Originally published as JCO Early Release 10.1200/JCO.2007.15.8659 on November 10 2008

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

Human Epidermal Growth Factor Receptor 2 Overexpression As a Prognostic Factor in a Large Tissue Microarray Series of Node-Negative Breast Cancers

Stephen Chia, Brian Norris, Caroline Speers, Maggie Cheang, Blake Gilks, Allen M. Gown, David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

From the Division of Medical Oncology, Breast Cancer Outcomes Unit, and Division of Radiation Oncology, British Columbia Cancer Agency; Genetic Pathology Evaluation Centre and Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; and PhenoPath Laboratories, Seattle, WA

Corresponding author: Stephen Chia, MD, FRCP(C), Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Ave, Vancouver, British Columbia, Canada, V5Z 4E6; e-mail: schia{at}bccancer.bc.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Human epidermal growth factor receptor 2 gene (HER2) is associated with a poorer outcome in node-positive breast cancer, but the results are conflicting in node-negative disease. This study assessed the prognostic impact of HER2 overexpression/amplification in a large series of node-negative breast cancers.

Patients and Methods A tissue microarray (TMA) series was constructed consisting of 4,444 invasive breast cancers diagnosed in British Columbia from 1986 to 1992. Within this series, 2,026 patients were node negative, of whom 70% did not receive adjuvant systemic therapy. The TMA series was assessed for estrogen receptor (ER) and HER2. Logistic regression modeling was used to estimate odds ratios at the 10-year follow-up.

Results HER2 was positive in 10.2% of the node-negative cohort. In this cohort, an inferior outcome was seen in patients with HER2-positive tumors compared with HER2-negative tumors for 10-year relapse-free survival (RFS; 65.9% v 75.5%, respectively; P = .01), distant RFS (71.2% v 81.8%, respectively; P = .004), and breast cancer–specific survival (BCSS; 75.5% v 86.3%, respectively; P = .001). A trend for a worse overall survival was also seen (P = .06). HER2 was an independent poor prognostic factor for RFS and BCSS at 10 years, with odds ratios of 1.71 (P = .01) and 2.03 (P = .003), respectively. The number of HER2-positive tumors that were 1 cm was small, but there was a trend for a worse outcome in T1b tumors.

Conclusion HER2 overexpression/amplification is correlated with a poorer outcome in node-negative breast cancer. Larger studies are needed to more clearly define the prognostic impact of HER2 in tumors 1 cm, particularly within the separate hormone receptor subgroups.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Mammographic screening has led to the increased diagnosis of smaller, node-negative breast cancers.^1-5 Adjuvant systemic therapy reduces the risk of recurrence and improves survival for patients with node-negative breast cancer, but the absolute benefit decreases as the risk of recurrence lessens.⁶ To better determine the absolute benefit of adjuvant therapy, current prognostic and predictive factors need to be refined.

The human epidermal growth factor receptor 2 gene (HER2) is both a prognostic and predictive factor. HER2 is amplified in approximately 10% to 20% of breast cancers.^7,8 Preclinical studies have demonstrated that amplification of HER2 or overexpression of its protein product play an important role in human breast cancer biology.^9-13 The first published report on the prognostic potential of HER2 was in 1987.⁷ Since then, there have been more than 200 studies investigating the prognostic impact of HER2 in breast cancer. A systematic review of the literature in 2001 concluded that HER2 was a weak to moderate prognostic factor and should not be used in the decision-making process regarding adjuvant systemic therapy.¹⁴

Since 1999, HER2 has been demonstrated to be a strong predictive factor for targeted therapy. Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2.¹⁵ In combination with chemotherapy in HER2-overexpressing metastatic breast cancer, trastuzumab improved clinical outcomes.^16-17 More importantly, the results of five randomized trials of adjuvant trastuzumab have demonstrated improved survival with the addition of trastuzumab during and/or after chemotherapy.^18-21 Four of these pivotal studies included patients with node-negative breast cancer, but they comprised a minority of patients.

Although the efficacy of trastuzumab was similar for the node-negative and node-positive cohorts, the absolute benefits were less in node-negative patients. Because of the significant cost of trastuzumab, the commitment to 1 year of therapy, and the potential for cardiotoxicity, a clearer understanding of the prognostic impact of HER2 overexpression in smaller, node-negative breast cancers would aid clinicians today.

