Abstract P4-09-03: Prognostic and predictive value of COX2 in breast cancer, correlation with PIK3CA mutations
Authors: Tury S , Becette V , Assayag F , Vacher S , Marangoni E , Bièche I , Lerebours F , Callens C 
Published: May 2016

Background: Cyclooxygenase-2 (COX2) is responsible for the synthesis of prostaglandins from arachidonic acid. This enzyme is weakly expressed in normal tissues and implicated in oncogenic and inflammatory processes. Treatment with a COX2 inhibitor (aspirin) increases overall survival of patients with colorectal cancer only for PIK3CA mutated tumors confirming an interaction between COX2 and the PI3K/AKT pathway. PIK3CA gene mutations are detected in 10-40% of BC depending on the molecular subtype. We hypothesized that COX inhibition could have an impact in Breast Cancer (BC) treatment.

Methods: COX2 mRNA expression levels were analyzed in 446 BC samples and 61 patient-derived xenografts (PDX) using qRT-PCR. Protein expression of COX2 was studied by immunohistochemistry (IHC) in 26 BC and 14 PDX. The prognostic impact of COX2 expression level according to PIK3CA mutation status was also analyzed in BC patients. The activity of celecoxib, a selective COX2 inhibitor, was tested in two PDX of triple-negative BC: the HBCx50 PDX (PIK3CA wild-type, expressing COX2) and the HBCx4B PDX (PIK3CA mutated, expressing COX2).

Results: COX2 transcript was under-expressed in 74% and overexpressed in 2% of the BC samples. COX2 overexpression is significantly associated with triple-negative subtype (11%, 7/68 cases, p&lt;0.0001). Moreover, immunostaining of COX2 was well correlated with COX2 mRNA expression level. PIK3CA mutations were detected in 33% of patients. We showed that metastasis-free survival (MFS) was significantly better in patients who do not under-express COX2 (p=0.007) or in patients with PIK3CA mutation (p=0.02) regardless the BC subtype and adjuvant treatment. In the PIK3CA wild-type (wt) subgroup, MFS of patients was significantly better in patients not under-expressing COX2 than in patients under-expressing COX2 (p=0.01). In PDX, the strongest expression levels of COX2 were found in triple-negative (median 36 [0-1673]) compared to luminal (median 0 [0-202]) and HER2 positive subtypes (median 6 [0-601]). In vivo studies showed that celecoxib has no effect on the HBCx50 (PIK3CA wt) PDX growth while a significant antitumoral effect of celecoxib is observed in HBCx4B (PIK3CA mutated) PDX (tumor growth inhibition=41%, p=0.03).

Conclusion: In BC, COX2 underexpression is frequent and impact prognosis. BC overexpressing COX2 are rare and mainly belong to the triple-negative subtype. In vivo PDX studies show that the antitumoral effect of celecoxib may be restricted to BC expressing COX2 with PIK3CA mutation. Analyses of signaling pathways, expression levels of COX2 and its target proteins, tumor proliferation and apoptosis induction are ongoing on tumors and serum of mice to elucidate the antitumoral effect of celecoxib. This work could help to identify a subgroup of BC patients who may benefit from celecoxib especially as COX2 immunostaining and PIK3CA mutation status could routinely be used as COX2 inhibitor sensitivity biomarkers. These results need to be validated in a phase II clinical trial.

Citation Format: Tury S, Becette V, Assayag F, Vacher S, Marangoni E, Bièche I, Lerebours F, Callens C. Prognostic and predictive value of COX2 in breast cancer, correlation with PIK3CA mutations. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-03.