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J Clin Oncol. 2010 Oct 1; 28(28): 4307–4315.
Published online 2010 Aug 9. doi:  10.1200/JCO.2009.26.2154
PMCID: PMC2954132

HER2 and Chromosome 17 Effect on Patient Outcome in the N9831 Adjuvant Trastuzumab Trial

Abstract

Purpose

We examined associations between tumor characteristics (human epidermal growth factor receptor 2 [HER2] protein expression, HER2 gene and chromosome 17 copy number, hormone receptor status) and disease-free survival (DFS) of patients in the N9831 adjuvant trastuzumab trial.

Patients and Methods

All patients (N = 1,888) underwent chemotherapy with doxorubicin and cyclophosphamide, followed by weekly paclitaxel with or without concurrent trastuzumab. HER2 status was determined by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) at a central laboratory, Mayo Clinic, Rochester, MN. Patients with conflicting local positive HER2 expression results but normal central laboratory testing were included in the analyses (n = 103).

Results

Patients with HER2-positive tumors (IHC 3+, FISH HER2/centromere 17 ratio ≥ 2.0, or both) benefited from trastuzumab, with hazard ratios (HRs) of 0.46, 0.49, and 0.45, respectively (all P < .0001). Patients with HER2-amplified tumors with polysomic (p17) or normal (n17) chromosome 17 copy number also benefited from trastuzumab, with HRs of 0.52 and 0.37, respectively (P < .006). Patients who received chemotherapy alone and had HER2-amplified and p17 tumors had a longer DFS than those who had n17 (78% v 68%; P = .04), irrespective of hormone receptor status or tumor grade. Patients with HER2-normal tumors by central testing (n = 103) seemed to benefit from trastuzumab, but the difference was not statistically significant (HR, 0.51; P = .14). Patients with hormone receptor–positive or –negative tumors benefited from the addition of trastuzumab, with HRs of 0.42 (P = .005) and 0.60 (P = .0001), respectively.

Conclusion

These results confirm that IHC or FISH HER2 testing is appropriate for patient selection for adjuvant trastuzumab therapy. Trastuzumab benefit seemed independent of HER2/centromere 17 ratio and chromosome 17 copy number.

INTRODUCTION

Human epidermal growth factor receptor 2 (HER2) is involved in the pathophysiology of breast cancer (BC), and its protein expression and gene amplification status help predict outcome of patients with early and advanced disease. Development and use of effective therapies that target the HER2 protein (eg, trastuzumab, lapatinib) depend on accurate HER2 testing of tumor specimens to optimize patient selection.1 However, HER2 testing remains controversial because of technical issues and laboratory experience, accuracy of testing and cut point determination, differential interpretation among pathologists, tumor heterogeneity, and preliminary clinical data suggesting that even patients with HER2-normal tumors (eg, immunohistochemistry [IHC] scores of 0 to 2+ and negative fluorescent in situ hybridization [FISH] results) may benefit from trastuzumab treatment.2,3

The successful conduct of our phase III, North Central Cancer Treatment Group–led N9831 trial with standardized HER2 testing and thorough patient follow-up allows us to critically examine the ability of HER2 protein expression and gene amplification to predict adjuvant trastuzumab benefit. N9831 evaluated patients with resected HER2-positive BC treated with combination chemotherapy with or without trastuzumab.4 Examination of our large N9831 HER2 data set in relation to standard clinicopathologic characteristics may result in more robust conclusions than those previously reached with data from small trials. Importantly, predicting benefit of anti-HER2 therapy may not be identical in the metastatic and adjuvant settings. There is speculation regarding whether HER2 protein overexpression or gene amplification is the better predictor of trastuzumab benefit. Chromosome 17 polysomy may be associated with trastuzumab response, particularly in patients with metastatic BC with HER2-nonamplified tumors.5,6 Because HER2 is differentially expressed between HER2-positive/hormone receptor–positive and HER2-positive/hormone receptor–negative tumors,715 hormone receptor status in relation to HER2 levels also may be important in predicting trastuzumab benefit.16 Because HER2 protein levels, HER2 gene copy number, chromosome 17 copy number, and hormone receptor status may influence trastuzumab response, we report their associations with disease-free survival (DFS) in 1,888 patients randomly assigned to receive chemotherapy with or without concurrent trastuzumab in N9831.

