Screening for PIK3CA mutations, PTEN loss, and RAS/RAF mutations in early-phase protocols with PI3K/mTOR pathway inhibitors.

Abstract

10507 Background: Activating mutations of PIK3CA or loss of PTEN function result in increased PI3K/mTOR signaling and may predict sensitivity to drugs targeting the PI3K/mTOR pathway, while simultaneous mutations in the MAPK pathway (RAS, RAF) may mediate resistance. Methods: From 10/2008, 922 consecutive tumor samples from advanced cancer patients referred to the Clinical Center for Targeted Therapy were screened (CLIA-certified tests) for PIK3CA, KRAS, NRAS, BRAF mutations and PTEN loss (mutation or complete loss of staining on immunohistochemistry). Patients with tumors carrying PIK3CA mutations and/or PTEN loss were preferentially treated with agents targeting the PI3K/mTOR pathway. Results: Overall, 922 patients with diverse histologies were tested, and 157 (17%) had PIK3CA mutations (n=86, 9%), PTEN loss (n=67, 7%), or a simultaneous PIK3CA mutation and PTEN loss (n=4, <1%). Of these 157 patients, 86 (55%) were treated in clinical trials containing a PI3K/mTOR pathway inhibitor (median age, 56; median number of prior therapies, 3). Of these 86 patients, 54 (63%) had PIK3CA mutations, 29 (34%) PTEN loss, 3 (4%) simultaneous PIK3CA mutation and PTEN loss; and 18 (21%, 95% CI 0.14-0.31) patients achieved a partial response (PR). In contrast, patients without known PIK3CA mutations and/or PTEN loss treated on the same protocols had a PR rate of 6% (26/458; 95% CI 0.04-0.08, p<0.001). Patients with PIK3CA/PTEN testing of primary tumor had a similar PR rate of 20% compared to 23% in patients with PIK3CA/PTEN testing of metastatic tumor (p=0.8). Treated patients with wild-type KRAS had a higher PR rate of 31% compared to 6% in patients with simultaneous KRAS mutations (p=0.05). Conclusions: Heavily pretreated patients with PIK3CA mutations and/or PTEN loss and wild-type KRAS had a significantly higher PR rate (31%) on protocols incorporating PI3K/mTOR inhibitors compared to unselected patients on the same protocols (PR rate = 6%) or patients with PIK3CA mutations and/or PTEN loss and simultaneous KRAS mutations (PR rate = 6%). Our observations suggest that screening for PIK3CA mutations, PTEN loss and KRAS mutations is warranted in patients who are treated with PI3K/mTOR pathway inhibitors.