Combination of COX-2 expression and PIK3CA mutation as prognostic and predictive markers for celecoxib treatment in breast cancer
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Sandrine Tury1, Véronique Becette2, Franck Assayag3, Sophie Vacher1, Camille Benoist1, Maud Kamal4, Elisabetta Marangoni3, Ivan Bièche1, Florence Lerebours4, Céline Callens1
1Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France
2Department of Pathology, Institut Curie, Hôpital René Huguenin, Saint-Cloud, France
3Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, Paris, France
4Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France
Céline Callens, email: [email protected]
Keywords: breast cancer, PIK3CA, celecoxib, prognosis, predictive biomarker
Received: April 29, 2016 Accepted: October 26, 2016 Published: November 08, 2016
COX-2 expression level and prognostic value are still a matter of debate in breast cancer (BC). We addressed these points in the context of PIK3CA mutational status. Based on an interesting study of aspirin efficacy in colorectal cancer, we hypothesized that celecoxib antitumoral activity may be restricted to PIK3CA mutated BC.
COX-2 mRNA expression was analyzed in 446 BC samples and in 61 BC patient-derived xenografts (PDX) using quantitative RT-PCR. The prognostic impact of COX-2 expression level was assessed independently and according to PIK3CA mutational status in our cohort and in a validation set of 817 BC. The antitumoral activity of celecoxib was tested in two triple-negative (TN) PDX with a PIK3CA wild-type (wt) or mutated genotype.
COX-2 mRNA was overexpressed in 2% of BC and significantly associated with TN subtype. Metastasis-free survival (MFS) was significantly better in patients with high COX-2 expression level, the prognosis of whom was similar to patients with PIK3CA mutations. TCGA validation cohort confirmed that patients with low COX-2 expression PIK3CA wt tumors had the worse disease-free survival (DFS) compared to all other subgroups. Celecoxib had a significant antitumoral effect in PIK3CA mutated PDX only. Celecoxib antitumoral activity involved S6 ribosomal protein and AKT phosphorylation.
Low expression of COX-2 has a significant negative impact on the MFS/DFS of BC patients. Antitumoral effect of celecoxib is restricted to PIK3CA mutated PDX. These results suggest that PIK3CA mutation may be a new predictive biomarker for celecoxib efficacy.
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