PATIENTS AND METHODS

Patients

The N9831 trial (Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-Expressing or Amplified Node Positive or High Risk Node Negative Breast Cancer) was approved by participating institutional review boards. The study had three arms: arm A, doxorubicin and cyclophosphamide followed by weekly paclitaxel; arm B, same as arm A but followed by 1 year of sequential trastuzumab; arm C, same as arm A but with 1 year of concurrent trastuzumab, started the same day as paclitaxel. The present analyses included patients randomly assigned to arms A versus C, enrolled from May 25, 2000, through January 23, 2002, and from September 2, 2002, through April 25, 2005, and tested for HER2 protein overexpression or gene amplification at a central laboratory (Mayo Clinic, Rochester, MN). Outcome data of patients in arm B had not been released by the study's independent data monitoring committee at time of analysis and are not included in this report.

HER2 Testing Methods

IHC staining was performed on paraffin-embedded 5-μm tissue sections using the HercepTest according to the manufacturer's instructions (DAKO, Carpinteria, CA).1719 Assay control cell lines (SK-BR-3:3+, MDA-175:1+, MDA-231:0) provided on slides in the HercepTest kit were analyzed in each assay. Invasive carcinoma cells (and not benign epithelial or ductal carcinoma in situ cells) were used for the assessment of HER2 status of the tumor. Specimens were scored as per the instructions in the trastuzumab package insert.20 A specimen with at least 10% invasive cells with complete membrane staining was classified as 3+ and considered HER2-positive according to pre–American Society of Clinical Oncology/College of American Pathologists 2007 guidelines.1

FISH analysis was performed on deparaffinized 5-μm tissue sections using the PathVysion HER2 DNA probe kit and the HER2/centromere 17(HER2/centromere enumerator probe for chromosome 17 [CEP17]) probe mixture (Abbott Molecular, Des Plaines, IL).1719 For each case, a parallel hematoxylin and eosin–stained slide was examined for regions of invasive carcinoma by a board-certified pathologist (D.W.V., R.P.K.). The complete tissue section was scanned by two certified cytogenetic technologists to detect any subpopulation of amplified cells. Thirty representative nuclei from the invasive tumor were scored by each technologist (60 nuclei total), with an overall evaluation performed by a board-certified pathologist (R.P.K., R.B.J.). When the red HER2 signals were clearly amplified (large clouds of amplification), we assigned ≥ 20 red signals and counted the green (CEP17) signals. For such cases, a number needs to be defined for the numerator and thus the ratio was defined as 20/average number of green signals per cell. As polysomy 17 increases, the ratio decreases. Scoring ranges were based on those determined for the US Food and Drug Administration–approved test for HER2 gene alterations in BC.21,22 A specimen with an HER2/CEP17 ratio ≥ 2.0 in invasive cells was classified as HER2 amplified and considered HER2 positive according to pre–American Society of Clinical Oncology/College of American Pathologists 2007 guidelines.1

Because many different HER2 and chromosome 17 alterations have been observed in BC,2327 we independently categorized the HER2 FISH results on the basis of HER2 and CEP17 signal patterns. For HER2-amplified tumors (HER2/CEP17 ratio ≥ 2), three ranges of CEP17 signals were observed: polysomy 17 (p17), ≥ 3 CEP17 signals in more than 30% of nuclei; monosomy 17 (m17), 0 to 1 CEP17 signals in more than 60% of nuclei; and normal (n17) all other cases. We carefully validated these polysomy and monosomy cutoffs by extensively analyzing our N9831 data and a large set (> 10,000 cases) of clinical HER2 FISH assays concurrently performed by the central testing laboratory (Data Supplement). Both cutoffs clearly distinguish chromosome 17 polysomic and monosomic cases from those cases without chromosome 17 centromere anomalies. All categorization thresholds were selected to reduce the rate of false-positive findings for gene amplification, gene deletion, and chromosome loss or gain. In our experience, these criteria have worked well to correct for truncation and nuclear overlap and the increase in four CEP17 signals due to G2M for nearly all solid tumors. Table 1 provides detailed definitions for HER2 amplification, small clones of HER2 amplification, HER2 duplication, and chromosome 17 loss or gain.

