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Clinical Cancer Research Vol. 10, 4639-4644, July 15, 2004
© 2004 American Association for Cancer Research

Clinical Trials

Her2/neu Expression Predicts the Response to Antiaromatase Neoadjuvant Therapy in Primary Breast Cancer

Subgroup Analysis from Celecoxib Antiaromatase Neoadjuvant Trial

Li Zhu1, Louis W. C. Chow1, Wings T. Y. Loo1, Xin-Yuan Guan2 and Mazakazu Toi3

1 Hung Chao Hong Integrated Centre For Breast Diseases, Department of Surgery, and 2 Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China, and 3 The Breast Unit, Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

ABSTRACT

Purpose: Many studies suggest that Her2/neu play an important role in neoadjuvant endocrine therapy. This study aimed to determine whether the level of Her2/neu expression in advanced breast cancer changes after antiaromatase neoadjuvant treatment, as well as to identify the relationship between Her2/neu expression and response to this kind of therapy.

Experimental Design: Thirty-six postmenopausal patients with hormonal receptor-positive primary breast cancer were included in a study of three monthly cycles of neoadjuvant endocrine therapy with either Aromasin (25 mg daily) or Femara (2.5 mg daily). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for Her2/neu were conducted both on pretreatment biopsies and surgical tumors.

Results: Using IHC, 5 of 36 (13.9%) of the patients had a Her2/neu overexpression after treatment, as compared with 16 of 36 (44.4%) before. Meanwhile, there was no change in 21 (58.3%) patients, and through FISH, there was a change from amplification to no amplification in 15 (41.7%) patients. The response rate to the treatment was 75% for Her2/neu (+) tumors and 35% for Her2/neu (–) tumors (P = 0.017) while FISH was performed. The response rate was also significantly affected by the decrease in Her2/neu status after the treatment, with 73% of the tumors showing decreased Her2/neu expression and with 38% of the tumors showing no change of Her2/neu expression (P = 0.037).

Conclusions: Using both IHC and FISH, advanced breast cancers show statistical evidence of decreasing incidence of Her2/neu expression after antiaromatase neoadjuvant treatment. Our data also suggest that Her2/neu expression and its change during the treatment might be predictive markers for this kind of therapy.

INTRODUCTION

Human epidermal growth factor receptor-2 is a proto-oncogene encoding a cell-surface glycoprotein designated the Her2 or c-erbB-2 receptor that belongs to the tyrosine kinase receptor family. The Her2/neu gene is amplified and/or its protein is overexpressed in 15–25% of breast cancers (1, 2, 3, 4) . Her2/neu status is a prognostic marker for poor clinical outcome (2 , 3) and possibly a predictive marker for tamoxifen resistance (5, 6, 7, 8, 9) . Although experimental data suggest an important role for Her2/neu in primary and acquired resistance to endocrine therapy using tamoxifen, early data from the neoadjuvant setting indicate that response to aromatase inhibitors may be maintained in patients with Her2/neu overexpression (10, 11, 12) .

The goal of neoadjuvant therapy is shrinkage of locally advanced and unresectable primary breast tumors, permitting their successful surgical removal (13 , 14) . It has been used more recently in patients with large operable breast cancers that would require mastectomy but in whom tumor shrinkage can permit breast-conserving surgery (15 , 16) . Agents used have been mainly limited to cytotoxins used in other forms of chemotherapy. However, endocrine treatment is becoming an attractive alternative in hormone receptor-positive postmenopausal women.

It has been widely demonstrated that various endocrine agents (including tamoxifen and the aromatase inhibitors) can reduce the tumor volume over a 3–4-month treatment in postmenopausal estrogen receptor (ER) (+) patients (10 , 11 , 17, 18, 19, 20) . Aromatase inhibitors have most recently been shown to be superior to tamoxifen as initial therapy and are being extensively tested in the neoadjuvant setting instead of tamoxifen. In this setting, aromatase inhibitors not only show enhanced efficacy but also overcome tamoxifen resistance (10 , 11) . Although studies as yet have failed to show any survival advantage in patients receiving neoadjuvant compared with adjuvant chemotherapy (16 , 21) , there could nevertheless be benefits from neoadjuvant endocrine therapy provided there was more appropriate patient selection. When selecting patients for endocrine treatment, ER (+) status and, to a lesser extent, progesterone receptor (+) status are important determinants of response (10) .

