens (lumpectomy or mastectomy) were pathologically evaluated at our institution, were identified. Fifteen patients had received neoadjuvant chemotherapy. For each of the patient's 2 specimens, 4-μm-thick unstained sections were prepared from selected blocks containing invasive carcinoma. On all specimens, HER-2/neu status was determined by IHC and FISH. “Discordance” was defined as disagreement in 1 of 3 scenarios: (1) between FISH results of the same tumor but different specimens (2) IHC and FISH results on the same specimen and (3) IHC and FISH results on the same tumor but different specimens. Statistical analyses were done on the resulting data.

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Immunohistochemistry

Immunohistochemical staining was carried out on all 200 specimens using the FDA-approved HercepTest kit (Dako, Carpinteria, CA), according to the manufacturer's instructions, with appropriate positive and negative controls.

HER-2/neu overexpression on each tumor was assessed according to the current CAP/ASCO guideline scoring system:

0=no staining observed in invasive tumor cells; 1+=weak, incomplete membrane staining in any proportion of invasive tumor cells, or weak, complete membrane staining in less than 10% of cells; 2+=complete membrane staining that is nonuniform or weak but with obvious circumferential staining in at least 10% of cells, or intense complete membrane staining in 30% or less of tumor cells; 3+=uniform intense membrane staining of more that 30% of tumor cells.

Scores of 0 or 1+were considered negative for overexpression; a score of 2+was considered equivocal; a score of 3+was considered positive for overexpression.

Immunohistochemical scoring was done concurrently by 2 of us (TD, SJS) while blinded to all other IHC and FISH results in the study group. In rare instances, in which there was initial disagreement of the IHC score between the 2 pathologists, the case was, in brief, discussed and consensus of the IHC score was quickly achieved.

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Fluorescent In Situ Hybridization

FISH analyses for HER-2/neu amplification were done on all specimens for which FISH had not been previously conducted (162 total cases). On each H&E slide, the area containing invasive carcinoma, excluding any intraductal component, was outlined with a marking pen and confirmed by 2 of us (TD, SJS). This area was analyzed by dual-color FISH using the PathVysion HER-2/neu DNA Probe Kit (Vysis/Abbott, Downers Grove, IL), with a batch control included in each run. The screening protocol included 2 screeners for each specimen, each reading 30 tumor cells, for a total of 60 cells per specimen. According to the 2007 CAP/ASCO guidelines, tumors were determined to be amplified if the ratio of fluorescent HER-2/neu signals to chromosome 17 centromere signals was >2.2. Tumors with a ratio of <1.8 were determined to show no amplification. Cases showing a ratio of ≥1.8 and ≤2.2 were considered equivocal. FISH analyses for the remaining 38 cases were done previously using the same probe kit and 10% of these cases (4 cases) were retested in our study that yielded 100% concordance with previously determined results.

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Biostatistical Analyses

Percentage of agreement and Cohen's unweighted κ statistic were used as primary measures of agreement between the different techniques.

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RESULTS

Concordance Between FISH Results Obtained on the Needle Core Biopsy Specimen and Subsequent Excisional Biopsy Specimen

FISH results were obtained on the needle core biopsy and subsequent excisional biopsy specimen on the same tumor for all 100 patients. Among 100 patients, there was an 87% concordance rate (Fig. 1) and 13 patients had discordant FISH results (Table 1). Of the 13 discordant cases, the majority (69%) was of a “negative” result in the needle core biopsy changing to an “equivocal” result in the subsequent excisional biopsy specimens, or vice-versa. Only 4 cases (4% overall) were completely discordant in which 2 cases were amplified on the needle core biopsy but unamplified on the subsequent excisional biopsy and the converse was true in the remaining 2 cases (Fig. 2). Of note, if the older FDA recommended cut-off ratio of ≥2 was applied, 5 cases (5%) would be deemed discordant (ie, 95% concordance rate).

Table 1
Table 1
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Figure 1
Figure 1
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Figure 2
Figure 2
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Concordance Between FISH Results Determined on the Needle Core Biopsy and Subsequent Excisonal Biopsy in the Subset of Patients Who Had a 2+ Staining by IHC on Needle Core Biopsy

Of the 100 needle core biopsies evaluated by IHC, 14 (14%) showed 2+ staining by IHC (Table 2). Ten of 14 (71%) cases were not amplified while 3 of 14 (29%) were amplified by FISH on the needle core biopsy specimen. The remaining case was equivocal (ratio 1.8).