Table 1.
Classification of HER2/CEP17 Data

Quality control of the HER2 FISH test is assessed routinely according to standard College of American Pathologists and the American College of Medical Genetics guidelines.28,29 The performance of the assay as assessed on a monthly basis has been stable according to Westgard rules.30

Eligibility criteria for N9831 trial enrollment were initially based on local laboratory HER2 test results (IHC score of 3+ or HER2/control probe ratio ≥ 2.0 or five or more gene copies of HER2).18,19 After analysis of the first 119 specimens showed poor concordance between HER2 results from local and central (Mayo Clinic) laboratories,19 the protocol was amended (amendment 7), to require validation of HER2 positivity by the central laboratory for eligibility and study participation. When the central laboratory's IHC and FISH test results were both negative, the local site was contacted and another set of slides was submitted to a reference laboratory (Laboratory Corporation of America, Research Triangle Park, NC). Enrollment into N9831 was then allowed only if HER2 positivity could be confirmed by IHC or FISH performed in the central or reference laboratories.18 One hundred three patients with HER2-normal tumors (as shown by central laboratory IHC and FISH test results) continued in the trial because of local laboratory positivity (90 patients enrolled before amendment 7 was established) or because of reference laboratory positivity (13 patients enrolled after amendment 7). In the present analyses, data from the central laboratory tests were used.

Statistical Methods

DFS was the primary end point, defined as local, regional, or distant recurrence, contralateral BC, another primary cancer (except squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast), or death from any cause. The duration of DFS was defined as the time from registration to the first event. DFS was estimated by the Kaplan-Meier method. Comparisons between arms A and C were performed using the Cox proportional hazards model, stratified by nodal status (negative, 1 to 3+, 4 to 9+, 10+, and sentinel node positive) and hormone receptor status (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive v negative for both receptors).

RESULTS

Study Patients

The trial enrolled 1,888 eligible patients into arms A and C; 1,795, 1,845, and 1,783 were evaluated for HER2 gene amplification, HER2 protein overexpression, or both, respectively. We found small clones of HER2 amplification (Table 1) in 4.5% of patient specimens. The clinicopathologic characteristics of the patients are described in the Data Supplement, and the clinicopathologic characteristics stratified by IHC and FISH status are described in Table 2.

Table 2.
Patient Characteristics for Patients by FISH/IHC Status (N = 1,783)

HER2 Protein Expression, Gene/Chromosome 17 Ratio, and Gene Copy Number

A 54%, 51%, and 55% improvement in DFS was observed with the addition of trastuzumab for patients whose tumors had HER2 IHC scores of 3+ (Fig 1A), HER2/CEP17 ratios of ≥ 2.0 (Fig 1B), or both (Fig 1C), respectively. The hazard ratios (HRs) for patients with IHC scores of 3+, HER2/CEP17 ratios of ≥ 2.0, or both were 0.46, 0.49, and 0.45, respectively (Fig 2). Patients with IHC scores of 0 to 2+ (Figs 1D and and2A),2A), HER2/CEP17 ratio less than 2.0 (Figs 1E and and2A),2A), or both (Figs 1F and and2B)2B) had HRs of 0.69, 0.54, and 0.51, respectively, with the addition of trastuzumab, but the differences were not statistically significant (P = .26, .12, and .14, respectively). Figure 2C shows that at least a 49% improvement in DFS was observed with the addition of trastuzumab for patients in the four HER2/CEP17 ratio subgroups (2 to 4.99, 5 to 7.99, 8 to 10.99, and 11 to 14.99). The subgroup with HER2/CEP17 ratio of ≥ 15.0 had an insufficient number of events to determine whether trastuzumab treatment was efficacious, but the HR was close to 1. Patients with HER2 copy number of four or more received benefit from receiving trastuzumab (HR, 0.51; 95% CI, 0.37 to 0.70; P < .0001). Similarly, patients with HER2 copy number less than four received benefit from receiving trastuzumab (HR, 0.52; 95% CI, 0.29 to 0.94; P = .03).

