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

Abstract

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 21mutations 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.

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

“…[18][19][20][21][22][23] Prior studies have failed to identify PIK3CA mutations in histologically normal breast tissue, even with the same sensitive methods employed here. 1,8,16,19 In this study, we demonstrated a 50% frequency of PIK3CA point mutations in usual ductal hyperplasia and columnar cell lesions across 62 lesions, representing the largest series to date. We also found similarly a high frequency of PIK3CA mutations in smaller cohorts of atypical ductal lesions (71%) and lobular neoplasia (44%), and a near-lack of other 'hotspot' activating mutations in genes such as AKT1.…”

“…Activating PIK3CA point mutations are among the most common genetic aberrations in invasive breast cancer, [1][2][3][4][5][6][7][8][9][10] and several studies have shown that these mutations exist at nearly the same frequency in DCIS. [14][15][16][17] Accumulating evidence suggests that PIK3CA point mutations may also be common in other proliferative breast lesions such as benign papillomas and columnar cell lesions.…”

“…Our data on PIK3CA mutations in DCIS (48% in this study and 45% combined) and invasive mammary carcinoma (35% in this study and 34% combined) matches the literature. [1][2][3][4][5][6][7][8] We identified point mutations in other genes in invasive carcinomas, but not in 'earlier' lesions, including TP53, FBXW7, FGFR2, and HRAS.…”

“…Activating mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are present in B25% of invasive carcinomas and are present in an even higher percentage (on the order of 40%) of low-grade estrogen receptorpositive carcinomas (luminal A intrinsic subtype). [1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development.…”

“…[1][2][3][4][5][6][7][8][9][10] PIK3CA mutations cluster in 'hotspots' in exon 9 (helical domain, E542K and E545K) and exon 20 (kinase domain, H1047R/L). [1][2][3][4][5][6][7][8][9][10] In addition, this pathway is activated by mutations in the plekstrinhomology domain of AKT1 in B5% of breast carcinomas, by the loss of the phosphatase PTEN (phosphatase and tensin homolog on chromosome 10), or rarely by amplification or alterations in other regulatory subunits, and is a target of active drug development. [8][9][10][11] In recent large studies of estrogen receptor-positive tumors, the presence of activating PIK3CA hotspot point mutations has been paradoxically associated with more favorable outcome as compared with breast carcinomas with wild-type PIK3CA.…”