IMPAKT 2015 News: Incidence of Breast Cancer Oncogenes Higher in the PIK3K/AKT Signalling Pathway than in the MAPK Pathway
Genetic profiling shows the PI3K-AKT pathway is the most frequently altered in both primary and metastatic breast cancers
Genetic mutations were seen infrequently in the MAPK versus the PIK3/AKT signalling pathways, according to a series presented during the Genomics and Proteomic Analysis of Breast Cancer part of a Poster Walk at the IMPAKT Breast Cancer Conference held 7–9 May 2015 in Brussels, Belgium.
Juan Miguel Cejalvo and colleagues at the Hospital Clinico Universitario de Valencia in Valencia, Spain, utillised high-throughput genomic profiling to evaluate the frequency at which the PI3K/AKT and MAPK signalling pathways are deregulated in breast cancer.
Ultimately, the investigators aimed to find frequently occurring oncogene alterations that could serve as druggable targets that would be clinically relevant.
Both primary and/or metastatic tumour samples were evaluated from 214 patients with metastatic breast cancer treated at the Hospital Clínico of Valencia to determine the incidence of mutations in genes including PIK3CA, AKT1, KRAS, NRAS and BRAF.
Genetic assessments were done by MassARRAY technology, which allows the analysis of multiple classes of genetic markers. Levels of PTEN expression were determined by immunohistochemistry performed on formalin-fixed paraffin embedded samples.
PIK3 upregulation figured most prominently in breast cancer samples evaluated in this series
The investigators found genomic alterations occurred most often in the PI3K/AKT pathway where PIK3 was upregulated in 46% of primary tumours and 26.9% of metastatic tumours. AKT was upregulated to a far lesser degree at 2.78% and 6.86% of primary and metastatic tumour samples, respectively. Decreased PTEN levels were detected in 27.91% of primary and in 38.1% of metastatic tumour samples tested.
Fewer mutations in the MAPK pathway than for PIK3 were detected.
The frequency of genetic alteration in primary and metastatic tumours respectively, was 14.29% and 11.88% for KRAS, 2.86% and 6.93% for NRAS and 2.63 and 4.39% for BRAF.
In 22 primary tumour samples, the PI3K mutations most frequently detected were E542K in 40.91% of samples, E545K in 31.82%, H1047R in 18.18% and C420R in 4.55%.Arg886Gln mutations were seen in 4.55% of primary tumour samples.
PIK3 alterations were seen in 32 metastatic tumour samples that included H1047R in 42.86% of samples, E545K in 25.71%, E542K in 17.14%, Arg88Gln in 5.71%, M1043I in 5.71%, and Asn345Lys was altered in 2.86% of specimens.
The most often detected mutation found in primary tumours was E542K, whereas H1047R was the most frequently occurring mutation in metastatic tumour samples.
Most tumour types showed specific genetic alteration patterns. Most notable was triple negative breast cancer, wherein PTEN loss was detected in 80% of primary and 60% of metastatic tumour samples; KRAS mutations were also detected in 33.3% and 7.14% of primary and metastatic triple negative breast cancer tumours, respectively.
In this series the investigators found MAPK mutations to be infrequent in both primary and metastatic breast cancer tumours. However, the PI3K-AKT pathway was commonly altered with PI3K mutations being the most relevant. Interestingly, the highest frequency of mutation in this pathway and the highest degree of PTEN loss were observed in triple negative breast cancer samples.