Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience

// Ming-Mo Hou 1, 4 , Xiaochun Liu 1 , Jennifer Wheler 1 , Aung Naing 1 , David Hong 1 , Robert L. Coleman 2 , Apostolia Tsimberidou 1 , Filip Janku 1 , Ralph Zinner 1 , Karen Lu 2 , Razelle Kurzrock 3 , Siqing Fu 1 1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 2 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 3 UC San Diego Moores Cancer Center, La Jolla, California 4 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan Correspondence to: Siqing Fu, e-mail: siqingfu@mdanderson.org Keywords: Cervical Cancer, Phase I Trial, Matched Therapy, PIK3CA mutation, PTEN loss Received: July 21, 2014      Accepted: October 09, 2014      Published: October 29, 2014 ABSTRACT Background: Activated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established. Methods: We analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013. Results: Patients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively). Matched therapy targeting the activated PI3K/AKT/mTOR pathway led to a favorable rate of SD ≥ 6 months/CR/PR (53%) and significantly longer progression-free survival (median, 6.0 months) than non-matched therapy (11% and 1.5 months; p = 0.08 and 0.026; respectively). In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019). Conclusions: Matched therapy targeting the activated PI3K/AKT/mTOR pathway provided meaningful clinical benefits. Thus, further evaluation of PI3K/AKT/mTOR pathway targeted therapy is warranted, especially in metastatic or recurrent squamous cell carcinoma.