Originally published as JCO Early Release 10.1200/JCO.2008.19.7939 on April 13 2009

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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

From the Department of Academic Biochemistry, Royal Marsden Hospital, London, United Kingdom; Frontier Science (Scotland) Ltd, Kincraig, Kingussie, Scotland; National Cancer Institute, National Institutes of Health, Bethesda, MD; Departments of Medical Oncology and Medicine, Institut Jules Bordet, Université Libre de Bruxelles; Breast European Adjuvant Studies Team, Brussels, Belgium; Department of Public Health, School of Nursing, University of Athens, Athens, Greece; TARGOS Molecular Pathology GmbH, Kassel, Germany; Roche Professional Diagnostics, F. Hoffmann-La Roche Ltd, Basel, Switzerland; VM Institute of Research, Montreal, Quebec, Canada; Division of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan, Milan, Italy; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and Emory Winship Cancer Institute, Atlanta, GA.

Corresponding author: Mitch Dowsett, PhD, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, United Kingdom; e-mail: mitch.dowsett{at}icr.ac.uk.

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.

Supported in part by NHS (National Health Service) funding to the Royal Marsden National Institute for Health Research Biomedical Research Centre (M.D.).

Presented in part at the 30th Annual San Antonio Breast Cancer Symposium, December 13-16, 2007, San Antonio, TX.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00045032 [ClinicalTrials.gov] .

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