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Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition.

ABSTRACT: INTRODUCTION: PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit ?) somatic mutations are the most common genetic alteration in breast cancer (BC). Their prognostic value and that of the phosphatidylinositol 3-kinase (PI3K) pathway in BC remains only partly defined. The effect of PIK3CA mutations and alterations of the PI3K pathway on the antiproliferative response to aromatase inhibitor treatment was determined. METHODS: The Sequenom MassARRAY System was used to determine the presence of 20 somatic mutations across the PIK3CA gene in 85 oestrogen receptor-positive (ER+) BC patients treated with 2 weeks of anastrozole before surgery. Whole-genome expression profiles were used to interrogate gene signatures (GSs) associated with the PI3K pathway. Antiproliferative activity was assessed by the change in Ki67 staining between baseline and surgery. Three GSs representing the PI3K pathway were assessed (PIK3CA-GS (Loi), PI3K-GS (Creighton) and PTEN-loss-GS (Saal)). RESULTS: In our study sample, 29% of tumours presented with either a hotspot (HS, 71%) or a nonhotspot (non-HS, 29%) PIK3CA mutation. Mutations were associated with markers of good prognosis such as progesterone receptor positivity (PgR+) (P=0.006), low grade (P=0.028) and luminal A subtype (P=0.039), with a trend towards significance with degree of ER positivity (P=0.051) and low levels of Ki67 (P=0.051). Non-HS mutations were associated with higher PgR (P=0.014) and ER (P<0.001) expression than both wild-type (WT) and HS-mutated samples, whereas neither biomarker differed significantly between WT and HS mutations or between HS and non-HS mutations. An inverse correlation was found between the Loi signature and both the Creighton and Saal signatures, and a positive correlation was found between the latter signatures. Lower pretreatment Ki67 levels were observed in mutation compared with WT samples (P=0.051), which was confirmed in an independent data set. Mutation status did not predict change in Ki67 in response to 2 weeks of anastrozole treatment; there was no significant difference between HS and non-HS mutations in this regard. CONCLUSIONS: PIK3CA mutations are associated with classical markers of good prognosis and signatures of PI3K pathway activity. The presence of a PIK3CA mutation does not preclude a response to neoadjuvant anastrozole treatment.

SUBMITTER: Lopez-Knowles E

PROVIDER: S-EPMC4227109 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition.

López-Knowles Elena E Segal Corrinne V CV Gao Qiong Q Garcia-Murillas Isaac I Turner Nicholas C NC Smith Ian I Martin Lesley-Ann LA Dowsett Mitch M

Breast cancer research : BCR 20140630 3

<h4>Introduction</h4>PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α) somatic mutations are the most common genetic alteration in breast cancer (BC). Their prognostic value and that of the phosphatidylinositol 3-kinase (PI3K) pathway in BC remains only partly defined. The effect of PIK3CA mutations and alterations of the PI3K pathway on the antiproliferative response to aromatase inhibitor treatment was determined.<h4>Methods</h4>The Sequenom MassARRAY System was used ...[more]

PMID: 24981670

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Project description:The phosphatidylinositol 3' kinase (PI3K) pathway is commonly activated in breast cancer and aberrations such as PI3K mutations are common. Recent exciting clinical trial results in advanced estrogen receptor-positive (ER) breast cancer support mTOR activation is a major means of estrogen-independent tumor growth. Hence the means to identify a responsive breast cancer population that would most benefit from these compounds in the adjuvant or earlier stage setting is of high interest. Here we study PIK3CA genotype as well as a previously reported PI3K/mTOR-pathway gene signature (PIK3CA-GS) and their ability to estimate the level of PI3K pathway activation in two clinical trials of newly diagnosed ER-positive breast cancer patients- a total of 81 patients- one of which was randomized between letrozole and placebo vs letrozole and everolimus. The main objectives were to correlate the baseline PIK3CA genotype and GS with the relative change from baseline to day 15 in Ki67 (which has been shown to be prognostic in breast cancer) and phosphorylated S6 (S240) immunohistochemistry (a substrate of mTOR). In the randomized dataset, the PIK3CA-GS could identify those patients with the largest relative decreases in Ki67 to letrozole/everolimus (R = -0.43, p = 0.008) compared with letrozole/placebo (R = 0.07, p = 0.58; interaction test p = 0.02). In a second dataset of pre-surgical everolimus alone, the PIK3CA-GS was not significantly correlated with relative change in Ki67 (R = -0.11, p = 0.37) but with relative change in phosphorlyated S6 (S240) (R = -0.46, p = 0.028). PIK3CA genotype was not significantly associated with any endpoint in either datasets. Our results suggest that the PIK3CA-GS has potential to identify those ER-positive BCs who may benefit from the addition of everolimus to letrozole. Further evaluation of the PIK3CA-GS as a predictive biomarker is warranted as it may facilitate better selection of responsive patient populations for mTOR inhibition in combination with letrozole.

Dataset Information

Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition.

Publications

Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition.

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