AKT1E17K mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection

被引:67
作者
Rudolph, Marion [1 ]
Anzeneder, Tobias [2 ]
Schulz, Anke [1 ]
Beckmann, Georg [1 ]
Byrne, Annette T. [3 ,6 ]
Jeffers, Michael [4 ]
Pena, Carol [4 ]
Politz, Oliver [1 ]
Koechert, Karl [1 ]
Vonk, Richardus [1 ]
Reischl, Joachim [1 ,5 ]
机构
[1] Bayer Pharma AG, Muellerstr 178, D-13353 Berlin, Germany
[2] Patients Tumor Bank Hope PATH, Augsburg, Germany
[3] Royal Coll Surgeons Ireland, Dept Physiol & Med Phys, Dublin, Ireland
[4] Bayer HealthCare Pharmaceut, Whippany, NJ USA
[5] AstraZeneca R&D, Personalized Healthcare & Biomarkers, Gothenburg, Sweden
[6] Bayer HealthCare Pharmaceut, Sci Fdn Ireland Funded Ind Secondment, Whippany, NJ USA
基金
爱尔兰科学基金会;
关键词
Breast cancer; AKT1(E17K) mutation; Blood-based mutation detection; PLECKSTRIN HOMOLOGY DOMAIN; PIK3CA MUTATIONS; PATHWAY MUTATIONS; AKT1; MUTATIONS; E17K MUTATION; DNA; INHIBITOR; ACTIVATION; CARCINOMAS; AGENTS;
D O I
10.1186/s12885-016-2626-1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The single hotspot mutation AKT1 [G49A:E17K] has been described in several cancers, with the highest incidence observed in breast cancer. However, its precise role in disease etiology remains unknown. Methods: We analyzed more than 600 breast cancer tumor samples and circulating tumor DNA for AKT1(E17K) and alterations in other cancer-associated genes using Beads, Emulsions, Amplification, and Magnetics digital polymerase chain reaction technology and targeted exome sequencing. Results: Overall AKT1(E17K) mutation prevalence was 6.3 % and not correlated with age or menopausal stage. AKT1(E17K) mutation frequency tended to be lower in patients with grade 3 disease (1.9 %) compared with those with grade 1 (11.1 %) or grade 2 (6 %) disease. In two cohorts of patients with advanced metastatic disease, 98.0 % (n = 50) and 97.1 % (n = 35) concordance was obtained between tissue and blood samples for the AKT1(E17K) mutation, and mutation capture rates of 66.7 % (2/3) and 85.7 % (6/7) in blood versus tissue samples were observed. Although AKT1-mutant tumor specimens were often found to harbor concurrent alterations in other driver genes, a subset of specimens harboring AKT1(E17K) as the only known driver alteration was also identified. Initial follow-up survival data suggest that AKT1(E17K) could be associated with increased mortality. These findings warrant additional long-term follow-up. Conclusions: The data suggest that AKT1(E17K) is the most likely disease driver in certain breast cancer patients. Blood-based mutation detection is achievable in advanced-stage disease. These findings underpin the need for a further enhanced-precision medicine paradigm in the treatment of breast cancer.
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页数:12
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