Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Abstract

<b>Purpose:</b> Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis.<b>Experimental Design:</b> Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K-AKT-mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions.<b>Results:</b><i>PIK3CA</i> mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (<i>P</i> < 0.01, <i>P</i> = 0.056, and <i>P</i> = 0.053, respectively). However, <i>PIK3CA</i> mutations alone were insufficient in predicting protein activation (<i>P</i> = 0.32 and <i>P</i> = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); <i>P</i> < 0.01, <i>P</i> = 0.02, and <i>P</i> = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) <i>P</i> < 0.01, mTOR (S2448) <i>P</i> < 0.01, 4EBP1 (S65) <i>P</i> = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined.<b>Conclusions:</b> Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of <i>PIK3CA</i> mutations and activation of the PI3K-AKT-mTOR signaling network. <i>Clin Cancer Res; 23(16); 4919-28. ©2017 AACR</i>.