Fig 1.
Kaplan-Meier curves for disease-free survival (DFS). Patients treated with doxorubicin, cyclophosphamide, and paclitaxel are shown by the solid gold line. Patients treated with doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab are shown by the ...
Fig 2.
Hazard ratios by HER2 protein expression and gene amplification subgroups according to (A) immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH); (B) IHC and FISH; and (C) FISH alone. (*) Disease-free survival hazard ratios calculated ...

Chromosome 17 Copy Number Aberrations

The distribution of copy number anomalies was as follows: HER2 amplified with n17, 29%; HER2 amplified with p17, 46%; HER2 amplified with m17, 4%; small clones of HER2 amplification, 5%; HER2 duplicated, 6%; HER2 not amplified, 6%; and HER2 not amplified with p17, 2% (n = 37; Fig 3A). Among the patients with HER2 amplification, HER2/CEP17 ratios tended to range from 6.00 to 15.00 with n17 background, 3.0 to 10.99 with p17 background, 15.0 to 18.99 with m17 background, and 2.00 to 5.99 with small clones. Ratios tended to be less than 3.00 if duplicated. Figure 3B illustrates cells with HER2 amplification with n17 and p17 backgrounds. Polysomy 17 was significantly associated with high Nottingham grade but not hormone receptor status. Among the 1635 patients with either p17 or n17, 75% of p17 had high-grade tumors, whereas 68% of n17 had high-grade tumors (P = .002; Data Supplemental).

Fig 3.
Distribution of human epidermal growth factor receptor 2 (HER2)/centromere enumerator probe for chromosome 17 (CEP17) ratios. (A) Distribution of HER2/CEP17 ratio (measured by fluorescent in situ hybridization [FISH]). Left, all patient data. Right, detailed ...

Patients with HER2 amplification and either p17 or n17 backgrounds had improved HRs (0.52 and 0.37, respectively) and similar 5-year DFS rates (89% and 88%, respectively) with addition of trastuzumab (Figs 4A and and4B).4B). Conversely, among patients who received chemotherapy alone, those with p17 seemed to have longer DFS than those with n17 (Fig 4A; P = .04). In multivariate analysis, p17 was still significant (P = .01), with hormone receptor status, nodal status, and tumor size being significant covariates (Data Supplement). Within arm A, there was a trend that p17 was associated with high Nottingham grade (P = .07), but not with hormone receptor status (P = .89; Data Supplement).

Fig 4.
Survival analyses by chromosome 17 and hormone receptor status. (A) Kaplan-Meier curves for disease-free survival by arm and chromosome 17 status in patients with HER2 amplification. The dashed gray line represents patients treated with trastuzumab (H; ...

Hormone Receptor Status

One thousand twenty-two patients (54%) had ER- and/or PR-positive tumors, and 866 patients (46%) had ER- and PR-negative tumors. Patients with ER/PR-positive or -negative tumors benefited from the addition of trastuzumab with HRs of 0.42 (95% CI, 0.27 to 0.65; P = .0001) and 0.60 (95% CI, 0.42 to 0.86; P = .005), respectively. Among the ER/PR-positive group, patients receiving trastuzumab had improved 3- and 5-year DFS of 7.2% (92.8; 95% CI, 90.1 to 95.7 v 85.6; 95% CI, 81.8 to 89.5) and 13.9% (89.1; 95% CI, 84.9 to 93.4 v 75.2; 95% CI, 69.3 to 81.5), respectively (Fig 4C). In the ER/PR-negative group, patients receiving trastuzumab also had improved 3- and 5-year DFS of 9.9% (83.0; 95% CI, 78.5 to 87.7 v 73.1; 95% CI, 67.7 to 78.8) and 12.0% (80.6; 95% CI, 75.5 to 86.0 v 68.6; 95% CI, 62.3 to 75.6), respectively (Fig 4D). There was no statistically significant interaction between hormone receptor status and study treatment (P = .15).

