Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial.
BACKGROUND
Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer.


METHODS
We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided.


RESULTS
Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16).


CONCLUSIONS
Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.
Affiliations of authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (SO, XL, YI, MY, NJM, KN, RJM, JAM, CSF); Department of Pathology (SO), Channing Division of Network Medicine, Department of Medicine (DS, CSF), and Department of Surgery (MMB), Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SO); Department of Epidemiology (SO, DS) and Department of Biostatistics (DS) , Harvard School of Public Health, Boston, MA; Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC (DN); Memorial Sloan-Kettering Cancer Center, New York, NY (LBS); Hôpital du Sacré-Coeur de Montréal, Montreal, Canada (RW); Loyola University Stritch School of Medicine, Maywood, IL (AH); current: Edward Cancer Center, Naperville, IL (AH); Northwestern University, Chicago, IL (ABB); Toledo Community Hospital Oncology Program, Toledo, OH (RBM); Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH (RMG).
Shuji
S
Ogino
Xiaoyun
X
Liao
Yu
Y
Imamura
Mai
M
Yamauchi
Nadine J
NJ
McCleary
Kimmie
K
Ng
Donna
D
Niedzwiecki
Leonard B
LB
Saltz
Robert J
RJ
Mayer
Renaud
R
Whittom
Alexander
A
Hantel
Al B
AB
Benson
Rex B
RB
Mowat
Donna
D
Spiegelman
Richard M
RM
Goldberg
Monica M
MM
Bertagnolli
Jeffrey A
JA
Meyerhardt
Charles S
CS
Fuchs
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin