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PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations.
J Clin Oncol 30, 2012 (suppl; abstr 10510)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Loss of PTEN function increases PI3K/mTOR signaling. Preclinical data suggest that PTEN aberrations can predict sensitivity to drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461 patients with diverse cancers referred to the Clinical Center for Targeted Therapy were tested for cytoplasmic immunohistochemical expression of PTEN using the following scoring system: negative (no staining); positive (intact staining); reduced staining, with stroma serving as an internal positive control. Whenever possible, tumors were also tested for mutations in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of patients treated with PI3K /mTOR with respect to their PTEN status. Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168 (36.5%) had positive PTEN expression, and 246 (53.5%) had reduced PTEN. In tumor types with >10 patients tested, negative PTEN was most frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either negative or reduced PTEN had more MAPK mutations than patients with positive PTEN expression (72/144, 50% vs. 20/62, 32%, p=0.02). A total of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and 17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN positive, and 12/90 (13%) for reduced PTEN. There was no significant difference in PR rate amongst patients with positive PTEN expression compared to patients with negative or reduced PTEN (3/50, 6% vs. 14/103, 14%; p=0.27). Conclusions: Complete loss of PTEN expression was found in 10% of patients. Positive PTEN expression was found in 36.5% of patients. PTEN status did not predict response to PI3K/mTOR inhibitors, perhaps because patients with negative and reduced PTEN expression had a higher incidence of simultaneous MAPK (KRAS, NRAS, BRAF) mutations.
Abstracts by Filip Janku:
- Meeting: 2014 Gastrointestinal Cancers Symposium | Abstract No: 209
c-Met abnormatities in patients with genitourinary (GU) malignancies and outcomes with c-MET inhibitors.Category: Genitourinary Cancer - Renal Cell Cancer
Characteristics and outcomes of patients with advanced hepatocellular carcinoma treated on phase I trials.
Educational Book Articles by Filip Janku:
Presentations by Filip Janku:
PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations.Session: Tumor Biology (Poster Discussion Session)
Target-based therapeutic matching in early-phase clinical trials in patients with advanced colorectal cancer and PIK3CA mutations.Session: General Poster Session C: Cancers of the Colon and Rectum (General Poster Session)
Screening for PIK3CA mutations, PTEN loss, and RAS/RAF mutations in early-phase protocols with PI3K/mTOR pathway inhibitors.Session: Tumor Biology (Oral Abstract Session)