PI3KCA mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy

Abstract

PI3K/AKT/mTOR pathway alterations are frequent in patients with infiltrating breast cancer (IBC). Their clinical and pathological relevance has been insufficiently documented. We evaluated PI3KCA for mutations and the expression of PTEN, AKT, mTOR and p70S6K by immunohistochemistry in 246 IBC patients treated with hormone therapy (median follow-up, 97 months). A PI3KCA mutation was observed in 50 out of 229 informative cases (21.8 %), PTEN loss in 107 out of 210 (51 %), moderate/high level of expression of AKT in 133 out of 188 (71 %), moderate/high level of expression of mTOR in 173 out of 218 (79 %) and moderate/high level of expression of p70S6K in 111 out of 192 cases (58 %). PI3KCA mutation was associated with the absence of Her2/neu amplification/overexpression and a low level of MIB1/Ki-67 labelling. The expression of p70S6K was associated with a high level of mTOR immunoreactivity, and high PTEN expression was associated with high AKT expression level. Univariate analysis showed that PI3KCA mutation status was not associated with clinical outcome in the series as a whole or in the node-negative subgroup. However, in the node-positive subgroup, exon 9 PI3KCA mutation was associated with unfavourable overall survival (OS), although its impact on the final model in multivariate analysis seemed to be limited. Of the other markers, only high p70S6K expression was associated with a significantly prolonged OS. PI3KCA mutation status is of limited prognostic relevance in oestrogen receptor-positive breast cancer patients treated with hormone therapy.

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.…”

“…One important question is the possible effect of PIK3CA status on cancer outcome and treatment efficacy. 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.…”

“…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.…”

p-mTOR expression is associated with better prognosis in luminal breast carcinoma

“…Moreover, in the same study, 62.8% of grade 1 carcinomas express p-mTOR (vs 31.9% of grade 2 and 23.4% of grade 3) 7. Furthermore, it was recently demonstrated in patients with locoregional relapse that p-mTOR expression is associated with decreased risk of early relapse, and that high levels of p70S6K (a downstream target of mTORC1), are associated with prolonged OS in lymph node-positive patients 21 22. Others have demonstrated that p-mTOR-expression is more frequent in invasive BCs as compared to carcinoma in situ, or normal breast epithelium,23 yet, based on these results, one cannot assume that the percentage of p-mTOR-expressing tumours will be higher in advanced disease compared to localised invasive disease, or that higher mTOR expression is a surrogate for mTOR pathway activation.…”

The kinome associated with estrogen receptor-positive status in human breast cancer

“…As mentioned above, the published data largely suggest that mutations in PIK3CA occur more frequently in ERC breast cancer with good prognosis and may also be associated with better clinical outcome in patients treated with endocrine therapy (Di Cosimo & Baselga 2009, Miller et al 2011a. However, this is not a universal finding (Cuorvo et al 2014). Recent reviews have discussed this aspect in detail (Fu et al 2013).…”