We have studied the expression of Her2/neu before and after neoadjuvant endocrine therapy in patients with breast cancer in an attempt to obtain more information on the effect of endocrine treatment on these patients. Her2/neu status was assessed by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). It was also examined in relation to clinicopathological variables and clinical response.

MATERIALS AND METHODS

Patients.
Thirty-six pathologically proven, post-menopausal patients with hormonal receptor positive breast cancer were included between October 2001 and July 2003 as part of the Celecoxib Antiaromatase Neoadjuvant Trial (22) . The third generation aromatase inhibitor either letrozole (Femara; Novartis Pharma AG, Basel, Switzerland) or exemestane (Aromasin; Pharmacia & Upjohn Company, Kalamazoo, MI) was given daily in a 2.5 or 25 mg dose over the monthly cycle after pathological confirmation from core biopsy of the primary tumor. Eighteen patients were admitted into each group. Each patient was treated for three cycles, and surgery was performed within 7 days after the last cycle.

Physical examination and ultrasound examination were repeated every cycle. Response categories were defined according to the standard Union International Contre Cancer criteria as complete remission, partial remission, no change, progressive disease and not assessable.

All core biopsy and surgically excised tumors of the above patients were fixed in formalin and embedded in paraffin wax. Her2/neu expression was determined using IHC and FISH simultaneously.

IHC.
The Hercep Test (Dako Corp., Carpinteria, CA) was performed according to the approved protocol as described by the manufacturer. Tissue sections were cut, mounted on plus slides, heat-treated for antigen retrieval, and immunostained. The sections were counterstained with H&E and then mounted in Permount. Immunostaining was interpreted with a bright-field Olympus microscope according to the scoring system of the manufacturer as 0, 1+, 2+, and 3+ (Dako Corp.). Controls without primary antibody and positive control tissues were included in all experiments to ensure the quality of staining.

FISH.
FISH was performed according to the PathVysion (Vysis, Inc., Downers Grove, IL) protocol, described in the package insert as approved by the United States Food and Drug Administration. In brief, the PathVysion protocol involves rehydration of paraffin-embedded, 4-µm thick, multitumor tissue sections. The sections were air-dried, pretreated, and digested with protease before being hybridized with fluorescent-labeled probes for Her2/neu gene and {alpha}-satellite DNA for chromosome 17. The nuclei were routinely counterstained with an intercalating fluorescent counterstain, 4',6-diamidino-2-phenylindole. For each tumor, 20 tumor cell nuclei were identified and scored for both Her2/neu and chromosome 17 centromere numbers. Her2/neu gene amplification was defined as a Her2-to-chromosome 17 ratio > 2.0 as required by the manufacturer.

Statistical Methods.
Statistical analysis was performed using the SPSS 11.0 (SPSS, Inc., Chicago, IL). Associations between clinicopathological variables and Her2/neu status before and after treatment were evaluated using the {chi}2 test. The paired samples t test was performed to compare the Her2/neu-to-chromosome 17 ratios before and after treatment. All P values reported were two-sided with P < 0.05 considered to be statistically significant. {kappa} was estimated to evaluate concordance among Her2/neu assay methods.

RESULTS

The median age of the patients at initial diagnosis was 66 years, ranging from 48 to 84 years. Histology was as follows: invasive ductal carcinoma in 31 (86%) patients; mixed invasive ductal carcinoma and mucinous in 2 (5.6%) patients; and invasive lobular carcinoma, ductal carcinoma in situ, and mucinous in 1 (2.8%) patient each. The invasive ductal carcinoma was calculated as grade 1 (Bloom and Richardson grade) in 11 (35.5%) patients, grade 2 in 15 (48.4%) patients, and grade 3 in 5 (16.1%) patients. There was no significant correlation between Her2/neu and any of the clinicopathological variables, including histological type, grade, or disease.

All 36 enrolled patients were fully assessable for response. The overall response rate in the intent-to-treat population of 36 patients was 53%, with 3 complete responses (8%) and 16 partial responses (45%). No changes were observed in 47% of assessable patients. Over the study period, none of the patients had direct disease progression without a period of stable disease. The percentage of patients with changes in tumor staging before and after the neoadjuvant therapy were compared (Fig. 1)Citation .