We have constructed a large tissue microarray (TMA) of 4,444 patients with early-stage breast cancer annotated with clinical data and long-term outcome. We assessed the impact of HER2 amplification and overexpression on clinical outcomes in node-negative breast cancer patients, with particular emphasis on T1 breast cancers.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Study Population
A TMA of 4,444 patients with a new diagnosis of invasive breast cancer in the province of British Columbia, Canada, from 1986 to 1992 was created from tumor specimens submitted to a central estrogen receptor (ER) laboratory. The methods used to create the TMAs have been described.²² The TMA cohort patients were all referred to the British Columbia Cancer Agency and represented approximately 70% of all breast cancer patients diagnosed in the province during 1986 to 1992. The median follow-up time for the TMA series was 12.4 years.

TMA and Immunohistochemistry Methods
The Vancouver Hospital ER laboratory retained single archival blocks from each specimen received for the ER dextran charcoal testing. The tissues had been frozen before fixation in formalin. Hematoxylin and eosin–stained slides from these blocks were reviewed by two pathologists, and areas of invasive breast carcinoma were circled. TMAs were constructed by removing 0.6-mm cores from selected formalin-fixed, paraffin-embedded tissue blocks and transferred to a recipient paraffin block. Four-micrometer thick sections of the TMA blocks were cut and stained using the DakoCytomation EnVision and System-HRP (Dako, Carpinteria, CA) in a two-step immunohistochemistry (IHC) technique. ER staining with SP1 and visual scoring are detailed in a previous publication.²² HER2 IHC expression was assessed by the SP3 clone (Lab Vision, Fremont, CA) in 1:100 concentration with heat antigen retrieval. Negative controls were performed by omission of the primary antibody. Positive controls consisted of patients with known high-level HER2 amplification and overexpression. Stained TMA slides were digitally scanned on a BLISS Workstation (Bacus Laboratories Inc, Lombard, IL). The digital images linked to our relational database are available for public access through https://www.gpecimage.ubc.ca/tma/web/viewer.php (username: her2sp3; password: her2big).

Fluorescence In Situ Hybridization Technique
All IHC 2+ patients and indeterminate patients were tested for gene amplification by fluorescence in situ hybridization (FISH; Vysis PathVysion; Abbott, Chicago, IL). Slides were hybridized with probes to LSI HER-2/neu and CEP17 with the PathVysion HER-2 DNA Probe Kit according to the manufacturer's instructions. Sections were counterstained with 4,6-diamidino-2-phenylindole and visualized on a fluorescent microscope. Scoring was performed by one pathologist according to the manufacturer's guidelines yielding an HER-2/CEP17 ratio. An HER-2/CEP17 ratio 2 was considered amplified.

HER2 Scoring System
HER2 IHC expression was scored by one pathologist (A.M.G.) as follows: 0 (no staining or faint membrane staining), 1+ (faint membrane staining in > 10% of tumor cells, incomplete membrane staining), 2+ (weak to moderate membrane staining in > 10% of tumor cells), and 3+ (strong complete membrane staining in > 10% of tumor cells). For this analysis, HER2 scores of 0 and 1+ were considered negative. HER2 IHC 3+ and FISH-amplified patients were considered positive.

