title: PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.
abstract: Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore, tumors from patients referred to the phase I program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20. Consecutive patients with diverse tumor types and PIK3CA mutation were treated whenever possible with agents targeting the PI3K/AKT/mTOR pathway. Overall, PIK3CA mutations were detected in 25 of 217 patients (11.5%; exon 9, n = 11; exon 20, n = 14). In tumor types with more than 10 patients tested, PIK3CA mutations were most frequent in endometrial (3 of 14, 21%), ovarian (5 of 30, 17%), colorectal (9 of 54, 17%), breast (2 of 14, 14%), cervical (2 of 15, 13%), and squamous cell cancer of the head and neck (1 of 11, 9%). Of the 25 patients with PIK3CA mutations, 17 (68%) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor, and 6 (35%) achieved a partial response. In contrast, only 15 of 241 patients (6%) without documented PIK3CA mutations treated on the same protocols responded (P = 0.001). Of the 17 patients with PIK3CA mutations, 6 (35%) had simultaneous KRAS or BRAF mutations (colorectal, n = 4; ovarian, n = 2). Colorectal cancer patients with PIK3CA and KRAS mutations did not respond to therapy, whereas both ovarian cancer patients with PIK3CA and KRAS or BRAF mutations did. In conclusion, PIK3CA mutations were detected in 11.5% of patients with diverse solid tumors. The response rate was significantly higher for patients with PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors than for those without documented mutations.
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., FC8.2057, Box 0455, Houston, TX 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garrido-Laguna
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: John W
authors.initials: JW
authors.lastname: Moroney
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D016283:Proto-Oncogene Proteins p21(ras); D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 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