title: PIK3CA mutations in advanced cancers: characteristics and outcomes.
abstract: 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.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. fjanku@mdanderson.org
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Vanda M
authors.initials: VM
authors.lastname: Stepanek
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garrido-Laguna
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis / Q000379:methods; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016017:Odds Ratio; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C117307:KRAS protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human