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Different Prognostic Roles of Mutations in the Helical and Kinase Domains of the PIK3CA Gene in Breast Carcinomas

Authors' Affiliations:¹ Unit of Surgical Pathology, Laboratory of Molecular Pathology and ² Unit of Medical Oncology, S. Chiara Hospital, Trento, Italy, and ³ Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy

Requests for reprints: Antonio Marchetti, Pathology Unit, Clinical Research Center, Center of Excellence on Aging (CeSI), University-Foundation, Via Colle Dell'Ara, 66013 Chieti, Italy. Phone: 39-871-357407/357408; Fax: 39-871-541337; E-mail: amarchetti{at}unich.it.

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.

Commentary

Phosphatidylinositol 3-Kinase in Breast Cancer: Where from Here?

Paradiso Angelo, Mangia Anita, Azzariti Amalia, and Tommasi Stefania
Clin. Cancer Res. 2007 13: 5988-5990. [Full Text] [PDF]

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