Abstract
BackgroundThe PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.MethodsTumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.ResultsPIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69–0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.ConclusionsThe present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.
Highlights
Phosphoinositide 3-kinase–protein kinase B (PI3K-AKT) is an important intracellular pathway regulating numerous cellular activities, mostly survival, proliferation, growth and glycogen metabolism
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy
A second hematoxcylin & eosin (H&E) evaluation round was employed for obtaining cores for tissue microarray (TMA) construction, which were used for immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH)
Summary
Phosphoinositide 3-kinase–protein kinase B (PI3K-AKT) is an important intracellular pathway regulating numerous cellular activities, mostly survival, proliferation, growth and glycogen metabolism. It is activated in many different tumor types and its therapeutic targeting has attracted significant interest [1]. PI3K-AKT signaling is an important driving pathway in breast cancer, triggered by growth factor receptor activation, such as insulin-like growth factor receptors (IGF-R), epidermal growth factor receptor (EGFR) and HER2, by steroid hormone receptors, estrogen (ER), progesterone receptors (PgR), as well as by genetic aberrations of some of its components, more frequently HER2 amplification, PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss [2]. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer. Health Data Specialists Ltd did not provide financial support in any other form
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