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. 2014 Oct 15;135(8):1898-910.
doi: 10.1002/ijc.28831. Epub 2014 Mar 20.

Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients

Andrea Markkula  1 , Maria Simonsson, Ann H Rosendahl, Alexander Gaber, Christian Ingvar, Carsten Rose, Helena Jernström
Affiliations

Impact of COX2 genotype, ER status and body constitution on risk of early events in different treatment groups of breast cancer patients

Andrea Markkula et al. Int J Cancer. .

Abstract

The COX2 rs5277 (306G>C) polymorphism has been associated with inflammation-associated cancers. In breast cancer, tumor COX-2 expression has been associated with increased estrogen levels in estrogen receptor (ER)-positive and activated Akt-pathway in ER-negative tumors. Our study investigated the impact of COX2 genotypes on early breast cancer events and treatment response in relation to tumor ER status and body constitution. In Sweden, between 2002 and 2008, 634 primary breast cancer patients, aged 25-99 years, were included. Disease-free survival was assessed for 570 rs5277-genotyped patients. Body measurements and questionnaires were obtained preoperatively. Clinical data, patient- and tumor-characteristics were obtained from questionnaires, patients' charts, population registries and pathology reports. Minor allele(C) frequency was 16.1%. Genotype was not linked to COX-2 tumor expression. Median follow-up was 5.1 years. G/G genotype was not associated with early events in patients with ER-positive tumors, adjusted HR 0.77 (0.46-1.29), but conferred an over 4-fold increased risk in patients with ER-negative tumors, adjusted HR 4.41 (1.21-16.02)(p(interaction) = 0.015). Chemotherapy-treated G/G-carriers with a breast volume ≥ 850 ml had an increased risk of early events irrespective of ER status, adjusted HR 8.99 (1.14-70.89). Endocrine-treated C-allele carriers with ER-positive tumors and a breast volume ≥ 850 ml had increased risk of early events, adjusted HR 2.30 (1.12-4.75). COX2 genotype, body constitution and ER status had a combined effect on the risk of early events and treatment response. The high risk for early events in certain subgroups of patients suggests that COX2 genotype in combination with body measurements may identify patients in need of more personalized treatment.

Keywords: COX2; body constitution; breast cancer; estrogen receptor; treatment response.

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Figures

Figure 1
Figure 1
Flow chart of the selection process of patients.
Figure 2
Figure 2
Kaplan–Meier estimates of breast cancer-free survival in relation to COX2 rs5277 genotype and ER status. There was a significant interaction between ER status and COX2 rs5277 genotype on risk of early events (pinteraction = 0.015). As this is an ongoing cohort, there are fewer patients with longer follow-up times. (a) Among all patients with invasive tumors (Log Rank; p = 0.99). (Adjusted HR 1.01; 95% CI 0.63–1.61; p = 0.97). (b) Among patients with invasive ER-positive tumors (Log Rank; p = 0.36). Adjusted HR adjusted HR 1.30; 95% CI 0.78–2.18; p = 0.32). (c) Among patients with invasive ER-negative tumors (Log Rank; p = 0.021). Adjusted HR 4.41 (95% CI 1.21–16.02; p = 0.024).
Figure 3
Figure 3
Kaplan–Meier estimates of breast cancer-free survival among chemotherapy-treated patients in relation to COX2 rs5277 genotype and breast volume. As this is an ongoing cohort, there are fewer patients with longer follow-up times. (a) In relation to breast volume (Log Rank; p = 0.17). (b) In relation to COX2 rs5277 genotype (Log Rank; p = 0.034). (c) In relation to breast volume and COX2 rs5277 genotype (Log Rank, 3 df; p = 0.050). Adjusted HR 8.99 (95% CI 1.14–70.89; p = 0.037).
Figure 4
Figure 4
Kaplan–Meier estimates of breast cancer-free survival among endocrine-treated patients with ER-positive tumors in relation to COX2 rs5277 genotype and breast volume. As this is an ongoing cohort, there are fewer patients with longer follow-up times. (a) In relation to breast volume (Log Rank; p = 0.006). (b) In relation to COX2 rs5277 genotype (Log Rank; p = 0.19). (c) In relation to breast volume and COX2 rs5277 genotype (Log Rank, 3 df; p = 0.005). Adjusted HR 2.30 (95% CI 1.12–4.75; p = 0.024).
Figure 5
Figure 5
The figure shows the hypothesized mechanisms of how COX2 rs5277 genotype impacts the risk of early events differently depending on host factors and ER status of the tumor. References to the steps that have been previously explored are indicted. Endo tx = endocrine treatment.
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