Statistical Analysis
Statistical analysis was performed using SPSS 13.0 (SPSS Inc, Chicago, IL), S-Plus 6.2 (Statistical Sciences, Seattle, WA), and R 2.1.1 (http://www.r-project.org). In univariate analysis, breast cancer–specific survival (BCSS; defined as the date of diagnosis of primary breast cancer to date of death with breast cancer as the primary or underlying cause) and relapse-free survival (RFS; defined as the date of diagnosis of primary breast cancer to the date of a local, regional, or distant recurrence) were estimated using Kaplan-Meier curves. The log-rank test was used to estimate the survival differences. For multivariate analysis, a Cox proportional hazards model was used to estimate the adjusted hazard ratios significance. To assess the violations of proportional hazard models, smoothed plots of weighted Schoenfeld residuals were used. When the proportional hazards assumption was violated, logistic regression modeling was used to estimate the odds ratio at the 10-year cutoff. This study was approved by the Clinical Research Ethics Board of the University of British Columbia.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Cohort Characteristics
There were 4,444 individual invasive breast cancer specimens arrayed into 17 recipient blocks (Appendix Fig A1, online only). Of these, 608 specimens were excluded for various reasons (282 were referred at recurrence, 90 had insufficient material, 182 had uninterpretable HER2, 29 had uninterpretable ER, and 23 were male breast cancers). Of the remaining 3,836 individual primary breast cancers, 53% (n = 2,026) were pathologic node negative, with a median of 10 lymph nodes removed (range, one to 37 nodes). These 2,026 breast cancers formed the study cohort. The baseline demographic, pathologic, and adjuvant treatments characteristics are listed in Table 1. Of note, 70% of patients (n = 1,420) did not receive any adjuvant systemic therapy, 18% received adjuvant hormonal therapy alone, and the remaining 12% received adjuvant chemotherapy ± hormonal therapy. Sixty-one percent of the cancers (n = 1,245) were stage I breast cancers, and the median tumor size was 2.0 cm (range, 0.1 to 9.9 cm).

Breast Cancer Outcomes in the Node-Negative Cohort
HER2 overexpression was associated with a higher risk of any relapse and of distant relapse. The 10-year RFS rates for HER2-overexpressing tumors and nonoverexpressing tumors was 65.9% (69 events in 206 tumors) and 75.5% (478 events in 1,820 tumors; P = .01; Fig 1A), respectively; likewise, the 10-year distant RFS (DRFS) rates were 71.2% (58 events) and 81.8% (366 events; P = .004; Fig 1B), respectively. Within the cohort of node-negative patients who did not receive adjuvant systemic therapy (n = 1,420 or 70%), similar results were seen; 10-year RFS rates in patients with and without HER2 overexpression were 63.2% (50 events in 138 patients) and 74.9% (340 events in 1,282 patients; P = .005; Fig 2A; Appendix Table A1, online only), respectively.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curves for 10-year outcomes based on HER2 status for the entire node-negative cohort (N = 2,026). (A) Relapse-free survival. (B) Distant relapse-free survival. (C) Breast cancer–specific survival. (D) Overall survival.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier curves for 10-year outcomes based on HER2 status for the node-negative cohort who did not receive any adjuvant systemic therapy (n = 1,420). (A) Relapse-free survival. (B) Breast cancer–specific survival. (C) Overall survival.

Breast Cancer Outcomes in Stage I Cohort
Within the node-negative cohort, 61% of patients (n = 1,245) had stage I disease (tumor size = 2 cm). HER2 overexpression was not significantly associated with RFS (10-year RFS, 71.6% [32 events in 117 patients] for HER2 overexpression v 78.7% [261 events in 1,128 patients] for no HER2 overexpression; P = .205). The DRFS trended to be worse in the HER2-overexpressing patients compared with those without overexpression (10-year DRFS, 77.5% [26 events] v 85.9% [184 events], respectively; P = .095), but the difference was not statistically significant. The 10-year BCSS was significantly worse in the HER2-positive cohort versus the HER2-negative cohort (81.3% [25 events] v 90.1% [156 events], respectively; P = .031), but the 10-year OS was not (70.9% [45 events] v 77.2% [402 events], respectively; P = .47). A similar pattern of outcomes was seen in the stage I cohort when restricted to patients not receiving adjuvant systemic therapy (n = 952).