Table 2
Table 2
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Of these 14 cases, there was good concordance of FISH-determined HER-2/neu status between the needle core biopsy and excisional biopsy specimens (79% agreement and κ=0.512, P=0.05). Three of these 2+ cases (21% of all 2+ cases) were discordant when comparing FISH results obtained from the needle core biopsy and excisional biopsy. One case was amplified by FISH on the needle core biopsy (ratio 2.7) but was negative by both IHC (0 staining) and FISH (ratio 1.7) on the excisional biopsy specimen. The remaining 2 cases were unamplified by FISH on the needle core biopsy specimens (ratio 1.1 and 1.0) but found to be equivocal on the excisional specimens (ratio 1.8 for both). If the prior FDA approved cut-off ratio of ≥2 was used, greater concordance would be achieved (86% agreement and κ=0.576, P=0.03).

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Concordance Between IHC Result Obtained on the Needle Core Biopsy Specimen and the FISH Result on the Subsequent Excisional Biopsy Specimen

The overall concordance rate was 94%. The concordance rate between the IHC result obtained on the needle core biopsy specimen and the FISH result on the subsequent excisional biopsy specimen differed depending on the initial IHC score (Table 3). Of the 14 cases in which the IHC score was 0 on the needle core biopsy, the concordance rate was 85.7% (12/14). One case was FISH positive (ratio 4.8) (Fig. 3) and the other was equivocal (ratio 1.95). Of the 64 cases with a score of 1+, 58 cases were concordant with the FISH result obtained on the excisional biopsy specimen (concordance of 90.6%). Four of the 6 remaining cases were equivocal and 2 were amplified (the latter, ratio 2.3 for both). The highest concordance (100%) was reached by the 3+scoring cases (8 cases total).

Figure 3
Figure 3
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Table 3
Table 3
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Constancy of HER-2/neu Status by IHC and FISH When Comparing Pre-neoadjuvant and Post-neoadjuvant Chemotherapy-treated Samples

Fifteen of our 100 study patients received neoadjuvant chemotherapy (Table 4). Whether trastzumab was included in this regimen is unknown. Thirteen of 15 (87%) tumors showed the same HER-2/neu status as determined by FISH on the needle core biopsy (prechemo) and subsequent excisional biopsy (postchemo). In 1 of 2 remaining patients, the IHC was 2+on the needle core biopsy and amplified by FISH (ratio-2.7), but FISH on the excisional biopsy was only equivocal (ratio-1.7) and IHC on the excisional biopsy was 0. In the other patient, HER-2/neu was negative by both IHC and FISH on the needle core biopsy but equivocal (ratio=2.0) in the excisional biopsy and IHC on the excisional biopsy was also negative (0 staining). The percentage of unchanged HER-2/neu status cases increased to 93% (14/15) if status was determined by IHC only.

Table 4
Table 4
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CONCLUSIONS

Accurately assessing HER-2/neu status is becoming critically more important as emerging data show the benefit of using trastuzumab (Herceptin) in conjunction with chemotherapy in the neoadjuvant setting for patients with HER-2/neu-positive breast cancer. Furthermore, the clinical impact will broaden as neoadjuvant therapy is offered not only to patients with locally advanced but also with operable breast cancer. Efficacy results from a recent randomized phase III trial have shown that the inclusion of trastuzumab (Herceptin) as part of a neoadjuvant chemotherapy regimen for women with HER-2/neu-positive breast cancer yielded a higher pathologic complete response (pCR) rate and higher percentage of patients disease-free than did neoadjuvant chemotherapy alone.6,7,8,10 Furthermore, trastuzumab used as a single agent in the neoadjuvant setting may be a future possibility, although, there are no trials currently addressing this option.10

Although the treatment landscape continues to evolve, assurance that HER-2/neu status is accurately determined remains the sole responsibility of the pathologist. The increasing number of breast cancer patients being treated in the neoadjuvant setting gives rise to the need to accurately assess biomarkers in the needle core biopsy material that is the only available tissue in these patients. This is also true in the subset of breast cancer patients who achieve a pCR, do not have residual tumor in the excisional biopsy for retesting, and are eligible for adjuvant therapy including trastuzumab. Interestingly, in 1 study, patients whose breast cancer tumors showed HER-2/neu amplification were more likely to experience pCR to neoadjuvant chemotherapy or endocrine therapy.15

