PIK3CAmutation, reduced AKT serine 473 phosphorylation, and increased ERα serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive early breast cancer

Abstract

Although endocrine therapy is the most important treatment option in estrogen receptor (ER)-positive breast cancer, new strategies, such as molecular targeted agents together with endocrine therapy are required to improve survival. PIK3CA is the most frequent mutated gene in ER-positive early breast cancers, and PIK3CA mutation status is reported to affect activation of AKT and ERα. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR). In this study, we examined expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERα Ser167 (ERα phospho-Ser167) by immunohistochemistry in ER-positive, HER2-negative early breast cancer. PIK3CA gene mutations were also detected in genomic DNA extracted from tumor blocks. Correlations between these biological markers, clinicopathological factors and prognosis were analyzed. Levels of AKT phospho-Ser473 were significantly higher in premenopausal women than in postmenopausal women. In contrast, AR expression was significantly higher in postmenopausal women than in premenopausal women. PIK3CA mutations were detected in 47% in premenopausal women and 47% in postmenopausal women. Postmenopausal women with PIK3CA wild-type tumors had significantly worse disease-free survival than patients with PIK3CA mutant tumors. Low levels of AKT phospho-Ser473 and high levels of ERα phospho-Ser167 were strongly associated with increased disease-free survival in postmenopausal women. Evaluation of ERα activation, in addition to PIK3CA mutation status, might be helpful in identifying patients who are likely to benefit from endocrine therapy alone versus those who are not in postmenopausal ER-positive early breast cancer.

The molecular genetic make-up of male breast cancer

“…Its somatic mutation frequency in our MBC cohort (36%) was in between that reported by Piscuoglio et al (MBC;20%) and ER-positive FBC (n = 1431; 48%). PIK3CA mutations were associated with more aggressive tumor characteristics and reduced survival, in line with findings in ER-positive FBC subgroups (Pereira et al 2016, Ishida et al 2018. Aside from PIK3CA, the serine/threonine protein kinase AKT1 was the only other mutated gene with hotspots corresponding to FBC.…”

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

“…Mutations of the PIK3CA gene are frequently observed in luminal A (49%) and luminal B (32%) subtypes 4 , 29 . Approximately 95% of mutations exist in the helical domain (exon 9, commonly E542 and E545) and the kinase domain (exon 20, commonly H1047) 30 .We and others previously reported that PIK3CA mutations were a positive prognostic marker in ER-positive, HER2-negative early breast cancer 31 – 33 . In contrast, activation of the PI3K pathway is suggested to cause endocrine resistance in ER-positive advanced breast cancer, and therefore inhibitors for PI3K, AKT, and mTOR have potential therapeutic utility in patients with this tumor subtype 12 , 13 .…”

The Correlation of Mutations and Expressions of Genes within the PI3K/Akt/mTOR Pathway in Breast Cancer—A Preliminary Study

“…Additionally, in the literature, no clear relationship between PIK3CA mutations and lymph node metastasis or histopathological diagnosis was observed [ 25 , 36 , 42 , 43 , 44 ]. In most of the analyzed publications, a significant relationship between the prevalence of mutations and the expression of the ER and PR receptors was observed [ 4 , 45 ]. In our cohort, the detected mutations do not depend on the expression level of those receptors.…”