Looking further within the subgroups of ER and HER2 in the stage I cohort, a pattern emerges (Fig 3). Although the number of HER2-positive/ER-positive patients was relatively small (n = 40; 3.2%), HER2 overexpression did not have a significant impact on prognosis (Table 2). The 10-year RFS and DRFS rates in the ER-positive/HER2-positive group compared with the ER-positive/HER2-negative group were similar (RFS, 77.5% [eight events in 40 patients] v 78.8% [203 events in 877 patients]; DRFS, 86.9% [six events] v 86.5% [138 events], respectively). Conversely in the ER-negative cohort, HER2 overexpression had an impact on prognosis. The 10-year RFS and DRFS rates in the ER-negative/HER2-positive group compared with the ER-negative/HER2-negarive group were 68.3% (24 events in 77 patients) compared with 78.2% (58 events in 251 patients) and 73.1% (20 events) compared with 83.5% (46 events), respectively (P = .12 and P = .16, respectively).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier curves for 10-year outcomes based on HER2 and estrogen receptor (ER) status for T1 cohort (n = 1,245). (A) Relapse-free survival. (B) Breast cancer–specific survival.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Kaplan-Meier curves for 10-year outcomes based on HER2 status for patients with 1-cm tumors (n = 326) and for the cohort who did not receive any adjuvant systemic therapy (n = 225). (A) Relapse-free survival in patients with T1a-b pN0 tumors. (B) Breast cancer–specific survival in patients with T1a-b pN0 tumors. (C) Relapse-free survival in patients with T1b pN0 tumors who did not receive adjuvant systemic therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
In this entire cohort of node-negative breast cancers, HER2 was a significant independent poor prognostic factor for both relapse and breast cancer death. HER2 overexpression was associated with a two-fold increase in the risk of dying of breast cancer by 10 years. This study is the largest node-negative series to assess the impact of HER2 overexpression. This cohort also has the advantage that the majority of patients (70%) did not receive any adjuvant systemic therapy.

Among our stage I breast cancers, HER2 overexpression did not seem to have the same adverse prognostic impact on RFS, although there was a trend for a worse DRFS and BCSS. This observation has also been noted in a study from a randomized trial (National Surgical Adjuvant Breast and Bowel Project B-06), in which the majority of patients enrolled were node negative and did not receive adjuvant systemic therapy.²³ This apparent discrepancy may be explained, in part, by a higher proportion of locoregional recurrences versus distant events in patients with smaller tumors relative to larger tumors.²⁴ HER2 may have less of a prognostic impact on locoregional recurrences than distant recurrences, which, in addition to the smaller at-risk population, may help to explain this discrepancy. Within this cohort (tumors 2 cm), however, there seemed to be a difference in the impact of HER2 within the hormone receptor subgroups. In ER-positive tumors, HER2 overexpression had little impact on RFS or DRFS. In ER-negative tumors, the HER2-overexpressing tumors had an absolute 10% worse RFS and DRFS compared with the ER-negative/HER2-negative tumors. This apparent differential impact of HER2 within ER cohorts of smaller tumors was also demonstrated in a series of 164 HER2-positive cancers from a single institution.²⁵

Since the initial publication demonstrating HER2 as a possible prognostic marker in breast cancer,⁷ there have been many studies investigating the impact of HER2 on outcome.¹⁴ The majority of the studies assessing HER2 in node-positive breast cancer have consistently shown HER2 to be associated with a worse prognosis.^26-35 However, the studies in node-negative breast cancer have produced conflicting results.^26-32,34-40 Many of these studies are limited because of smaller sample sizes, heterogeneity in adjuvant systemic therapy, and differences in methods of detection, antibodies, and cutoffs for demonstrating HER2 overexpression or amplification. In one of the larger initial series of 453 node-negative breast cancers from the Intergroup Study 0011, HER2 was not associated with a poorer outcome.⁴¹ In a study of 1,056 breast cancers from the South Australian Breast Cancer Study Group, in which HER2 amplification was assessed by the slot-blot technique, only an amplification of 3 was found to be prognostic.⁴² In the node-negative cohort (n = 597), HER2 was not prognostic in multivariate analysis. Conversely, in a population-based study of 852 stage I breast cancer patients from Finland, of whom only 5% received any adjuvant systemic therapy, HER2 amplification was associated with a worse DRFS.⁴³ The Finnish study found HER2 to be prognostic in a subset of 65 T1b tumors. In our study, there were 225 T1b tumors, and among these tumors, there was no adverse prognostic effect of HER2 overexpression. Selection bias, the small absolute number of HER2-positive patients, and differences in detection of HER2 may have contributed to the discrepancies in outcome.

