Abstract P1-08-18: PIK/AKT/MTOR pathway activation in triple negative breast cancer and outcomes with matched therapy in phase I clinical trials: Response in both patients with and without direct molecular alterations
Authors: Ganesan P , Moulder S , Janku F , Naing A , Fu S , Tsimberidou AM , Hong DD , Stephens P , Yelensky R , Meric F , Kurzrock R , Wheler JJ 
Published: August 2014

Introduction

The PI3K/AKT/MTOR pathway is a known driver in triple negative breast cancers (TNBC). We analyzed patients with TNBC seen in our Phase I clinic including molecular subtyping and correlation with response to therapies targeting the PI3K/AKT/mTOR pathway.

Methods

Patients with advanced TNBC [negative (&lt;1%) expression for estrogen and progesterone receptors and negative Her 2 (&lt;/ = 1+ by IHC or non-amplified by FISH)] whose tumors had undergone molecular profiling (including PIK3CA/PTEN mutation analysis and/or PTEN immunohistochemistry (IHC)). We evaluated sequential patients seen in the Phase I clinic at M.D. Anderson Cancer Center treated on at least one Phase I clinical trial and correlated molecular status with clinical outcomes on therapy. Molecular profiling methods including hotspot analysis, next generation sequencing and IHC.

Results

Forty-four patients (median age 56, range 27-81; all female; white race76%) with a median of 2 (0-7) prior therapies (40% received ≥3 prior systemic therapies) and 2 metastatic sites (range, 1-6) were included. Histology: invasive ductal carcinoma 29 (66%), metaplastic 12 (27%), other 3 (7%). Nine out of 42 patients tested (19%) had a PIK3CA mutation and, 11 out of 33 patients tested (33%) demonstrated PTEN loss on IHC and 2 patients had PTEN mutations. Altogether, 21 out of 44 patients had at least one alteration in the PI3K/AKT/mTOR pathway. Sixteen of these 21 patients received “matched” therapy consisting of at least one agent targeting the PI3K/AKT/mTOR pathway. Four out of 16 patients (25%) with at least one molecular alteration, treated with one or more regimens containing at least one agent targeting the PI3K/AKT/mTOR pathway (“matched” therapy), demonstrated clinical benefit: complete response (CR) (N = 1)/partial response (PR) (N = 1)/stable disease ≥ 6 months (SD) (N = 2). Similarly, three out of 12 patients (25%) who did not demonstrate a direct molecular alteration in the PI3K/AKT/mTOR pathway and who were treated with PI3K-directed therapy, had either CR (N = 1)/PR (N = 1)/SD ≥ 6 months (N = 1). Twenty-eight patients received PI3K/AKT/mTOR pathway directed therapy yielding CR (N = 2), PR (N = 3) and CR/PR/ SD ≥ 6 months (N = 1) while those who received other therapies had CR (N = 0), PR (N = 1) and CR/PR/SD&gt;6mo (N = 3)and a median TTF of 3.1 (2.1-4.8) vs. 1.8 (1.4-2.5) months (p = 0.23).

Conclusions

A significant percentage of patients with TNBC demonstrate a direct alteration in the PI3K/AKT/mTOR pathway. Our data shows that PI3K-directed therapies benefit both those patients with and without direct molecular alterations in this pathway. Further molecular testing results will be presented. This data suggests that there may be additional molecular alterations that activate PI3K/AKT/mTOR in patients with TNBC.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-18.