PIK3CAmutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer

Abstract

PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor–positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation–associated gene signature ( PIK3CA -GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression–induced changes. However, in ER+/HER2− BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA -GS was also assessed. Although the PIK3CA -GS was not associated with prognosis in ER− and HER2+ BC, it could identify better clinical outcomes in ER+/HER2− disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA -mutant BCs and the development of PI3K/mTOR inhibitors.

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…The role of PIK3CA mutations as markers of tumor progression in DCIS is uncertain. PIK3CA mutations in invasive breast cancers have been associated with favorable tumor features 41 and better prognosis in patients with ERpositive, HER2-negative tumors; 40 however, we saw no association of PIK3CA mutations with clinicopathological features in our cohort.…”

“…4,5,40,41 The relatively small number of cases included in this and other DCIS each studies (involving between six and 202 cases), 7,8,14,15,38,39 may account for the variation in prevalence. Alternatively, the high read-depth of our targeted sequencing may have led to increased detection rates compared with exome or Sanger studies: four DCIS cases had a PIK3CA variant frequency of o20%, which could have been missed by less sensitive methods.…”

Prevalence ofPIK3CAmutations and the SNP rs17849079 in Arab breast cancer patients

“…This could be due to the lack of standard treatments for breast cancer, different samples size, different patient populations or combinations thereof. The disease-free or overall survival for patients whose tumors harbor PIK3CA mutations have been reported to be either favorable, [29][30][31] unfavorable, 32,33 or not statistically significant [34][35][36] as compared with patients with tumors containing wildtype PIK3CA. Further studies are needed to provide clarity to this important issue.…”

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

“…[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. 3,12,13 We and other groups have previously shown that the PIK3CA genotype is concordant between ductal carcinoma in situ (DCIS) and concurrent invasive carcinoma in 66-100% of tested samples. [14][15][16][17] However, several small studies suggest that pre-neoplastic or benign breast lesions, such as papillomas, radial scars, or columnar cell lesions, may also very frequently harbor PIK3CA mutations.…”