Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer

Mariaelena Pierobon, Corinne Ramos, Shukmei Wong, K. Alex Hodge, Jessica Aldrich, Sara Byron, Stephen P. Anthony, Nicholas J. Robert, Donald W. Northfelt, Mohammad Jahanzeb, Linda Vocila, Julia Wulfkuhle, Guido Gambara, Rosa I. Gallagher, Bryant Dunetz, Nicholas Hoke, Ting Dong, David W. Craig, Massimo Cristofanilli, Brian Leyland-JonesLance A. Liotta, Joyce A. O'Shaughnessy, John D. Carpten, Emanuel F. Petricoin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


Purpose: 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. Experimental Design: 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. Results: PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 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); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined. Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K–AKT–mTOR signaling network.

Original languageEnglish
Pages (from-to)4919-4928
Number of pages10
JournalClinical Cancer Research
Issue number16
StatePublished - 15 Aug 2017
Externally publishedYes


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