Abstract 2838: Differential effects of PIK3CA mutations and PTEN loss in patients with advanced endometrial cancers on matched therapy
Authors: Liu Xiaochun , Hou Mingmou , Wheler Jennifer , Naing Aung , Hong David , Tsimberidou Apostolia , Piha-Paul Sarina , Falchook Gerald , Zinner Ralph , Janku Filip , Lois Ramondetta , Schmeler Kathleen , Lu Karen , Kurzrock Razelle , Fu Siqing 
Published: May 2015

Abstract
Purpose: To evaluate whether PIK3CA mutations and/or PTEN loss predict better clinical outcomes to phase I trials of PI3K/AKT/mTOR inhibition-based therapies in patients with metastatic, recurrent or refractory endometrial cancers.
Methods: Outcome analyses were conducted on 73 patients with advanced endometrial cancers who were seen in a designated Phase I clinic at MD Anderson Cancer Center from 1/1/2006 to 4/30/2013, and tested for PIK3CA mutations and/or PTEN loss (an immunoreactive score of 3 or less) in a CLIA-certified molecular diagnostic laboratory, in accordance with the IRB guidelines. All data were obtained from patients' electronic medical records.
Results: All patients (n=73) had received at least one systemic therapy before the referral (median = 2). Approximately 24% of tested patients (n=13/55) harbored PIK3CA mutations. Of the 13 patients with PIK3CA mutations, 12 (92%) were treated in clinical trials including a PI3K/AKT/mTOR pathway inhibitor with or without chemotherapy (matched therapy). Matched therapy led to a total of 54% PR/SD≥6months (23% PR and 31% SD≥6months) and a median PFS of 7.9 months. The response rate and PFS are much lower in the 17 patients who did not have PIK3CA and PTEN tested; 17.6% SD≥6months and median PFS of 1.9 months (p=0.037and p=0.013, respectively). Of those who had PTEN tested (n=41), 21 patients (51%) had PTEN loss. All 21 patients with PTEN loss received matched therapies, which led to a total of 38% PR/SD≥6months (14% PR and 24% SD≥6months) and a median PFS of 5 months. That is not significantly different from therapy in patients who do not have PIK3CA and PTEN tested (p=0.167and p=0.076, respectively). Of 30 patients with PIK3CA mutations and/or PTEN loss (n=30), matched therapy led to a significantly longer median PFS of 4.8 months (p=0.03) but similar response rate (15% PR and 25% SD≥6months) to those in patients without PIK3CA and PTEN tests (p=0.114). Patients with unknown PIK3CA and PTEN status received significantly fewer regimens targeting at PIK3CA pathway compared to those with known status (p&lt;0.001).
Conclusions: Matched therapy using PI3K/AKT/mTOR pathway inhibitor -based regimens led to higher clinical response rate including CR/PR/SD ≥ 6months and PFS in patients with PI3Kinase mutation but not PTEN loss, indicating that different biological mechanisms are involved in these molecular aberrations. Further evaluation in patients with advanced endometrial cancers may require dissect individual molecular aberration for personalized cancer therapy.
Citation Format: Xiaochun Liu, Mingmou Hou, Jennifer Wheler, Aung Naing, David Hong, Apostolia Tsimberidou, Sarina Piha-Paul, Gerald Falchook, Ralph Zinner, Filip Janku, Ramondetta Lois, Kathleen Schmeler, Karen Lu, Razelle Kurzrock, Siqing Fu. Differential effects of PIK3CA mutations and PTEN loss in patients with advanced endometrial cancers on matched therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2838. doi:10.1158/1538-7445.AM2014-2838