Background: Better predictors of adjuvant chemotherapy benefit would improve clinical management of breast cancer patients. The Shc proteins, implicated in many pathways associated with aggressive cancers, can be measured in tumors by the OncoPlanTM immunohistochemical test, which reports on phosphorylated (PY)-Shc and an inhibitory form of the protein, p66 Shc. Previous studies have shown that OncoPlan is a strong predictor of disease outcome. Here we report on the ability of p66 Shc to identify those patients most likely to benefit from chemotherapy.Methods: Population-based primary invasive tumors from 2380 women from BC were arrayed in TMA format (no adjuvant therapy=1663; chemotherapy=717; relapsed=854; died of disease=501; 13yrs median follow-up). Shc staining was scored on a continuous 0-5 scale by two pathologists, blinded to patient data.Results: In 1663 patients not receiving chemotherapy prior to first relapse, p66 Shc as a continuous variable had strong ability to predict relapse-free survival (RFS) (hazard ratio (HR) = 0.64, 95% CI 0.44-0.93, P = 0.018) and disease-specific survival (DSS) (HR = 0.47, 95% CI 0.30-0.75, P = 0.001) in multivariate Cox models adjusted for nodal status, Her2 and ER status, age, tumor size and grade. In contrast, p66 Shc did not predict outcome in chemotherapy-treated patients (RFS HR = 1.06, 95% CI 0.67-1.65, P = 0.81; DSS HR = 1.00 95% CI 0.61-1.67, P = 0.98). This suggested that p66 Shc levels predicted tumor responsiveness to chemotherapy. To test this hypothesis, we examined chemotherapy's protective ability in patients subgrouped by p66 Shc levels, using fully adjusted Cox model.The 60% of patients classified as high risk by OncoPlan (low p66 Shc levels) were strongly protected by chemotherapy (RFS HR = 0.53, 95% CI 0.38-0.75, P = 0.0001; DSS HR = 0.51, 95% CI 0.34-0.74, P = 0.001), whereas for the 40% of patients classified as low risk by OncoPlan, chemotherapy appeared to be a hazard (RFS HR = 1.2, 95% CI 0.79-1.8, P = 0.41; DSS HR = 1.9, 95% CI 1.15-3.02, P = 0.01). For the total population of patients, chemotherapy appeared to be protective (RFS HR = 0.74, 95% CI 0.59-94, P = 0.01; DSS HR = 0.81, 95% CI 0.62-1.05, P = 0.12).By drug, high risk patients were protected by AC (DSS HR = 0.31, 95% CI 0.017-0.57, P < 0.0001) and CMF (DSS HR = 0.48, 95% CI 0.30-0.76, P = 0.002); low risk patients were not protected by AC or CMF (HR >1.5, P > 0.10).Conclusions: These data suggest that p66 Shc levels in primary tumors identify patients with a low risk profile who will derive little benefit from chemotherapy and also patients with a high risk profile, who will derive the most benefit.Supported in part by a Susan G. Komen Breast Cancer Foundation grant

[First AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Sep 12-15, 2006]