This is the first report of an association between clinicopathological features and AKT1 mutation status in women with breast and endometrial cancers in Asia.
In the present study, we found AKT1 mutations in 7.3 and 4.1% of breast and of endometrial cancer samples. The reported frequency of AKT1 mutations in breast cancer is between 1.4 and 8.2% [5, 6], and they are associated with histogenesis of hormone receptor positive subtype . Thus, our finding that AKT1 mutations are associated with HER2-negative status in breast cancer agrees with those of a previous study . The TCGA (The Cancer Genome Atlas Program) data showed that in a predominantly Caucasian breast cancer cohort, AKT1 mutations had a frequency of 3% in most hormone receptor positive breast cancers . On the other hand, a report from China also showed that AKT1 mutations were found in 7.1 and 8.2% of breast cancer patients [6, 17], suggesting that AKT1 mutations may be particularly common in Asians.
Previous reports have suggested that activation of the PI3K/AKT pathway is involved in the development of endometrioid adenocarcinoma [7, 8, 18], and that atypical hyperplasia is also associated with AKT1 mutations, leading to benign and (pre) malignant endometrial lesions . In addition, AKT1 mutations were found in atypical hyperplasia, suggesting that AKT1 mutations may be involved in the carcinogenesis of endometrial carcinoma in benign and (pre) malignant endometrial lesions . Louis J.M. van der Putten et al. reported We did not find a relationship between clinicopathological features and AKT1 mutations because of the rarity of the mutation. However, none of the patients with mutated AKT1 died. A longer follow-up might reveal a correlation between AKT1 mutation status and its prognostic importance.
Our survival results themselves are difficult to say definitively due to the small number of cases. However, recently published results from the AACR Project GENIE, which incorporated a large group of estrogen receptor positive breast cancer patients, reported that AKT1 mutant cases had comparable survival rates compared to AKT1 wild-type controls .
Despite these positive findings, this study has three major limitations. The AKT1 mutation is rare, and rates of relapse or death are extremely low. Therefore, we cannot reach any conclusions on the survival based on prognostic factors. Recently, with the development of next generation sequencing (NGS), cancer genomic profiling including AKT1 are now being evaluated using NGS tests. It is an important limitation that this study only examined AKT1 E17K hotspot mutation. Finally, there is fact that a large proportion of endometrial cancer is associated with a hypermutator phenotype, mainly due to MSI (microsatellite instability) and POLE (DNA polymerase epsilon) mutations. It is hard to distinguish the real AKT1 driver mutations from random mutations caused by this phenotype.
Precision medicine is becoming important in the treatment of cancer, and the AKT1 mutation is a promising target. Active point mutations (hot spots), are limited in breast and endometrial cancers, and E17K is a representative mutation site. The development of systems for detecting single mutations has progressed. Moreover, recent clinical trials have suggested that the AKT1 mutation is a potent predictive marker of a response to AKT inhibitors [3, 4]. Therefore, the AKT1 mutation might be a target of liquid biopsies, particularly in cell-free plasma DNA .
In conclusion, the rate of mutated AKT1 in breast cancer was 7.4%, and it correlated with the HER2-negative subtype. The rate in endometrial cancer was 4.1%. AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance.