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. 2010 Oct 1;28(28):4307-15.
doi: 10.1200/JCO.2009.26.2154. Epub 2010 Aug 9.

HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial

Edith A Perez  1 , 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
Affiliations

HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial

Edith A Perez et al. J Clin Oncol. .

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.

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Conflict of interest statement

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

Figures

Fig 1.
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 dashed blue line. (A) DFS of patients with human epidermal growth factor receptor 2 (HER2) protein overexpression (immunohistochemistry [IHC] score, 3+). (B) DFS of patients with HER2 gene amplification (HER2/centromere enumerator probe for chromosome 17 [CEP17] ratio, ≥ 2.0). The HER2/CEP17ratio was determined by fluorescent in situ hybridization. (C) DFS of patients with HER2 protein overexpression and gene amplification (IHC score, 3+; HER2/CEP17 ratio, ≥ 2.0). (D) DFS of patients with normal HER2 protein expression (IHC score, 0 to 2+). (E) DFS of patients with normal HER2 amplification (HER2/CEP17 ratio, < 2.0). (F) DFS of patients with normal HER2 protein expression and HER2 nonamplification (IHC score, 0 to 2+; HER2/CEP17 ratio, < 2.0). AC, doxorubicin plus cyclophosphamide; T, paclitaxel; H, trastuzumab.
Fig 2.
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 for comparing patients treated with and without trastuzumab. Comparisons for each subgroup were performed using Cox proportional hazard models stratified by nodal status and hormone receptor status. HR, hazard ratio; CEP17, centromere enumerator probe for chromosome 17.
Fig 3.
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 findings for ratios between 0 and 8. (B) Illustration of amplification of HER2 (red) and normal or polysomic CEP17 (p17; green) by FISH. Left, amplified HER2 normal (disomic) chromosome 17 (n17). Right, amplified HER2 p17. Amp, amplified; m17, monosomic chromosome 17; Dup, duplication; NACA, no apparent chromosome abnormality; ND, not determined.
Fig 4.
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; polysomic chromosome 17 [p17] background). The dashed blue line represents patients treated with H (normal [disomic] chromosome 17 [n17] background). The dashed red line represents patients treated without H (p17 background). The solid gold line represents patients treated without H (n17 background). (B) Disease-free survival hazard ratios (HR) by chromosome 17 status. The HRs were calculated comparing patients treated with and without H. Comparisons for each subgroup were performed using Cox proportional hazard models stratified by nodal status and hormone receptor status. (C) Kaplan-Meier curves for disease-free survival by arm and chromosome 17 status in patients with estrogen receptor (ER) –positive or progesterone receptor (PR) –positive tumors. The dashed gray line represents patients treated with H (p17 background). The dashed blue line represents patients treated with H (n17 background). The dashed red line represents patients treated without H (p17 background). The solid gold line represents patients treated without H (n17 background). (D) Kaplan-Meier curves for disease-free survival by arm and chromosome 17 status in patients with ER- and PR-negative tumors. The dashed gray line represents patients treated with H (p17 background). The dashed blue line represents patients treated with H (n17 background). The dashed red line represents patients treated without H (p17 background). The solid gold line represents patients treated without H (n17 background). AC, doxorubicin plus cyclophosphamide; T, paclitaxel; IHC, immunohistochemistry; FISH, fluorescent in situ hybridization; Amp, amplified; m17, monosomic chromosome 17; sc, small clone.
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