ABSTRACT
Tumor blocks for 992 (64%) node-positive breast cancer patients enrolled in an adjuvant CALGB trial of 3 different CAF doses (CALGB 8541) were assessed for c-erbB-2 (HER2/neu) with a monoclonal antibody (CB-11; positive test 50% membrane staining) and a test of gene amplification. p53 status (positive test 1% staining) was also assessed by immunohistochemistry (IHC). In the parent trial, OS was lower for patients in the low-dose arm. This study sought to validate the previously generated hypothesis among 397 patients [70], that for c-erbB-2-positive tumors, OS is improved with high-dose CAF, and thus these tumors may be uniquely sensitive to anthracycline dose intensity. An independent correlation between c-erbB-2 status, p53 status, and outcome (DFS and OS) was evident when known prognostic factors were included in multivariate analysis. For all patients (sets A [hypothesis set] B [validation set]), IHC and gene amplification for c-erbB-2 were well correlated. Both were independently associated with poorer DFS (p 0.004) and OS (p 0.001), as were the number of positive nodes, no tamoxifen use, Tm size, and p53-positivity (p 0.04 for DFS, p 0.02 for OS). Median follow-up for set AB was 9.3 years. A test of interaction between CAF dose and c-erbB-2 status demonstrated significantly better DFS and OS for women with c-erbB-2-positive tumors treated with high-and moderate-dose CAF, while for patients with c-erbB-2-negative tumors, outcome was similar regardless of CAF dose (set AB). This interaction was not significant for set B alone; however, patients with c-erbB-2-positive tumors and low-dose CAF in this set had significantly worse baseline prognostic factors than their counterparts in set A; when these were adjusted for, the interaction between CAF dose and c-erbB-2 positivity emerged. The opposite interaction was observed between p53 status and CAF dose: patients with p53-negative tumors had a superior OS with high-dose CAF than those with p53-positive tumors. Ten-year OS for p53-negative, c-erbB-2-positive patients was 90% with high-dose and 39% with low-dose CAF (n 34, 33, respectively).
