PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Abstract

IntroductionInhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins.MethodsPrimary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction.ResultsPIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found.ConclusionPIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive, postmenopausal, early breast cancer patients.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50]. In the present study, we showed PTPN2 gene loss as a new potential marker of endocrine resistance.…”

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

“…Our PIK3CA mutation rate (23.3%) was consistent with the literature, as well as our rate of different hotspot mutations [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, we confirmed significant associations of different types of PIK3CA mutations with clinicopathological and molecular characteristics.…”

“…Therefore, PIK3CA mutations do not seem to have Notably, PTEN loss and PIK3CA mutations are regarded in the literature to be the most frequent downstream molecular aberrations affecting PI3K-AKT signaling, nevertheless only a minority of studies has examined the possible role of such combined effect [26,31,33,34]. Interestingly, each one of these studies provided different results, which may be attributed to the diverse population characteristics and treatments applied, for example only HER2 positive [33], only postmenopausal [26,31], or only hormone receptor positive cases [34]. Also, the differences in the methodologies and/or cutoffs used in assessing PTEN protein expression may have further influenced the results as well.…”

“…Notably, many studies examining the prognostic significance of PIK3CA mutations in breast cancer [35] have been published, however very few included a large enough number of patients [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, less than half of them [22,24,26,28,30,31,33] used data from clinical trials, thus excluding the effect of treatment heterogeneity when evaluating prognostic factors. Up to now, results are largely inconclusive with some studies showing favorable and other adverse impact of PIK3CA mutations on patient outcome, while a significant number of reports did not show any prognostic significance.…”

Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

“…104 However, constitutive activation of PI3K does not seem to confer this resistant phenotype. [105][106][107] Despite the lack of a correlation between response to anti-estrogen therapy and PI3K alterations, there is preclinical evidence pointing to the benefit of a combination of inhibitors of ER and the PI3K pathway. 108,109 In fact, we have reported that PI3K pathway inhibition upregulates ER transcriptional activity and increases cell survival dependency on ER, which translates into a synergism between PI3K inhibitors and ER degraders with increased tumor control.…”