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  		Fig. 1. The comparison of tumor stage before and after neoadjuvant endocrine therapy. Most of the tumors are down-staged significantly after the treatment (P = 0.018). {square}, before; , after.

 
A total of 36 pairs of core biopsy and surgically excised tumors were available for IHC and FISH assays. Change in the distribution of Her2/neu IHC expression scores before and after therapy is shown in Fig. 2Citation . Before therapy, 4 (11.1%), 16 (44.4%), 12 (33.4%), and 4 (11.1%) patients achieved scores of 0, 1+, 2+, 3+ (Fig. 3)Citation , respectively, yielding overexpression in 16 of the 36 patients (55.6%). In general, the IHC scores decreased after operation, except for 9 patients (Table 1)Citation . Thus, 5 of 36 (13.9%) of the patients had a Her2/neu expression of 2+ and 3+ after treatment, as compared with 16 of 36 (44.4%) before. Fig. 2Citation depicts the change in percentage of patients scored at each staining level before and after treatment by IHC assay. Using FISH, the Her2/neu-to-chromosome 17 ratios varied from 0.68 to 13.07. The ratios decreased significantly after the treatment. (t = 4.947, P < 0.001). Her2/neu amplification (Fig. 4)Citation was determined in 20 patients (55.6%) before neoadjuvant therapy compared with 5 patients (13.9%) during surgery (Fig. 5)Citation . Concordance between the IHC and FISH results for the patients in whom data from both assays were available is listed in Table 2Citation . The {kappa} value of 0.875 suggests that there was excellent agreement between IHC and FISH in our population.



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  		Fig. 2. The comparison of immunohistochemistry (IHC) scores of Her2/neu status before and after neoadjuvant endocrine therapy. The overexpression of Her2/neu are decreased significantly after the treatment (P < 0.001). {square}, before; , after.

 


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  		Fig. 3. Her2/neu overexpression (3+) determined by immunohistochemistry, original magnification, x200.

 

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  		Table 1 Change of Her2/neu status before and after treatment

 


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  		Fig. 4. Her2/neu amplification determined by fluorescence in situ hybridization, x400.

 


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  		Fig. 5. The comparison of fluorescence in situ hybridization (FISH) results of Her2/neu status before and after neoadjuvant endocrine therapy. The amplification of Her2/neu are decreased significantly after the treatment (P < 0.001). {square}, before; , after.

 

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  		Table 2 Concordance of Her2/neu assay results: IHC versus FISHa

 
As shown in Table 3Citation , the response rate to the treatment was significantly influenced by initial Her2/neu status, which was confirmed by FISH, with a response rate of 75% for Her2/neu (+) tumors and 35% for Her2/neu (–) tumors (P = 0.017). In addition, the response rate was also significantly affected by the decrease in Her2/neu status after the treatment, with a response rate of 73% for tumors showing decreased Her2/neu expression and 38% for tumors showing no change in Her2/neu expression (P = 0.037). There was no significant difference in either response rate (P = 0.52) or the change of Her2/neu expression (P = 0.50) between the Femara group and the Aromasin group.


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  		Table 3 Clinical response according to initial and decrease of Her2/neu status

 
DISCUSSION

Her2/neu positivity of breast cancer has been suggested that may be indicative of resistance to hormonal (predominantly tamoxifen) therapy, but the data are by no means conclusive (23, 24, 25, 26, 27) . The heterogeneity of the published data may in part result from the ER status of the tumor not being considered. Much of the reported hormonal insensitivity of Her2/neu (+) tumors could result from ER (–) rather than Her2/neu (+) per se (27) . So in this study, we had an attempt to solve this problem by selecting an entirely ER (+) group of patients.

Currently, no single assay is globally accepted as the gold standard for Her2/neu testing. Of a wide range of techniques, two technologies are now predominant in the routine clinical practice: determination of Her2/neu protein overexpression by IHC; and Her2/neu gene amplification by FISH (28) . After directly comparing parallel IHC and FISH assessment of the same samples (29, 30, 31, 32, 33, 34, 35, 36, 37) , some studies suggest the combination of these two assays provide comprehensive and valuable information on both Her2/neu protein concentrations and gene amplification (29, 30, 31) . We also conducted both of these methods to help us make crucial management decisions. The variables produced by clonal selection using IHC can be overcome by detection of Her2/neu copy number. Although there is high concordance of IHC and FISH results in our group ({kappa} = 0.875), discrepancies are still known to occur because of the transcriptional or posttranscriptional regulation for increased surface receptor expression in the absence of gene amplification (32) .

