Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer.
Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Exons 9 (helical domain) and 20 (kinase domain-KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials.Interactions with clinical, pathological, and biomarker response parameters were examined. A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected(N = 235 P < or = 0.05), but not with treatment-induced changes in Ki67-based proliferation index (N = 418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log-rank P = 0.02) in the P024 trial (N = 153). The favorable prognostic effect was maintained in a multivariable analysis(N = 125) that included the preoperative endocrine prognostic index, an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER, and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9-105 P = 0.01). PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor-positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained.
Ellis
Matthew J
MJ
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63119, USA. mellis@dom.wustl.edu
Lin
Li
L
Crowder
Robert
R
Tao
Yu
Y
Hoog
Jeremy
J
Snider
Jacqueline
J
Davies
Sherri
S
DeSchryver
Katherine
K
Evans
Dean B
DB
Steinseifer
Jutta
J
Bandaru
Raj
R
Liu
WeiHua
W
Gardner
Humphrey
H
Semiglazov
Vladimir
V
Watson
Mark
M
Hunt
Kelly
K
Olson
John
J
Baselga
José
J
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D009154:Mutation; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D058534:Class I Phosphatidylinositol 3-Kinases; D019394:Ki-67 Antigen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human