There is a clear benefit of trastuzumab delivered either concurrent or sequential to chemotherapy in early-stage HER2-positive breast cancer. Five trials have demonstrated significant reductions in the risk of relapse, and four have shown a significant improvement in overall survival.^18,44,45 In all of the trials, the majority of patients had node-positive disease. The proportion of node-negative patients ranged from 0% to 33%. Only one trial included node-negative tumors of 1 cm in size. In subgroup analyses in the trials, the treatment effect was consistent across nodal status. Our study supports the use of adjuvant trastuzumab in node-negative, HER2-overexpressing breast cancer, but the use of trastuzumab in node-negative, less than 1-cm tumors is unclear. The extremely small sample sizes and event rates resulted in a lack of statistical significance for HER2 as a prognostic factor in the T1a-b cohort and, thus, limit any clinically relevant conclusions. Furthermore, the majority of patients in this cohort did not receive any adjuvant systemic therapy; thus, it is not possible to extrapolate from these data the magnitude of benefit (if any) for trastuzumab in addition to chemotherapy.

The frequency of HER2 overexpression or amplification in our series was 10%. This may seem low; however, similar rates are documented in other large node-negative, population-based studies.^41,43,46 A lower rate of HER2 overexpression could also be a result of loss of antigenicity from older material and the selective sampling process used to create TMAs.

A potential limitation of this study is the method of HER2 detection used. The IHC antibody used in our study, SP3, is a rabbit monoclonal antibody and was not one of the antibodies used in any of the trastuzumab trials. However, we have performed a concordance study between the SP3 antibody and FISH for all of the IHC 2+ patients in the entire TMA series and also a proportion of the IHC 3+ patients in the node-negative cohort (n = 106). HER2 amplification was detected in 14.3% of the IHC 2+ patients and 91.5% of the IHC 3+ patients. These findings are in keeping with the concordance study between the clinical trial IHC assay and FISH from the early metastatic trials.⁴⁷ We have also compared the SP3 antibody to the Dako HercepTest (clone A0485; Dako) with FISH as the gold standard and found the SP3 antibody to have a better agreement with FISH than the HercepTest ( = 0.890 for SP3 v = 0.799 for A0485; P < .0001).

In conclusion, this large TMA series of node-negative breast cancers confirms HER2 to be an independent poor prognostic factor and justifies the use of adjuvant trastuzumab in tumors larger than 1 cm. Further studies, including combining datasets and tumor specimens from multiple sources, are needed to more clearly assess the prognostic impact of HER2 in node-negative, less than 1-cm tumors. Additional predictive factors to identify which node-negative HER2-overexpressing patients benefit from adjuvant trastuzumab are also needed.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Karen Gelmon, Hoffmann LaRoche Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Stephen Chia, Brian Norris, Blake Gilks, David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

Financial support: Karen Gelmon

Administrative support: Ivo A. Olivotto, Torsten O. Nielsen

Provision of study materials or patients: David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen

Collection and assembly of data: Caroline Speers, Maggie Cheang, Blake Gilks, Allen M. Gown, David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

Data analysis and interpretation: Stephen Chia, Brian Norris, Caroline Speers, Maggie Cheang, Blake Gilks, Allen M. Gown, David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

Manuscript writing: Stephen Chia, Caroline Speers, Blake Gilks, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

Final approval of manuscript: Stephen Chia, Brian Norris, Caroline Speers, Maggie Cheang, Blake Gilks, Allen M. Gown, David Huntsman, Ivo A. Olivotto, Torsten O. Nielsen, Karen Gelmon

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (31K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Representation of patient groups in tissue microarray (TMA) series. ER, estrogen receptor; HER2, human epidermal growth factor receptor gene.

	NOTES

 
published online ahead of print at www.jco.org on November 10, 2008

Supported in part by grants from the Canadian Breast Cancer Research Alliance and Hoffmann LaRoche Inc.

Presented in part at the 29th San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Vacek PM, Geller BM, Weaver DL, et al: Increased mammography use and its impact on earlier breast cancer diagnosis in Vermont, 1975-1999. Cancer 94:2160-2168, 2002[CrossRef][Medline]

2. Luke C, Nguyen AM, Priest K, et al: Female breast cancers are getting smaller, but socio-demographic differences remain. Aust N Z J Public Health 28:312-316, 2004[Medline]

3. Fracheboud J, Otto SJ, van Diijck JA, et al: National Evaluation Team for Breast Cancer Screening (NETB): Decreased rates of advanced breast cancer due to mammographic screening in the Netherlands. Br J Cancer 91:861-867, 2004[Medline]

