PIK3CA-activating mutations and chemotherapy sensitivity in stage II–III breast cancer

Cornelia Liedtke,W Fraser Symmans,Alberto Bardelli,Rebekah E Hubbard,Attila Tordai,Luca Cardone,Henry L Gomez,Kai Yan,Eduardo A Souchon,Vicente Valero,Luis J Barajas Figureoa,Lajos Pusztai,Gabriel N Hortobagyi

doi:10.1186/bcr1984

Abstract

IntroductionIn vitro evidence suggests that PIK3CA (phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) activation may be associated with altered chemotherapy sensitivity in cancer.MethodsTumor DNA from 140 patients with stage II–III breast cancer undergoing neoadjuvant chemotherapy was sequenced for PIK3CA mutations on exons 1, 9, and 20. Mutation status was correlated with clinical/pathological parameters and chemotherapy response as (a) pathological complete response (pCR) versus residual cancer or (b) quantitative residual cancer burden (RCB) scores, including stratification for estrogen receptor (ER) expression status, type of chemotherapy, and by exons.ResultsTwenty-three patients (16.4%) harbored a PIK3CA mutation, with 12, 11, and 0 mutations located in exons 9, 20, and 1, respectively. PIK3CA exon 9 mutations were more frequent among node-negative (52% versus 25%; P = 0.012) than node-positive tumors, particularly among ER-positive tumors. pCR rates and RCB scores were similar among patients with the wild-type and mutant PIK3CA genes, even after stratification by ER status, chemotherapy regimen (anthracycline versus anthracycline plus paclitaxel), or exon.ConclusionPIK3CA mutations are not associated with altered sensitivity to preoperative anthracycline-based or taxane-based chemotherapies in ER-positive and ER-negative breast tumors. In this study, PIK3CA mutation was associated with a decreased rate of node-positive disease, particularly among ER-positive tumors.

Highlights

Introduction In vitro evidence suggests thatPIK3CA activation may be associated with altered chemotherapy sensitivity in cancer
PIK3CA exon 9 mutations were more frequent among node-negative (52% versus 25%; P = 0.012) than node-positive tumors, among estrogen receptor (ER)-positive tumors. Pathological complete response (pCR) rates and residual cancer burden (RCB) scores were similar among patients with the wild-type and mutant PIK3CA genes, even after stratification by ER status, chemotherapy regimen, or exon
PIK3CA mutations are not associated with altered sensitivity to preoperative anthracycline-based or taxane-based chemotherapies in ER-positive and ER-negative breast tumors

Summary

Introduction

PIK3CA (phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) activation may be associated with altered chemotherapy sensitivity in cancer. PI3K activity controls multiple cellular functions through its second messenger, 3,4,5'-phosphatidylinositol trisphosphate, and its downstream targets, including the serine/threonine protein kinases Akt and mammalian target of rapamycin. D. Anderson Cancer Center; mTOR = mammalian target of rapamycin; pCR = pathological complete response; PCR = polymerase chain reaction; PI3K = phosphoinositol 3-kinase; PIK3CA = phosphatidylinositol 3-kinase, catalytic, alpha polypeptide; PR = progesterone receptor; RCB = residual cancer burden; RD = residual disease; TFAC = paclitaxel followed by 5-fluoruracil, doxorubicin, and cyclophosphamide; TFEC = paclitaxel followed by 5-fluoruracil, epirubicin, and cyclophosphamide. Activating mutations induce a gain of function that results in constitutive signaling through the PI3K/Akt and mTOR pathways [6]. PIK3CA mutations occur in approximately 18% to 40% of human cases and are observed in up to 50% of breast cancer cell lines [8,9,10,11,12,13,14]

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