To address the clinical impact of PIK3CA
mutations on breast cancer, we performed a search on PubMed using the following keywords: “breast”, “cancer”, “pik3ca”, and “mutation” (December 1st
, 2011). We identified 12 studies–
from the 119 abstracts evaluated. Clinical characteristics of the studies are summarized in . The 12 studies reported the outcomes of 2587 breast cancer patients. The discrepancies in observed clinical outcomes are likely due to variations in patient population and tumor characteristics. In fact, the effects of PIK3CA
mutations are likely dependent on the subtype of breast cancer and the location where the mutation in PIK3CA
occurs. Indeed, estrogen receptor (ER)-positive and HER2-positive breast tumors are two molecularly distinct diseases that differ in both biological and clinical behaviors
. Moreover, previous studies suggest that mutations in the HD and the KD have different biological and clinical consequences.
Characteristics of the analyzed studies
In the 12 studies analyzed, 4 studies reporting outcomes of 1211 women found that PIK3CA
mutations was associated with either a longer disease-free survival (DFS) or overall survival (OS)–,
(). In these 4 studies, multivariate analyses confirmed that PIK3CA
mutations were associated with a favorable prognosis regardless of other conventional prognostic factors. In the largest study, Kalinski et al.
analyzed samples from 590 patients with primary invasive ductal or lobular breast carcinomas, with a long-term patient follow-up of 12.8 years, using a Sequenom MassArray system. Patients with PIK3CA
mutations had superior DFS, OS, and breast cancer-specific survival compared with those without PIK3CA
mutations. Interestingly, analysis of PIK3CA
mutation sites revealed that HD hotspot mutations were not associated with an improvement in OS (10-year OS rate was 62% for patients with wild-type PIK3CA
vs. 59% for those with HD mutations, P
= 0.54). In contrast, KD mutations was associated with superior OS when compared with wild-type PIK3CA
(10-year OS rate was 62% for patients with wild-type PIK3CA
vs. 76% for those with KD mutations, P
= 0.005). A similar finding was also reported by Barbareschi et al.
, in which patients with KD mutations showed a significantly better OS. Data from this study also demonstrated that patients with HD mutations had a worse prognosis.
Six studies did not find a significant relationship between somatic PIK3CA
mutations and either DFS or OS–,–
. Nevertheless, 3 of these studies reported a favorable trend that related PIK3CA
mutations with improved clinical outcomes. However, these differences were not significant, possibly due to the small sample size and the subsequent lack of power of these studies,,
Against evidences presented by the above-mentioned studies, one study found that, although the OS was not significantly different in patients with all PIK3CA
mutations, specific mutations in the KD were independently associated with a shorter OS
. Two additional studies that included 306 patients found that PIK3CA
mutations were associated with a poor OS,
. Nevertheless, these two studies have several limitations. In the first study, by Li et al.
, the mutation status failed to reach significance as an independent prognostic factor of OS. The second study, by Lerma et al.
addressed only the role of PIK3CA
mutations in HER-2- positive breast cancer while excluding patients with hormone receptor-positive tumors.
To analyze the association between PIK3CA mutations and ER status, relevant studies containing data on both of these factors were combined and a strong association between PIK3CA mutations and ER positivity was found (P < 0.001) (). Furthermore, wild-type PIK3CA was associated with higher tumor stage (P < 0.03) (). In both cases, we excluded studies that lacked necessary information.
PIK3CA mutations and estrogen receptor (ER) status in breast cancer patients
PIK3CA mutations and tumor stage in breast cancer patients
We propose that the clinical benefit observed in the presence of PIK3CA mutations may pertain mainly to ER-positive breast tumors and mutations in the KD. The unexpected and counterintuitive observation that PIK3CA mutations appear to be associated with a better clinical outcome in some patients remains unsolved. Below, we propose three hypotheses to explain this paradoxical association of oncogene activation with better patient outcomes.