HRs were examined across the FISH HER2/CEP17 ratio subgroups in patients with ER/PR-positive and -negative tumors (Data Supplement). All subgroups had HRs of less than 1.0, but the patients with hormone receptor–positive tumors had lower HRs than patients with ER/PR-negative tumors, except for the HER2 nonamplified patients with FISH ratios less than 2.0. Examining FISH ratio as a continuous covariate, the DFS benefit was similar between ER/PR-positive and -negative tumors and was not statistically significant.

DISCUSSION

This expanded analysis of our N9831 study results further confirms that patients with HER2-overexpressing and/or amplified tumors clearly benefit from adjuvant trastuzumab, administered concurrently with combination chemotherapy. Our analyses also elucidate important findings applicable to patient care. Among patients whose tumors had discordant central IHC and FISH results, those with HER2 protein overexpression and no gene amplification had an HR of 0.57 (P = .56; Fig 2B), and those with normal protein expression and gene amplification had an HR of 1.11 (P = .86; Fig 2B). Preanalytic challenges and the semiquantitative interpretation of IHC may obscure the importance of protein expression, as compared with the quantitative determination of gene copy number and gene/centromere copy number ratio by FISH. Our results are not statistically significant and warrant further follow-up.

We did not observe a linear dose-effect between the level of HER2 gene amplification and trastuzumab response. Patients whose tumors had FISH ratios between 2 and less than 15 derived similar benefit from trastuzumab. These patients typically had tumors with normal chromosome 17 copy number (ratios 8 to 15) or with chromosome 17 polysomy (ratios 4 to 11). An HR of 0.96 was observed for patients whose tumors had FISH ratios more than 15, which typically had monosomy 17. A recent analysis of another adjuvant trastuzumab trial, Herceptin Adjuvant trial (HERA), also did not show a true linear dose response between level of HER2 amplification and trastuzumab benefit.31

The relative benefit to adjuvant trastuzumab seems to be similar between patients whose tumors were found to be HER2 normal by IHC and FISH central testing (n = 103; HR, 0.51) and those patients whose tumors had HER2 protein overexpression (HR, 0.46) or gene amplification (HR, 0.49). However, we note that the DFS events are limited for the 103 patients, resulting in a nonsignificant HR (P = .14), and that these tumors had been described to be HER2 positive by the original local pathologist. This observation of a trend for benefit to trastuzumab independent of whether the tumors could be corroborated to be HER2 positive by a central laboratory may be explained by several factors: (1) limited number of patients and observed events; (2) enhanced chemosensitivity by combined chemotherapy and trastuzumab compared with trastuzumab alone in patients with low-to-intermediate tumor HER2 protein levels or gene copy number; (3) tumor HER2 heterogeneity, as 45% of specimens had different tissue blocks tested by the local and central laboratories; or (4) other mechanisms of action of trastuzumab, such as modulation of the immune system, possibly being more relevant in the adjuvant setting. The possibility of enhanced chemosensitivity is supported by preclinical data suggesting that cell lines with low-to-intermediate HER2 expression may have enhanced sensitivity to trastuzumab when combined with chemotherapy compared with trastuzumab alone.3235 Alternatively, anti-HER2 treatments may partially work via activity against the so-called BC stem cell, and not directly related to HER2 gene amplification.36,37 Of note is that our data are consistent with retrospective findings from the B-31 trial.2,3 Bearing the caveats described above, if these data can be validated by larger studies, threshold values for HER2 positivity may then need to be redefined for patients receiving adjuvant chemotherapy with trastuzumab. Theoretically, the guidelines regarding adjuvant trastuzumab administration would then need to include many more new BC cases.