We have evaluated 36 primary breast cancers to determine whether Her2/neu status changes after the neoadjuvant endocrine therapy. Overexpression and amplification of Her2/neu was 44.4 and 55.6%, respectively. Our findings indicate a higher level of overexpression of Her2/neu in other groups with the primary diagnosis of breast cancers (1, 2, 3, 4) , which is possibly due to the patients included in our group having developed more aggressive tumors (38 , 39) . Although we didn’t find any significant correlation between Her2/neu positivity and clinicopathological factors, which might be due to the small size of our cohort, a statistically significant decrease in positivity for Her2/neu has been shown after neoadjuvant endocrine therapy.

To date, there have been few controlled studies of neoadjuvant endocrine therapy, especially for the use of the new selective third generation aromatase inhibitors. In appropriately selected patients, the Edinburgh group indicated that neoadjuvant endocrine therapy also produces significant responses compared with the preoperative chemotherapy (40) . The overall response rates were 78–96%. The Duke group has shown that letrozole produces a superior response rate to tamoxifen (60 versus 48%), and the differences in response rates between letrozole and tamoxifen were most marked for Her2/neu (+) tumors (88 versus 21%), whereas Her2/neu (–) tumors did not show a statistically significantly higher response rate for letrozole compared with tamoxifen (54 versus 42%; Ref. 10 ). Although our study showed a slightly lower clinical response rate of 53%, we can confirm that Her2/neu (+) tumors show a significantly higher response rate than their Her2/neu (–) counterparts. This remarkable finding suggests that the Her2/neu-activated second messenger pathway mediates estrogen-dependent growth through ER, presumably via ER phosphorylation. Preclinical modeling is consistent with the conclusion that ER (+) and Her2/neu (+) tumors are highly estrogen dependent (41) . Additional data also indicate that ER-dependent transcriptional activity in a Her2/neu (+) breast cell line can be impeded by estrogen deprivation caused by aromatase inhibitors (42) , which would suggest that a higher sensitivity to these agents might exist in breast cancer.

More interestingly, we found that the amplification of Her2/neu decreased in 41.7% of patients after the therapy by FISH. These results suggest that aromatase inhibitors might frequently repress the aggressive nature of breast cancer. The mechanism of aromatase inhibitor-induced Her2/neu down-regulation is unclear and extremely variable (43) . A molecular explanation for these findings might be related to inactivation of signal transduction of Her2/neu through the mitogen-activated protein kinase pathway. Additional exploration of the molecular mechanism underlying this phenomenon may prove very useful in explaining and in controlling breast cancer progression in the future. Most importantly, we found that tumors, which show decreasing Her2/neu expression during the treatment, also show a significantly higher response rate than tumors, which show no change of Her2/neu expression. These remarkable observations suggest that positive Her2/neu status and a decrease in Her2/neu expression became significantly sensitive markers for the neoadjuvant endocrine therapy based on aromatase inhibitors. Because it generally takes longer for endocrine therapy than chemotherapy to act, it seems essential to identify nonresponse early in the course of treatment so that the patient can be transferred to alternative therapies. Defining the best way to monitor response is therefore of fundamental importance. The determination of Her2/neu status by repeated biopsy during the therapy may be carried out in the future study. Nevertheless, our study has attempted to explore the role of a decrease in Her2/neu expression as a predictive marker for neoadjuvant endocrine therapy.

In conclusion, we have shown that Her2/neu gene amplification and protein expression decrease after neoadjuvant therapy using aromatase inhibitors. Despite the limited size of the cohort and immature survival data, our findings that both the positive Her2/neu expression and a decrease in Her2/neu expression have a predictive value with respect to the treatment could be clinically relevant.

ACKNOWLEDGMENTS

We thank Xie Dan and Chan Kaifun for their technical assistance.

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.

Requests for reprints: Louis W. C. Chow, Department of Surgery, Queen Mary Hospital, Pokfulam, Hong Kong. Phone: 852-2855-4773; Fax: 852-2817-2291; E-mail: lwcchow{at}hkucc.hku.hk

Received 1/19/04; revised 4/13/04; accepted 4/16/04.