4. Jemal A, Clegg LX, Ward E, et al: Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer 101:3-27, 2004[CrossRef][Medline]

5. Schootman M, Jeffe D, Reschke A, et al: The full potential of breast cancer screening use to reduce mortality has not yet been realized in the United States. Breast Cancer Res Treat 85:219-222, 2004[CrossRef][Medline]

6. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

7. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987[Abstract/Free Full Text]

8. Akiyama T, Sudo C, Ogawara H, et al: The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644-1646, 1986[Abstract/Free Full Text]

9. Hudziak RM, Schlessinger J, Ulrich A: Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci U S A 84:7159-7163, 1987[Abstract/Free Full Text]

10. Di Fiore PP, Pierce JH, Krasu MH, et al: ErbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237:178-182, 1987[Abstract/Free Full Text]

11. Guy CT, Webster MA, Schaller M, et al: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A 89:10578-10582, 1992[Abstract/Free Full Text]

12. Chazin VR, Kaleko M, Miller AD, et al: Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene 7:1859-1866, 1992[Medline]

13. Pietras RJ, Arboleda J, Reese DM, et al: HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone independent growth in human breast cancer cells. Oncogene 10:2435-2446, 1995[Medline]

14. Yamauchi H, Stearns Y, Hayes DF: When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 19:2334-2356, 2001[Abstract/Free Full Text]

15. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2 overexpressing metastatic breast cancer that have progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999[Abstract/Free Full Text]

16. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001[Abstract/Free Full Text]

17. Marty M, Cognetti F, Maraninchi D, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment in the M77001 study group. J Clin Oncol 23:4265-4274, 2005[Abstract/Free Full Text]

18. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005[Abstract/Free Full Text]

19. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005[Abstract/Free Full Text]

20. Slamon D, Eiermann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94:S5, 2005 (suppl 1, abstr 1)

21. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-820, 2006[Abstract/Free Full Text]

22. Cheang MCU, Treaba DO, Speers CH, et al: Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24:5637-5644, 2006[Abstract/Free Full Text]

23. Paik S, Hazan R, Fisher ER, et al: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: Prognostic significance of erB-2 protein expression in the primary breast cancer. J Clin Oncol 8:103-112, 1990[Abstract/Free Full Text]

24. Chia SK, Speers C, Hayes M, et al: Ten-year outcomes in a population based cohort of node negative, lymphatic and vascular invasion negative early breast cancer without adjuvant systemic therapies. J Clin Oncol 22:1630-1637, 2004[Abstract/Free Full Text]

25. Black D, Younger J, Martei Y, et al: Recurrence risk in T1a-b, node negative, HER2 positive breast cancer. Breast Cancer Res Treat 100:2037, 2006 (suppl 1, abstr)

26. Wright C, Angus B, Nicholson S, et al: Expression of c-erbB-2 oncoprotein: A prognostic indicator in human breast cancer. Cancer Res 49:2087-2090, 1989[Abstract/Free Full Text]

27. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989[Abstract/Free Full Text]

28. Tsuda H, Hirohashi S, Shimosato Y, et al: Correlation between long term survival in breast cancer patients and amplification of two putative oncogene-coamplfication units: Hst-1/int2 and c-erbB2/ear 1. Cancer Res 49:3104-3108, 1989[Abstract/Free Full Text]

29. Tandon AK, Clark GM, Chamness GC, et al: HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol 7:1120-1128, 1989[Abstract]

30. Borg A, Tandon AK, Sigurdsson H, et al: HER-2/neu amplification predicts poor survival in node positive breast cancer. Cancer Res 50:4332-4337, 1990[Abstract/Free Full Text]

31. Lovekin C, Ellis IO, Locker A, et al: C-erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J Cancer 63:439-443, 1991[Medline]

32. Thor AD, Schwartz LH, Koerner FC, et al: Analysis of c-erbB-2 expression in breast carcinomas with clinical follow-up. Cancer Res 49:7147-7152, 1989[Abstract/Free Full Text]

33. Winstanley J, Cooke T, Murray GD, et al: The long term prognostic significance of c-erbB-2 in primary breast cancer. Br J Cancer 63:447-450, 1991[Medline]

