The prognostic impact of COX‐2 expression in breast cancer depends on oral contraceptive history, preoperative NSAID use, and tumor size

Abstract

The association between tumor cyclooxygenase 2 (COX-2) expression and breast cancer prognosis has been inconsistent. The purpose of this study was to evaluate the prognostic significance of COX-2 tumor expression according to adjuvant treatment, and potential effect modifications of non-steroid anti-inflammatory drug (NSAID) use, and other tumor and lifestyle factors. A prospective cohort of 1,116 patients with primary breast cancer in Lund, Sweden, included 2002-2012 was followed until June 2014 (median 5 years). Tumor-specific COX-2 expression was evaluated on tissue microarrays using immunohistochemistry. Associations between COX-2 intensity (negative, weak-moderate, high) and patient and tumor characteristics as well as prognosis were analyzed. Tumor-specific COX-2 expression was available for 911 patients and was significantly associated with higher age at diagnosis and less aggressive tumor characteristics. Higher COX-2 expression was associated with lower risk for breast cancer events during the first five years of follow-up, adj HR 0.60 (95%CI: 0.37-0.97), per category. The association between COX-2 expression and prognosis was significantly modified by oral contraceptive (OC) use (P interaction 5 0.048), preoperative NSAID use (P interaction 5 0.009), and tumor size (P interaction 5 0.039). COX-2 negativity was associated with increased risk for events during the first five years in ever OC users, adj HR 1.94 (1.01-3.72) and during the 11-year follow-up in preoperative NSAID users, adj HR 4.51 (1.18-11.44) as well as in patients with large tumors, adj HR 2.57 (1.28-5.15). In conclusion, this study, one of the largest evaluating COX-2 expression in breast cancer, indicates that the prognostic impact of COX-2 expression depends on host factors and tumor characteristics.Breast cancer is a heterogeneous disease where most patients have a good prognosis. Improved tumor classification could identify subgroups of patients with a poorer prognosis who are in need of more personalized treatment. 1 In breast cancer, cyclooxygenase 2 (COX-2)-mediated prostaglandin aromatase gene activation increases both aromatase and estrogen levels that may lead to increased proliferation, primarily in patients with estrogen receptor positive (ER-positive) tumors and in postmenopausal patients. 2 COX-2 catalyzes the conversion of arachidonic acid to prostaglandins and have pro-inflammatory effects. 2 COX-2 expression in predominantly ER-negative tumors was shown to lead to Akt-pathway activation. 2,3 Regarding prognosis, most, 1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] but not all, 20-27 studies have found an association between high COX-2 expression and worse prognosis. Whether COX-2 expression was associated with prognosis in the different studies also depended on tumor characteristics, type of breast cancer treatment, body constitution, and concomitant medications. 1,6 Non-steroidal anti-inflammatory drugs (NSAIDs) including both selective COX-2 inhibitors and non-selective COX-1/2 inhibitors as well as ac...

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