Predictive immunohistochemical biomarkers in the context of neoadjuvant therapy for breast cancer.

The adoption of personalized medicine has led to the search for prognostic and predictive markers that can be applied to individual patients to give optimal information for their clinical management. We have used samples from randomized clinical trials of hormonal and chemotherapy to identify relevant markers of sensitivity and resistance using a neoadjuvant approach by linking expression of a panel of proteins involved in growth factor receptor signaling, angiogenesis, estrogen receptor signaling, and hypoxia to individual patient response. We evaluated samples from randomized clinical trials of epirubicin with or without tamoxifen, and letrozole with or without metronomic cyclophosphamide, to study chemotherapy, hormonal therapy, and antiangiogenic effects. We present a proof of principle of this approach in identifying several key pathways that are associated with clinical and pathological response. Thus, we have shown that the hypoxia-inducible factor (HIF) pathway, mitogen activated protein kinase, and phosphorylated estrogen receptor-α can identify patients who are likely to respond to hormonal therapy and that HIF signaling is also a marker of resistance for anthracycline-based chemotherapy. To redress the role of HIF, we then evaluated samples from a randomized control trial of an anthracycline chemotherapy with and without erythropoietin. These studies demonstrate that the approach of using primary systemic therapy in breast can identify markers of response and potentially targets for rationale design of new therapies.