Although many studies have been published to ascertain the concordance rate as determined by different methodologies11,16 or in different sized specimens,9 there is a surprising lack of published evidence that shows the concordance rate between FISH-determined HER-2/neu status in a needle core biopsy sample and subsequent excisional biopsy specimen of the same tumor. This deficiency in the medical literature has only become evident owing to the rising need to accurately assess HER-2/neu status on needle core biopsy material in breast cancer patients undergoing neoadjuvant therapy. To date, only 2 publications have studied this relationship, one of which was a subanalysis of 18 patients and not the main focus of the study.2,5 The need to confirm the reliability of carrying out FISH on needle core biopsy material stems from the known phenomenon of genotypic intratumoral heterogeneity of HER-2/neu amplification in breast cancer tissues. This phenomenon is well documented4,14 and the majority of studies report its potentially confounding impact to be minimal on excisional biopsy specimens. Our study revealed that when comparing FISH-determined HER-2/neu status on needle core biopsy with that of the excisional biopsy of the same tumor, the concordance rate is excellent and that a majority of “discordant” results were directly related to the use of the new “equivocal” category implemented in the current ASCO/CAP guidelines. In fact, if the older FDA recommended cut-off ratio of ≥2 was used, the discordance rate would be very low (5%) in our study. Similar to our findings, Apple et al2 reported a concordance rate of 92%. Although our concordance rate is lower, we believe that this likely represents a more accurate figure owing to our study design. Whereas in their study, IHC and FISH results were retrospectively collected from tests conducted at the time of clinical evaluation over the course of several years, both types of analyses in our investigation were done at the time of our research in test batches. The latter approach ensured most uniform test conditions.

From a practical standpoint, we were most interested in validating the accuracy of HER-2/neu status determined by FISH on needle core biopsy in cases of IHC 2+ staining. Currently, IHC 2+ excisional biopsy specimens are routinely submitted to FISH analysis. We found that 14% of cases showed 2+ staining by IHC on needle core specimens. Comparison of the FISH result determined on the excisional biopsy specimen (representing the gold standard) to that of the FISH result determined on the needle core biopsy of the same tumor in these 14 cases yielded good concordance (79% agreement and κ=0.512, P=0.05). A study by Chivukula et al9 made the same comparison in 37 cases, which resulted in a concordance rate of 81%. Higher concordance (89%) was achieved in their nonamplified as compared with their amplified (72%) cases. Also, not surprisingly, if the prior FDA-approved cut-off ratio of ≥2 was used, greater concordance would be achieved (86% agreement and κ=0.576, P=0.03). The study by Apple et al2 did not specifically address this query but rather recommended repeat studies on the excisional biopsy specimen if “indeterminate/borderline HER-2/neu results by immunohistochemical stain/FISH” were obtained on the initial needle core biopsy. Practically speaking, clinicians would likely prefer to obtain FISH on the needle core biopsy specimen than wait to retest on the excisional biopsy tissue if the results were known to be equally reliable.

Lastly, it is well known that chemotherapy can induce morphologic alterations (pleomorphism and regressive changes) in breast cancer tissue, which can be appreciated on the excisional biopsy specimen after neoadjuvant therapy. If this routinely occurs, there may be concern that similar changes can occur in biomarker status thus prompting retesting on the excisional biopsy specimen to plan for adjuvant treatment. A number of studies have investigated the potential effect of chemotherapy in altering biomarker expression such as ER, PR, and HER-2/neu.1–3,12,13 These reports assessed HER-2/neu status by IHC and/or FISH. Overall, FISH-determined HER-2/neu status has been found to be stable in patients receiving neoadjuvant chemotherapy whereas it was less so when determined by IHC.1,2,13 Our findings further validate that HER-2/neu status as determined by FISH or IHC analysis remains unchanged in breast cancer tissue after the administration of neoadjuvant chemotherapy in the majority of cases.

