PIK3CA mutations in advanced cancers: characteristics and outcomes. Oncotarget 2012 Dec;3(12):1566-75
Date
12/19/2012Pubmed ID
23248156Pubmed Central ID
PMC3681495DOI
10.18632/oncotarget.716Scopus ID
2-s2.0-84874736849 (requires institutional sign-in at Scopus site) 78 CitationsAbstract
PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors.
Author List
Janku F, Wheler JJ, Naing A, Stepanek VM, Falchook GS, Fu S, Garrido-Laguna I, Tsimberidou AM, Piha-Paul SA, Moulder SL, Lee JJ, Luthra R, Hong DS, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Antineoplastic Agents
Class I Phosphatidylinositol 3-Kinases
DNA Mutational Analysis
Disease-Free Survival
Exons
Female
GTP Phosphohydrolases
Genetic Predisposition to Disease
Humans
Kaplan-Meier Estimate
Logistic Models
Male
Membrane Proteins
Middle Aged
Molecular Targeted Therapy
Multivariate Analysis
Mutation
Neoplasms
Odds Ratio
Phenotype
Phosphatidylinositol 3-Kinases
Polymerase Chain Reaction
Precision Medicine
Proportional Hazards Models
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins p21(ras)
Retrospective Studies
Risk Factors
TOR Serine-Threonine Kinases
Time Factors
Treatment Outcome
Young Adult
ras Proteins