We found that p17 did not predict for trastuzumab benefit in patients with HER2 amplification. Patients with HER2-amplified tumors, irrespective of p17 status, significantly benefitted from trastuzumab. This benefit was not significantly different between HER2-amplified/p17 and HER2-amplified/n17 patients (P = .36). Although, we cannot presently determine definitive associations between p17 and trastuzumab efficacy in patients with HER2-normal tumors (Data Supplement), we observed that HER2-normal patients with n17 seemed to benefit from trastuzumab (P = .04), whereas those with p17 did not appear to benefit from trastuzumab (P = .85). However, due to the limited number of HER2-normal patients/events, an interaction term cannot be defined. These results need to be interpreted with caution.

We did observe that in patients with HER2 amplification and treated with chemotherapy alone, those with p17 benefited more than those with n17, suggesting that p17 may have some prognostic utility. Outside the stratification factors of hormone receptor and nodal status, the only significant covariate was tumor size and not Nottingham grade. Recent preliminary data from preclinical and independent non-HER2 directed clinical trials (MA5, BR9601, NEAT) support our findings that patients with p17 may have a better prognosis than those patients with n17 when treated with anthracyclines.38,39

Our data support previous findings that showed that patients with hormone receptor–positive and –negative BC have different patterns of relapse.15 Although both cohorts in N9831 experienced a similar magnitude of benefit from trastuzumab therapy, irrespective of chromosome 17 status, the patients with hormone receptor–positive BC had a lower rate of relapse than patients with hormone receptor–negative BC (HR, 0.46; P < .0001) early in the follow-up period. However, these results should be interpreted with caution because longer follow-up is required. We recommend combining our data with data from other adjuvant trastuzumab-based clinical trials to analyze the various subpopulations.

In summary, our findings showed that accurate HER2 testing strategies are critical for appropriate management of patients with BC. We still advocate use of US Food and Drug Administration package insert guidelines for HER2 positivity. Newer ongoing studies may help determine whether new definitions of HER2 positivity or other biologic markers should be incorporated for decision to recommend trastuzumab in the adjuvant setting.20,40

Supplementary Material

Data Supplement:

Acknowledgment

We thank the patients, physicians, nurses, data managers, and trial coordinators who participated in this study. We thank Alvaro Moreno-Aspitia, MD, and Melisa Walker for their editorial assistance.

Footnotes

See accompanying editorials on pages 4289 and 4293 and article 4300

Supported by the National Institutes of Health (Grant Nos. CA25224, CA129949, and CA114740); the Breast Cancer Research Foundation; the National Cancer Institute; and Genentech (35–03).

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; and the 30th Annual San Antonio Breast Cancer Symposium, December 13-16, 2007, San Antonio, TX.

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

Clinical trial information can be found for the following: NCT00898898 NCT00005970.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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: George W. Sledge, Genentech (C); Peter A. Kaufman, Genentech (C) Stock Ownership: None Honoraria: George W. Sledge, Genentech; Peter A. Kaufman, Genentech Research Funding: Edith A. Perez, Genentech, GlaxoSmithKline; Julie R. Gralow, Amgen, Novartis, Roche, Genentech, sanofi-aventis, Eli Lilly, Bristol-Myers Squibb; Peter A. Kaufman, Genentech Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Edith A. Perez, Monica M. Reinholz, Nancy E. Davidson, Silvana Martino, Peter A. Kaufman, Robert B. Jenkins

Financial support: Edith A. Perez

Administrative support: Edith A. Perez

Provision of study materials or patients: Edith A. Perez, Nancy E. Davidson, Silvana Martino, George W. Sledge, James N. Ingle

