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

Abstract

Purpose: To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy.

Patients and methods: IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up.

Results: Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab.

Conclusion: There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.

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.

Distribution of (A) HER2 FISH ratio, (B) HER2 copy number, (C) CEP17 copy number (for patients with FISH ratio ≥ 2) for patients in the 1-year trastuzumab and observation arms of the HERA trial showing cut-offs used for comparative analysis. CEP17, chromosome 17 centromere; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2 gene.

Fig 2.

Disease-free survival according to (A) HER2 FISH ratio, (B) HER2 copy number, and (C) CEP17 copy number (for patients with FISH ratio ≥ 2) in the observation arm of the HERA trial: details of the populations defined by cut-offs shown in Figure 1 and (D) CEP17 copy number according to NCCTG cut-offs (see text). CEP17, chromosome 17 centromere; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2 gene.

Fig 3.

Forest plots of the relative benefit from trastuzumab according to (A) HER2 FISH ratio, (B) HER2 copy number, and (C) CEP17 copy number (for patients with FISH ratio ≥ 2) in the HERA trial: details of the populations defined by cut-offs shown in Figure 1 and (D) CEP17 copy number according to NCCTG cut-offs (see text). CEP17, chromosome 17 centromere; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2 gene; HR, hazard ratio; IHC, immunohistochemistry; obs, observation; T, trastuzumab.