title: Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Elena
authors: E
authors: López-Knowles
authors: Corrinne V
authors: CV
authors: Segal
authors: Qiong
authors: Q
authors: Gao
authors: Isaac
authors: I
authors: Garcia-Murillas
authors: Nicholas C
authors: NC
authors: Turner
authors: Ian
authors: I
authors: Smith
authors: Lesley-Ann
authors: LA
authors: Martin
authors: Mitch
authors: M
authors: Dowsett
mesh_terms: D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009570:Nitriles / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib; D019394:Ki-67 Antigen; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C484760:PIK3CA protein, human