Collection and assembly of data: Edith A. Perez, Monica M. Reinholz, David W. Hillman, Matthew J. Schroeder, Silvana Martino, Rhett P. Ketterling, Wilma L. Lingle, Daniel W. Visscher, Robert B. Jenkins

Data analysis and interpretation: Edith A. Perez, Monica M. Reinholz, David W. Hillman, Kathleen S. Tenner, Silvana Martino, Julie R. Gralow, Amylou C. Dueck, Rhett P. Ketterling, Wilma L. Lingle, Peter A. Kaufman, Daniel W. Visscher, Robert B. Jenkins

Manuscript writing: Edith A. Perez, Monica M. Reinholz, David W. Hillman, George W. Sledge, Lyndsay N. Harris, Amylou C. Dueck, James N. Ingle, Wilma L. Lingle, Peter A. Kaufman, Robert B. Jenkins

Final approval of manuscript: Edith A. Perez, Monica M. Reinholz, David W. Hillman, Kathleen S. Tenner, Matthew J. Schroeder, Nancy E. Davidson, Silvana Martino, George W. Sledge, Lyndsay N. Harris, Julie R. Gralow, Amylou C. Dueck, Rhett P. Ketterling, James N. Ingle, Wilma L. Lingle, Peter A. Kaufman, Daniel W. Visscher, Robert B. Jenkins