REFERENCES

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGurie WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2 /neu oncogene. Science (Wash. DC), 235: 177-82, 1987.[Abstract/Free Full Text]
  2. Slamon DJ, Godolphin W, Jones LA, et al Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (Wash. DC), 244: 707-12, 1989.[Abstract/Free Full Text]
  3. Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta, 1198: 165-84, 1994.[Medline]
  4. Revillion F, Bonneterre J, Peyrat JP. ERBB2 oncogene in human breast cancer and its clinical significance. Eur J Cancer, 34: 791-808, 1998.
  5. 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 the HER-2/c-neu protein. J Clin Oncol, 15: 2518-25, 1997.[Abstract/Free Full Text]
  6. Berns EM, Foekens JA, van Staveren IL, et al Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene (Amst.), 159: 11-8, 1995.[CrossRef][Medline]
  7. Archer SG, Eliopoulos A, Spandidos D, et al Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy. Br J Cancer, 72: 1259-66, 1995.[Medline]
  8. 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, 14: 2702-8, 1996.[Abstract/Free Full Text]
  9. Lipton A, Ali SM, Leitzel K, et al Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol, 21: 1967-72, 2003.[Abstract/Free Full Text]
  10. Ellis MJ, Coop A, Singh B, et al Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1 and /or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a Phase III randomized trial. J Clin Oncol, 19: 3808-16, 2001.[Abstract/Free Full Text]
  11. Eiermann W, Paepke S, Appfelstaedt J, et al Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blinded multicenter study. Ann Oncol, 12: 1527-32, 2001.[Abstract/Free Full Text]
  12. Dixon JM, Jackson J, Renshaw L, Miller WR. Neoadjuvant tamoxifen and aromatase inhibitors: comparisons and clinical outcomes. J Steroid Biochem Mol Biol, 86(3–5): 295-9, 2003.
  13. Perloff M, Lesnick GJ. Chemotherapy before and after mastectomy in stage III breast cancer. Arch Surg, 117: 879-81, 1982.[Abstract]
  14. Schick P, Goodstein J, Moor J, Butler J, Senter KL. Preoperative chemotherapy followed by mastectomy for locally advanced breast cancer. J Surg Oncol, 22: 278-82, 1983.[Medline]
  15. Bonadonna G, Veronesi U, Brambilla C, et al Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst (Bethesda), 82: 1539-45, 1990.[Abstract/Free Full Text]
  16. Fisher B, Brown A, Mamounas E, et al Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol, 15: 2483-93, 1997.[Abstract/Free Full Text]
  17. Horobin JM, Preece PM, Dewar JA, Wood RAB, Cushieri A. Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifen only. Br J Surg, 78: 213-7, 1991.[Medline]
  18. Dixon JM, Love CD, Bellamy CO, et al Letrozole as primary medical therapy for locally advanced and large operable breast cancer. Breast Cancer Res Treat, 66: 191-9, 2001.[CrossRef][Medline]
  19. Dixon JM, Renshaw L, Bellamy C, Stuart M, Hoctin-Boes G, Miller WR. The effect of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blinded, single-center study. Clin Cancer Res, 6: 2229-35, 2000.[Abstract/Free Full Text]
  20. Dixon JM, Anderson T, Miller WR. Phase II b study of neoadjuvant exemestane (EXE) in locally advanced breast cancer. Proc Am Soc Clin Oncol, 20: 1908 2001.
  21. Fisher B, Bryant J, Wolmark N, et al Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol, 16: 2672-85, 1998.[Abstract]
  22. Chow LW, Wong JL, Toi M. Celecoxib anti-aromatase neoadjuvant (CAAN) trial for locally advanced breast cancer: preliminary report. J Steroid Biochem Mol Biol, 86(3–5): 443-7, 2003.
  23. Wright C, Nicholson S, Angus B, et al Relationship between cerbB2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer, 65: 118-21, 1992.[Medline]
  24. Newby JC, Johnston SRD, Smith IE, Dowsett M. Expression of epidermal growth factor receptor and cerbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res, 3: 1643-51, 1997.[Abstract]
  25. Bianco AR, DeLaurentis M, Carlomagno C. 20 year update of the Naples GUN trial of adjuvant breast cancer therapy: evidence of interaction between cerbB2 expression and tamoxifen efficacy. Proc Am Soc Clin Oncol, 17: 97 1998.
