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

PurposeTo 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 MethodsIHC 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.ResultsCentral 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.ConclusionThere 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.

Letter to the editor regarding ‘Seol H, Lee HJ, Choi Y, et al. Intratumoural heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance'

“…2 Rather, high/unequivocal HER2 amplification is a favorable predictor of response to (antracyclinebased) chemotherapy-a result that has been well documented. 3,4 Moreover, patients with low-HER2-amplification-and heterogeneity, perhaps-still benefit from trastuzumab in addition to chemotherapy. 1,3 Seol et al 1 rightly highlight the importance of determining the HER2 amplification status accurately, both overall and taking into account intratumoral heterogeneity.…”

“…3,4 Moreover, patients with low-HER2-amplification-and heterogeneity, perhaps-still benefit from trastuzumab in addition to chemotherapy. 1,3 Seol et al 1 rightly highlight the importance of determining the HER2 amplification status accurately, both overall and taking into account intratumoral heterogeneity. Based on our own work, a fully satisfactory definition of heterogeneity has not been forthcoming.…”

“…However, a recent study revealed that the tumor cells with 3:1 HER2/CEP17 ratio, which may reflect technical issues, were determining factor for heterogeneity in 46% of heterogeneous cases. 3 Furthermore, Allison et al 4 reported that the ratio criteria and the criteria based on HER2 signals per cell for definition of HER2 genetic heterogeneity were not equivalent and the ratio-based definition resulted in large numbers of non-amplified cases being classified as heterogeneous. Thus, to avoid artifactual heterogeneity caused by technical issues, such as nuclear truncation and inadequate hybridization, cutoff values of percentage and cell ratio for HER2 genetic heterogeneity need to be validated.…”

High concordance between HercepTest immunohistochemistry and ERBB2 fluorescence in situ hybridization before and after implementation of American Society of Clinical Oncology/College of American Pathology 2007 guidelines

“…3 Subsequent studies, however, have displayed a lower percentage of HER2-positive cases, from 15-25% of breast cancers to as low as 7%. 22,23 A small number of our cases were rated as negative by HercepTest immunohistochemistry and yet demonstrated amplification by PathVysion fluorescence in-situ hybridization, thus considered as a false-negative result. Using a stepwise algorithm of performing immunohistochemistry first, then subsequent fluorescence in-situ hybridization testing based on immunohistochemistry results, a small percentage of samples would inevitably be scored as falsely negative, thereby inappropriately excluding these patients from trastuzumab (Herceptin) therapy.…”

Optimal Systemic Therapy for Early Breast Cancer in Women: A Clinical Practice Guideline

“…The hera trial 63,71,73,74 , a large phase iii international rcT, randomized patients with her2-positive early breast cancer to 1 or 2 years or no years of trastuzumab after completion of adjuvant systemic therapy (investigator choice). Regardless of the chemotherapy backbone, patients experienced a significant clinical benefit with the addition of trastuzumab to chemotherapy.…”