Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas.PURPOSE: In breast cancer, the PIK3CA gene is frequently mutated at "hotspots" in exons 9 and 20, corresponding to the helical and kinase domains, respectively. We decided to investigate the association of PIK3CA mutations with pathologic features and clinical outcome in a large series of patients with breast cancer. EXPERIMENTAL DESIGN: Frozen samples from 163 consecutive patients were analyzed for PIK3CA mutations using PCR single-strand conformation polymorphism and sequence analyses. RESULTS: We identified 46 missense mutations, 24 (53%) in exon 9, and 21 (47%) in exon 20. Twelve (50%) of the 24 mutations in exon 9 were of the E542K type and 11 (46%) were of the E545K type. Twenty (95%) of the 21 mutations in exon 20 were H1047R substitutions. Mutations in exon 9 were more frequent in lobular carcinomas (42% of cases) than in ductal carcinoma (11% of cases; P = 0.002). At univariate survival analysis, PIK3CA exon 20 mutations were associated with prolonged overall and disease-free survival, whereas mutations in exon 9 were associated with significantly worse prognosis. At multivariate analysis, exon 9 PIK3CA mutations were the strongest independent factor to predict poor prognosis for disease-free survival (P = 0.0003) and overall survival (P = 0.001). CONCLUSION: Our data show that exon 9 PIK3CA mutations are typical of infiltrating lobular carcinomas. In addition, they indicate that PIK3CA mutations in different exons are of different prognostic value: exon 9 mutations are independently associated with early recurrence and death, whereas exon 20 PIK3CA mutations are associated with optimal prognosis.
- Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Barbareschi, M., Buttitta, F., Felicioni, L., Cotrupi, S., Barassi, F., Del Grammastro, M., Ferro, A., Dalla Palma, P., Galligioni, E., Marchetti, A. Clin. Cancer Res. (2007) [Pubmed]