  26. Muss HB, Berry DA, Thor AD, et al Lack of interaction of tamoxifen use and ErbB-2/ HER-2/ neu expression in CALGB 8541: a randomized adjuvant trial of three different doses of cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-positive primary breast cancer. Proc Am Soc Clin Oncol, 18: 68 1999.
  27. 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]
  28. Bilous M, Dowsett M, Hanna W, et al Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol, 16: 173-82, 2003.[CrossRef][Medline]
  29. Wang S, Saboorian MH, Frenkel E, Hyman L, Gokaslan ST, Ashfaq R. Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridization assays. J Clin Pathol, 53: 374-81, 2000.[Abstract/Free Full Text]
  30. Ridolfi RL, Jamehdor MR, Arber JM. HER-2/neu testing in breast carcinoma: a combined immunohistochemical and fluorescence in situ hybridization approach. Mod Pathol, 13: 866-73, 2000.[CrossRef][Medline]
  31. Lebeau A, Deimling D, Kaltz C, et al HER/neu analysis in archival tissue samples of human breast cancer: comparison of immunohistochemistry and fluorescence in situ hybridization. J Clin Oncol, 19: 354-63, 2001.[Abstract/Free Full Text]
  32. Hoang MP, Sahin AA, Ordòñez NG, Sneige N. HER-2/neu gene amplification compared with HER-2/neu protein overexpression and interobserver reproducibility in invasive breast cancer. Am J Clin Pathol, 113: 852-9, 2000.[CrossRef][Medline]
  33. Jiminez RE, Wallis T, Tabasczka P, Visscher DW. Determination of Her-2/neu status in breast carcinoma: comparative analysis of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol, 13: 37-45, 2000.[CrossRef][Medline]
  34. Birner P, Oberhuber G, Stani J, et al Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res, 7: 1669-75, 2001.[Abstract/Free Full Text]
  35. Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ. Specificity of HercepTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration-approved scoring system. J Clin Oncol, 17: 1983-7, 1999.[Abstract/Free Full Text]
  36. Onody P, Bertrand F, Muzeau F, Bieche I, Lidereau R. Fluorescence in situ hybridisation and immunohistochemical assays for HER-2/neu status determination. Arch Pathol Lab Med, 125: 746-50, 2001.[Medline]
  37. Tubbs RR, Pettay JD, Roche PC, Stoler MH, Jenkins RB, Grogan TM. Discrepancies in clinical laboratory testing eligibility for trastuzumab therapy: apparent immunohistochemical false-positives do not get the message. J Clin Oncol, 19: 2714-21, 2001.[Abstract/Free Full Text]
  38. De Potter CR, Schelfhout AM. The neu-protein and breast cancer. Virchows Arch, 426: 107-15, 1995.[Medline]
  39. Yu DH, Liu BL, Tan M, et al Overexpression of cerbB2/neu in breast cancer cells confers increased resistance to Taxol via MDR-1-independent mechanisms. Oncogene, 13: 1359-65, 1996.[Medline]
  40. Dixon JM, Love CD, Renshaw L, et al Lessons from the use of aromatase inhibitors in the neoadjuvant setting. Endocr Relat Cancer, 6: 227-30, 1999.[Abstract]
  41. Benz CC, Scott GK, Sarup JC, et al Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat, 24: 85-95, 1993.
  42. Kurokawa H, Lenferink AE, Simpson JF, et al Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res, 60: 5887-94, 2000.[Abstract/Free Full Text]
  43. Ellis MJ, Coop A, Singh B, et al Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res, 63: 6523-31, 2003.[Abstract/Free Full Text]



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M. C. Gutierrez, S. Detre, S. Johnston, S. K. Mohsin, J. Shou, D. C. Allred, R. Schiff, C. K. Osborne, and M. Dowsett
Molecular Changes in Tamoxifen-Resistant Breast Cancer: Relationship Between Estrogen Receptor, HER-2, and p38 Mitogen-Activated Protein Kinase
J. Clin. Oncol., April 10, 2005; 23(11): 2469 - 2476.
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C. K. Osborne and R. Schiff
Estrogen-Receptor Biology: Continuing Progress and Therapeutic Implications
J. Clin. Oncol., March 10, 2005; 23(8): 1616 - 1622.
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