Molecular subtypes of breast cancer and cyclooxygenase-2 overexpression: Predictive role in patients treated with adjuvant anthracycline-based chemotherapy

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3621 High levels of cyclooxygenase-2 (COX-2), an inducible enzyme involved in prostaglandin biosynthesis, have been shown to correlate with a worse prognosis in patients with several types of tumors including breast cancer (BC). Moreover, epidemiological, experimental and clinical studies have collectively identified COX-2 as a relevant target for the prevention and treatment of a variety of epithelial malignancies overexpressing this enzyme. Purpose of our study is to evaluate the prognostic value of COX-2 in the context of chemoresponsiveness in BC patients submitted to anthracycline-based adjuvant therapy. We further analyzed the potential differences in treatment effect due to COX-2 expression within the BC molecular subtypes, namely luminal A, basal-like, HER2, normal-like, as defined by immunohistochemistry. To this end, 186 stage I-IIA-B BC patients enrolled in a prospective clinical trial using epirubicin plus cyclophosphamide in the adjuvant setting were investigated using immunohistochemical methods. COX-2 overexpression was significantly associated to nodal status (p=0.01) and proliferation index (Ki67) (p=0.009). We evidenced a lower percentage of COX-2 positive tumors in the basal-like subtype than in the other three groups. This difference was statistically significant (p=0.022). Multivariate analysis (COX model) indicated that COX-2 was an independent prognostic variable influencing disease free survival (DFS) (HR=3.82, CI=1.54-9.50, p=0.004), but not overall survival (OS). We also estimated the DFS and OS within the four BC subtypes according to COX-2 overexpression demonstrating that a significant higher probability of relapsing, but not of dying was observed in COX-2 positive luminal A (p=0.03) and basal-like (p=0.05) BC. In contrast, the outcomes of HER2 (p=0.11) and normal-like (p=0.66) subtypes were not affected by COX-2 overexpression. The current data suggest that, in our series, COX-2 up-regulation may be strongly informative in predicting response to adiuvant anthracycline therapy mainly in two subtypes, luminal A and basal-like, usually characterized by significant differences in prognosis and response to therapy. In this context, treatment with selective inhibitors of COX-2 may be an additional therapeutic option. Supported by AIRC, Lega Italiana per la Lotta contro i Tumori, Ministero della Salute.