Reference Detail

Ref Type

Journal Article

PMID

(21216929)

Authors

Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, Naing A, Falchook GS, Moroney JW, Piha-Paul SA, Wheler JJ, Moulder SL, Fu S, Kurzrock R

Title

PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	10	3	2011 Mar	558-65	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600X PIK3CA H1047X	ovarian carcinoma	predicted - sensitive	Bevacizumab + Pegylated liposomal doxorubicin + Temsirolimus	Case Reports/Case Series	Actionable	In a clinical study, the combination of Torisel (temsirolimus) plus Avastin (bevacizumab) and Doxil (pegylated liposomal-doxorubicin) resulted in a partial response in a patient with ovarian clear cell carcinoma harboring PIK3CA H1047 and BRAF V600 mutations (PMID: 21216929).	21216929
PIK3CA H1047X	small intestine adenocarcinoma	predicted - resistant	Bortezomib + Temsirolimus + Topotecan	Case Reports/Case Series	Actionable	In a clinical study, the combination of Torisel (temsirolimus) plus Velcade (bortezomib) and Hycamtin (topotecan) resulted in progressive disease in a patient with small intestine adenocarcinoma harboring a PIK3CA H1047 mutation (PMID: 21216929).	21216929
PIK3CA mutant	Advanced Solid Tumor	sensitive	Bevacizumab + Pegylated liposomal doxorubicin + Temsirolimus	Clinical Study	Actionable	In a clinical study, the combination of Torisel (temsirolimus) plus Avastin (bevacizumab) and Doxil (pegylated liposomal-doxorubicin) resulted in a partial response in patients with advanced solid tumors harboring PIK3CA mutations (PMID: 21216929).	21216929
PIK3CA mutant	ovarian cancer	sensitive	Temsirolimus	Case Reports/Case Series	Actionable	In a clinical study, an ovarian cancer patient harboring a PIK3CA E542 mutation demonstrated stable disease when treated with Torisel (temsirolimus) (PMID: 21216929).	21216929
PIK3CA H1047X	endometrial adenocarcinoma	predicted - sensitive	Temsirolimus	Case Reports/Case Series	Actionable	In a clinical study, a patient with endometrial adenocarcinoma harboring a PIK3CA H1047 mutation demonstrated a partial response when treated with Torisel (temsirolimus) (PMID: 21216929).	21216929
PIK3CA H1047X	colorectal cancer	predicted - resistant	Bevacizumab + Temsirolimus	Case Reports/Case Series	Actionable	In a clinical study, a colorectal cancer patient harboring a mutation at PIK3CA H1047 demonstrated progressive disease when treated with Torisel (temsirolimus) and Avastin (bevacizumab) (PMID: 21216929).	21216929
PIK3CA mutant	Advanced Solid Tumor	sensitive	Bevacizumab + Pegylated liposomal doxorubicin + Temsirolimus	Clinical Study	Actionable	In a clinical study, the combination of Torisel (temisirolimus) plus Avastin (bevacizumab) and Doxil (pegylated liposomal-doxirubicin) resulted in stable disease in patients with advanced solid tumors harboring PIK3CA mutations (PMID: 21216929).	21216929