We have shown that PIK3CA pathway aberrations are common in breast cancer, pointing to a critical role for this signaling pathway in breast carcinogenesis. PIK3CA
oncogene mutations are particularly common, whereas AKT
mutations occur less frequently (). The AKT1
_E17K mutation was detected in only 6 of 418 breast cancers (1.4%), confirming a role in breast cancer pathophysiology albeit in a limited number of breast cancers. Amplification of PDK1, PIK3CA, PIK3CB, AKT1, AKT2,
and p70S6K is also among the extensive list of known aberrations that can activate PI3K pathway signaling in cancer (1
). The frequency of PI3K pathway mutational aberrations was markedly different among the different breast cancer subtypes, being most common in hormone receptor–positive tumors and least common in basal-like cancers. This breast cancer subtype specificity suggests that PIK3CA
mutations and other PI3K pathway aberrations may play a distinct role in the pathogenesis of these different diseases. Further, because genomic aberrations can predict responsiveness to targeted therapies, and because multiple PI3K pathway members are frequently aberrant in human breast tumors through mutation and other anomalies, this creates an expectation that targeting this pathway will provide an effective therapeutic approach in breast cancer (1
). Genomic aberrations such as those studied herein may facilitate identification of patients who will benefit from PI3K pathway-targeted therapies.
mutations have been reported to be mutually exclusive in many cancers with a notable exception being endometrial tumors (17
). In the breast cancer cell lines and tumors analyzed herein, AKT1
, and PTEN
mutations were also mutually exclusive. PTEN loss and PIK3CA
mutation have not been studied extensively but where they have, they have not been reported to be mutually exclusive, an observation confirmed herein (19
PI3K pathway activation has been reported to be associated with poor outcomes in certain cancers (9
). We have shown that an integrated signature of PTEN protein loss and PIK3CA
mutation in HER2-positive breast cancer is an even stronger predictor of trastuzumab resistance than either PIK3CA
mutation or PTEN loss alone (9
). Herein, PIK3CA
mutations were not associated with a significant effect on hormone receptor–positive breast cancer patient outcome after adjuvant tamoxifen therapy, compatible with the results of a previous study (19
). Another recent study found that, although PIK3CA
mutation status overall was not prognostic, the presence of helical domain mutations predicted a poor outcome whereas the presence of kinase domain mutations predicted an improved outcome (20
). However, unlike our study, this study was not confined to a homogeneous group of breast cancer patients as described herein. Our study is the largest study to date of the outcome implications of PIK3CA
pathway deregulation in a homogeneous group of patients with early-stage hormone receptor–positive breast cancer who received adjuvant tamoxifen. In contrast, it has previously been reported that PTEN loss is associated with adverse outcomes in breast cancer (9
Notwithstanding the lack of an outcome association with PIK3CA
mutation status, there remains a high probability that appropriate PI3K pathway manipulation could alter outcomes for hormone receptor–positive breast cancer patients in response to hormonal manipulation or chemotherapy. However, a phase 3 trial of a mTOR inhibitor in combination with an aromatase inhibitor failed to show significant activity in an unselected hormone receptor–positive breast cancer patient population (21
). Whether mTOR represents a suboptimal target for therapy in breast cancer, whether other combinations of therapies with mTOR inhibition will be effective, or whether feedback loops bypass the activity of mTOR inhibitors requires additional analysis (22
). Novel PI3K- and AKT-targeted therapies are being introduced into trials [e.g., perifosine (Keryx), SF1126 (Semafore), PX166 (ProlX), BEZ256 (Novartis), and EX147 (Exelixis)] with the expectation that these compounds may bypass feedback loops and have more efficacy than mTOR inhibitors. It is clear that a systems biology approach to kinase signaling interconnections will facilitate the rational implementation of drugs and particularly drug combinations targeting the PI3K pathway in breast cancers with different genomic aberrations targeting this pathway.
_E17K mutations that were not detected in 41 cell lines, PIK3CA
mutations were more common in cell lines than patient tumors (). A higher frequency of PIK3CA
mutations could be due to a failure to detect mutations in tumors as a result of technical factors. However, this alone is unlikely to account for these differences because AKT1
mutations should then be more readily identified in cell lines. Thus, there is likely to be a selection pressure for PIK3CA
but not AKT1
_E17K mutations during adaptation to culture. Due to the low frequency of aberrations and the generally good outcome associated with hormone receptor–positive cancers, determining whether AKT1
_E17K mutations contribute to patient outcomes and therapy responsiveness requires analysis of a large number of tumors. In our study, the breast tumors with AKT
mutations had high AKT phosphorylation levels, although the low number precluded this from reaching statistical significance. However, none of the six patients with AKT1
_E17K-mutant hormone receptor–positive tumors in this study has recurred, suggesting that AKT1
mutations may be associated with a good outcome. If confirmed in a larger series, this may indicate that AKT activation confers a selective advantage during early hormone receptor–positive tumorigenesis but inhibits tumor dissemination during progression. Consistent with this, although AKT1 is necessary for optimal initiation of tumorigenesis, it inhibits invasion and metastasis (23
). AKT may thus be an initiating oncogene for hormone receptor–positive breast cancers but its anti-invasive properties may prevent disease progression contributing to a good prognosis.
As shown herein, PTEN protein loss and PIK3CA mutations have markedly different functional effects on activation of signaling through the PI3K pathway in human breast cancers and in breast cancer cell lines, likely leading to differential sensitivity to the pathway inhibitor LY294002. Thus, PI3K pathway activation by PTEN loss versus PIK3CA mutation could lead to different outcomes and is likely to have important implications for the use of pathway-targeted therapies in human tumors.
In summary, PI3K pathway aberrations are common in breast cancer, pointing to an important role for this signaling pathway in breast carcinogenesis and as a potential target for therapy. The clear breast cancer subtype specificity of these aberrations suggests that they may play a distinct role in the pathogenesis of different breast cancer subtypes. PI3K pathway aberrations are particularly common in hormone receptor–positive breast cancer. Despite the lack of an outcome association with common PIK3CA mutations, these mutations may have important implications for the clinical selection of targeted therapies in patients with hormone receptor–positive tumors that possess these aberrations.