Combination of COX-2 expression and PIK3CA mutation as prognostic and predictive markers for celecoxib treatment in breast cancer.
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.
Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France.
Sandrine
S
Tury
Department of Pathology, Institut Curie, Hôpital René Huguenin, Saint-Cloud, France.
Véronique
V
Becette
Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, Paris, France.
Franck
F
Assayag
Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France.
Sophie
S
Vacher
Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France.
Camille
C
Benoist
Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.
Maud
M
Kamal
Laboratory of Preclinical Investigations, Translational Research Department, Institut Curie, Paris, France.
Elisabetta
E
Marangoni
Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France.
Ivan
I
Bièche
Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.
Florence
F
Lerebours
Pharmacogenomic Unit, Genetics Laboratory, Institut Curie, Paris, France.
Céline
C
Callens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000068579:Celecoxib / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000068579:Celecoxib
PIK3CA; breast cancer; celecoxib; predictive biomarker; prognosis