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

Authors

Edith A. Perez

From Mayo Clinic, Jacksonville, FL; Mayo Clinic, Rochester, MN; University of Pittsburgh Cancer Institute, Pittsburgh, PA; The Angeles Clinic and Research Institute, Santa Monica, CA; Indiana University Medical Center Cancer Pavilion, Indianapolis, IN; Yale University, New Haven, CT; Seattle Cancer Care Alliance, Seattle, WA; Mayo Clinic, Scottsdale, AZ; Dartmouth Hitchcock Medical Center, Lebanon, NH; and University of Michigan, Ann Arbor, MI.

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

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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.

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).

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.

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.