34. Anbazaghan R, Gelber RD, Bettelheim R, et al: Association of c-erbB-2 expression and S-phase fraction in prognosis of node positive breast cancer. Ann Oncol 2:47-53, 1991[Abstract/Free Full Text]

35. O'Reilly SM, Barnes DM, Camplejohn RS, et al: The relationship between c-erbB-2 expression, S-phase fraction and prognosis in breast cancer. Br J Cancer 63:444-446, 1991[Medline]

36. Gullick WJ, Love SB, Wright C, et al: C-erbB-2 protein overexpression in breast cancer is a risk factor in patient with involved and uninvolved lymph nodes. Br J Cancer 63:434-438, 1991[Medline]

37. Ro J, El-Naggar A, Ro JY, et al: C-erbB-2 amplification in node negative breast cancer. Cancer Res 49:6941-6944, 1989[Abstract/Free Full Text]

38. Richner J, Gerber HA, Locher GW, et al: C-erbB-2 protein expression in node negative breast cancer. Ann Oncol 1:263-268, 1990[Abstract/Free Full Text]

39. Dykin R, Corbett IP, Henry JA, et al: Long term survival in breast cancer related to overexpression of the c-erbB-2 oncoprotein: Immunohistochemical study using the monoclonal antibody NCL-CB11. J Pathol 161:358A, 1990 (abstr)

40. Paterson MC, Dietrich KD, Kanyluk J, et al: Correlation between c-erbB-2 amplification and risk of recurrent disease in node negative breast cancer. Cancer Res 51:556-567, 1991[Abstract/Free Full Text]

41. Allred DC, Clark GM, Tandon AK, et al: HER-2/neu in node negative breast cancer: Prognostic significance of over-expression influenced by the presence of in situ carcinoma. J Clin Oncol 10:599-605, 1992[Abstract/Free Full Text]

42. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance of c-erbB-2 expression in breast cancer. J Clin Oncol 10:1049-1056, 1992[Abstract]

43. Joensuu H, Isola J, Lundin M, et al: Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: A nationwide population based study. Clin Cancer Res 9:923-930, 2003[Abstract/Free Full Text]

44. Smith I, Marion P, Gelber RD, et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomized controlled trial. Lancet 369:29-36, 2007[CrossRef][Medline]

45. Slamon D, Eiermann W, Robert N, et al: BCIRG 006: Second interim analysis of phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in ERBB2 positive early breast cancer patients. Breast Cancer Res Treat 100:52, 2006 (suppl 1, abstr)

46. Van de Vijver MJ, Peterse JL, Mooi WJ, et al: Neu-protein overexpression in breast cancer: Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 319:1239-1245, 1988[Abstract]

47. Dybdal N, Leiberman G, Anderson S, et al: Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 93:3-11, 2005[Medline]

Submitted December 18, 2007; accepted July 10, 2008.

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

This article has been cited by other articles:

				G. Curigliano, G. Viale, V. Bagnardi, L. Fumagalli, M. Locatelli, N. Rotmensz, R. Ghisini, M. Colleoni, E. Munzone, P. Veronesi, et al. Clinical Relevance of HER2 Overexpression/Amplification in Patients With Small Tumor Size and Node-Negative Breast Cancer J. Clin. Oncol., December 1, 2009; 27(34): 5693 - 5699. [Abstract] [Full Text] [PDF]

				H. J. Burstein and E. P. Winer Refining Therapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: T Stands for Trastuzumab, Tumor Size, and Treatment Strategy J. Clin. Oncol., December 1, 2009; 27(34): 5671 - 5673. [Full Text] [PDF]

				W. Kwan, A. J. Al-Tourah, C. Speers, R. Woods, H. Kennecke, and I. A. Olivotto Does HER2 status influence locoregional failure rates in breast cancer patients treated with mastectomy for pT1-2pN0 disease? Ann. Onc., October 13, 2009; (2009) mdp396v1. [Abstract] [Full Text] [PDF]

				A. Goldhirsch, J. N. Ingle, R. D. Gelber, A. S. Coates, B. Thurlimann, H.-J. Senn, and Panel members Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2009 Ann. Onc., August 1, 2009; 20(8): 1319 - 1329. [Abstract] [Full Text] [PDF]

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