REFERENCES

1. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–145. [PubMed]
2. Paik S, Kim C, Jeong J, et al. Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31. J Clin Oncol. 2007;25(suppl; abstr 511):5s.
3. Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer. N Engl J Med. 2008;358:1409–1411. [PubMed]
4. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. [PubMed]
5. Hofmann M, Stoss O, Gaiser T, et al. Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: Assessment of test sensitivity and impact of chromosome 17 polysomy. J Clin Pathol. 2008;61:89–94. [PubMed]
6. Kaufman PA, Broadwater G, Lezon-Geyda K, et al. CALGB 150002: correlation of HER2 and chromosome 17 (ch17) copy number with trastuzumab (T) efficacy in CALGB 9840, paclitaxel (P) with or without T in HER2+ and HER2- metastatic breast cancer (MBC) J Clin Oncol. 2007;25(suppl; abstr 1009):34s.
7. Kim MJ, Ro JY, Ahn SH, et al. Clinicopathologic significance of the basal-like subtype of breast cancer: A comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol. 2006;37:1217–1226. [PubMed]
8. Konecny G, Pauletti G, Pegram M, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst. 2003;95:142–153. [PubMed]
9. Kun Y, How LC, Hoon TP, et al. Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor. Hum Mol Genet. 2003;12:3245–3258. [PubMed]
10. Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123:541–546. [PubMed]
11. Marchio C, Natrajan R, Shiu KK, et al. The genomic profile of HER2-amplified breast cancers: The influence of ER status. J Pathol. 2008;216:399–407. [PubMed]
12. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752. [PubMed]
13. Read LD, Keith D, Jr, Slamon DJ, et al. Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res. 1990;50:3947–3951. [PubMed]
14. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–10874. [PMC free article] [PubMed]
15. Untch M, Gelber RD, Jackisch C, et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol. 2008;19:1090–1096. [PubMed]
16. Peintinger F, Buzdar AU, Kuerer HM, et al. Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab. Ann Oncol. 2008;19:2020–2025. [PMC free article] [PubMed]
17. 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. [PubMed]
18. Perez EA, Suman VJ, Davidson NE, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol. 2006;24:3032–3038. [PubMed]
19. Roche PC, Suman VJ, Jenkins RB, et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst. 2002;94:855–857. [PubMed]
20. Package insert. San Francisco, CA: Genentech; 2008. May, Herceptin (trastuzumab) http://www.gene.com/gene/products/information/pdf/herceptin-prescribing.pdf.
21. Masood S, Bui MM, Yung JF, et al. Reproducibility of LSI HER-2/neu SpectrumOrange and CEP 17 SpectrumGreen Dual Color deoxyribonucleic acid probe kit for enumeration of gene amplification in paraffin-embedded specimens: A multicenter clinical validation study. Ann Clin Lab Sci. 1998;28:215–223. [PubMed]
22. Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: A direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol. 2000;18:3651–3664. [PubMed]
23. Bose S, Mohammed M, Shintaku P, et al. Her-2/neu gene amplification in low to moderately expressing breast cancers: Possible role of chromosome 17/Her-2/neu polysomy. Breast J. 2001;7:337–344. [PubMed]
24. Morrison LE, Jewell SS, Usha L, et al. Effects of ERBB2 amplicon size and genomic alterations of chromosomes 1, 3, and 10 on patient response to trastuzumab in metastatic breast cancer. Genes Chromosomes Cancer. 2007;46:397–405. [PubMed]
25. Reinholz MM, Bruzek AK, Visscher DW, et al. Breast cancer and aneusomy 17: Implications for carcinogenesis and therapeutic response. Lancet Oncol. 2009;10:267–277. [PubMed]
26. Vanden Bempt I, Drijkoningen M, De Wolf-Peeters C. The complexity of genotypic alterations underlying HER2-positive breast cancer: An explanation for its clinical heterogeneity. Curr Opin Oncol. 2007;19:552–557. [PubMed]
27. Zaczek A, Welnicka-Jaskiewicz M, Bielawski KP, et al. Gene copy numbers of HER family in breast cancer. J Cancer Res Clin Oncol. 2008;134:271–279. [PubMed]
28. Clinical laboratory assays for HER-2/neu amplification and overexpression: Quality assurance, standardization, and proficiency testing. Arch Pathol Lab Med. 2002;126:803–808. [PubMed]
29. Mascarello JT, Brothman AR, Davison K, et al. Proficiency testing for laboratories performing fluorescence in situ hybridization with chromosome-specific DNA probes. Arch Pathol Lab Med. 2002;126:1458–1462. [PubMed]
30. Westgard JO, Barry PL, Hunt MR, et al. A multi-rule Shewhart chart for quality control in clinical chemistry. Clin Chem. 1981;27:493–501. [PubMed]
31. Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: The HERA Trial. J Clin Oncol. 2009;27:2962–2969. [PMC free article] [PubMed]
32. Arteaga CL. Can trastuzumab be effective against tumors with low HER2/Neu (ErbB2) receptors? J Clin Oncol. 2006;24:3722–3725. [PubMed]
33. Henson ES, Hu X, Gibson SB. Herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1 expression. Clin Cancer Res. 2006;12:845–853. [PubMed]
34. Menendez JA, Mehmi I, Lupu R. Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression. J Clin Oncol. 2006;24:3735–3746. [PubMed]
35. Pero SC, Shukla GS, Cookson MM, et al. Combination treatment with Grb7 peptide and doxorubicin or trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells. Br J Cancer. 2007;96:1520–1525. [PMC free article] [PubMed]
36. Korkaya H, Wicha MS. HER-2, notch, and breast cancer stem cells: Targeting an axis of evil. Clin Cancer Res. 2009;15:1845–1847. [PubMed]
37. Magnifico A, Albano L, Campaner S, et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res. 2009;15:2010–2021. [PubMed]
38. Bartlett JMS, Campbell FM, Mallon EA. Determination of HER2 amplification by in situ hybridization: When should chromosome 17 also be determined? Cancer Res. 2008;69(abstr 3002):3002. [PubMed]
39. Bartlett JMS, Munro A, Desmedt C, et al. Duplication of chromosome 17 CEP predicts for anthracycline benefit: A meta-analysis of 4 trials. Cancer Res. 2009;69(abstr 4030):6059.
40. Perez EA, Reinholz MM, Dueck AC, et al. Do the ASCO/CAP 2007 HER2 testing guidelines improve prediction of benefit to adjuvant trastuzumab? Data from North Central Cancer Treatment Group N9831 adjuvant trial. Cancer Res. 2009;69(abstr 70):524s.

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