In summary, pathologists are continually challenged to maintain reporting accuracy in the milieu of evolving treatment practices of breast cancer patients. Although the new ASCO/CAP guidelines seem to show improved concordance between IHC and FISH-determined HER-2/neu status, the new equivocal category for reporting FISH results seems to cause an increase in discordance. We found that submitting IHC 2+staining needle core biopsies to FISH analyses on the same material will yield a reliable result that is comparable to testing on the excisional biopsy specimen in most cases. However, owing to the relatively small number of cases studied, more studies investigating this issue would be needed for confirmation. Presently, we recommend that FISH analysis be done on 2+staining IHC needle core biopsies with retesting on the excisional biopsy specimen in equivocal cases only.

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ACKNOWLEDGMENT

The authors thank Swarna Gogineni for her assistance with the FISH images presented in this paper.

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REFERENCES

1. Adams AL, Eltoum I, Krontiras H, et al. The effect of neoadjuvant chemotherapy on histologic grade, hormone receptor status, and Her2/neu status in breast carcinoma. Breast J. 2008;14:141–146.

2. Apple SK, Lowe AC, Rao PN, et al. Comparison of fluorescent in situ hybridization HER-2/neu results on core needle biopsy and excisional biopsy in primary breast cancer. Mod Pathol. 2009;22:1151–1159.

3. Arens N, Bleyl U, Hildenbrand R. HER2/neu, p53, Ki67, and hormone receptors do not change during neoadjuvant chemotherapy in breast cancer. Virchows Arch. 2005;446:489–496.

4. Brunelli M, Manfrin E, Martignoni G, et al. Genotypic intratumoral heterogeneity in breast carcinoma with HER-2/neu amplification: evaluation according to ASCO/CAP criteria. Am J Clin Pathol. 2009;131:678–682.

5. Burge CN, Chang HR, Apple SK. Do the histologic features and results of breast cancer biomarker studies differ between core biopsy and surgical excision specimens? Breast. 2005;15:167–172.

6. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin chemotherapy: results of a randomized trial in human epidermal group factor receptor 2-positive disease. J Clin Oncol. 2005;23:3676–3685.

7. Buzdar AU, Valero V, Ibrahim NK, et al. Prospective data of additional patients treated with neoadjuvant therapy with paclitaxel followed by FEC chemotherapy with trastuzumab in HER-2 positive operable breast cancer, and an update of initial study population [abstract]. Breast Cancer Res Treat. 2005;94(Suppl. 1):A5049.

8. Buzdar AU, Valero V, Ibrahim NK, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228–233.

9. Chivukula M, Bhargava R, Brufsky A, et al. Clinical importance of HER2 immunohistologic heterogeneous expression in core-needle biopsies vs resection specimens for equivocal (immunohistochemical score 2+) cases. Mod Pathol. 2008;21:363–368.

10. Madarnas Y, Trudeau M, Franek JA, et al. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systemic review. Cancer Treat Rev. 2008;34:539–557.

11. Perez EA, Roche PC, Jenkins RB, et al. HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc. 2002;77:148–154.

12. Quddus MR, Sung CJ, Zhang C, et al. HER-2/neu expression in locally advanced breast carcinomas: pre- and post-neoadjuvant chemotherapy. Breast Cancer. 2005;12:294–298.

13. Ridolfi RL, Jamehdor MR, Arber JM. HER-2/neu testing in breast carcinoma: a combined immunohistochemical and fluorescence in situ hybridization approach. Mod Pathol. 2000;13:866–873.

14. Shin SJ, Hyjek E, Early E, et al. Intratumoral heterogeneity of HER-2/neu in invasive mammary carcinomas using fluorescence in-situ hybridization and tissue microarray. Int J Surg Pathol. 2006;14:279–284.

15. Tan MC, Mushawah FA, Gao F, et al. Predictors of complete pathological response after neoadjuvant systemic therapy for breast cancer. Am J Surg. 2009;198:520–525.

16. Yaziji H, Goldstein LC, Barry TS, et al. HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004;291:1972–1977.

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Keywords:

HER-2/neu; breast; immunohistochemistry; fluorescence in-situ hybridization; FISH; needle core biopsy; intratumoral heterogeneity; neoadjuvant; chemotherapy; trastuzumab

© 2010 Lippincott Williams & Wilkins, Inc.

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