Faculty Collaboration Database

Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations. Mol Cancer Ther 2013 Dec;12(12):2857-63

Date

10/05/2013

Pubmed ID

24092809

Pubmed Central ID

PMC4158732

DOI

10.1158/1535-7163.MCT-13-0319-T

Scopus ID

2-s2.0-84890520181 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer were analyzed for PIK3CA, KRAS, and BRAF mutations. PIK3CA-mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type PIK3CA (71%, 22/31 vs. 43%, 68/158; P = 0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors [median age, 57 years; median number of prior therapies, 4; mTORC1 inhibitors (11), phosphoinositide 3-kinase (PI3K) inhibitors (5), or an AKT inhibitor (1)]. None (0/17) had a partial or complete response (PR/CR) and only 1 [6%, 95% confidence interval (CI), 0.01-0.27] had stable disease 6 months or more, which was not significantly different from a stable disease ≥6 month/PR/CR rate of 16% (11/67; 95% CI, 0.09-0.27) in patients with colorectal cancer without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (P = 0.44). Median progression-free survival was 1.9 months (95% CI, 1.5-2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced colorectal cancer, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.

Author List

Ganesan P, Janku F, Naing A, Hong DS, Tsimberidou AM, Falchook GS, Wheler JJ, Piha-Paul SA, Fu S, Stepanek VM, Lee JJ, Luthra R, Overman MJ, Kopetz ES, Wolff RA, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Agents
Class I Phosphatidylinositol 3-Kinases
Colorectal Neoplasms
Female
Humans
Male
Middle Aged
Mutation
Neoplasm Staging
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins p21(ras)
Signal Transduction
TOR Serine-Threonine Kinases
Treatment Outcome
ras Proteins