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

Research output: Contribution to journalArticle

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Abstract

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 (US)
Pages (from-to)4919-4928
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

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Phosphatidylinositol 3-Kinases
Breast Neoplasms
Neoplasm Metastasis
Liver
Protein Array Analysis
70-kDa Ribosomal Protein S6 Kinases
Mutation
Exome
Neoplasms
Research Design
Incidence
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Pierobon, M., Ramos, C., Wong, S., Hodge, K. A., Aldrich, J., Byron, S., ... Petricoin, E. F. (2017). Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer. Clinical Cancer Research, 23(16), 4919-4928. https://doi.org/10.1158/1078-0432.CCR-16-2656

Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer. / Pierobon, Mariaelena; Ramos, Corinne; Wong, Shukmei; Hodge, K. Alex; Aldrich, Jessica; Byron, Sara; Anthony, Stephen P.; Robert, Nicholas J.; Northfelt, Donald W; Jahanzeb, Mohammad; Vocila, Linda; Wulfkuhle, Julia; Gambara, Guido; Gallagher, Rosa I.; Dunetz, Bryant; Hoke, Nicholas; Dong, Ting; Craig, David W.; Cristofanilli, Massimo; Leyland-Jones, Brian; Liotta, Lance A.; O'Shaughnessy, Joyce A.; Carpten, John D.; Petricoin, Emanuel F.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4919-4928.

Research output: Contribution to journalArticle

Pierobon, M, Ramos, C, Wong, S, Hodge, KA, Aldrich, J, Byron, S, Anthony, SP, Robert, NJ, Northfelt, DW, Jahanzeb, M, Vocila, L, Wulfkuhle, J, Gambara, G, Gallagher, RI, Dunetz, B, Hoke, N, Dong, T, Craig, DW, Cristofanilli, M, Leyland-Jones, B, Liotta, LA, O'Shaughnessy, JA, Carpten, JD & Petricoin, EF 2017, 'Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer', Clinical Cancer Research, vol. 23, no. 16, pp. 4919-4928. https://doi.org/10.1158/1078-0432.CCR-16-2656
Pierobon, Mariaelena ; Ramos, Corinne ; Wong, Shukmei ; Hodge, K. Alex ; Aldrich, Jessica ; Byron, Sara ; Anthony, Stephen P. ; Robert, Nicholas J. ; Northfelt, Donald W ; Jahanzeb, Mohammad ; Vocila, Linda ; Wulfkuhle, Julia ; Gambara, Guido ; Gallagher, Rosa I. ; Dunetz, Bryant ; Hoke, Nicholas ; Dong, Ting ; Craig, David W. ; Cristofanilli, Massimo ; Leyland-Jones, Brian ; Liotta, Lance A. ; O'Shaughnessy, Joyce A. ; Carpten, John D. ; Petricoin, Emanuel F. / Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4919-4928.
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abstract = "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.",
author = "Mariaelena Pierobon and Corinne Ramos and Shukmei Wong and Hodge, {K. Alex} and Jessica Aldrich and Sara Byron and Anthony, {Stephen P.} and Robert, {Nicholas J.} and Northfelt, {Donald W} and Mohammad Jahanzeb and Linda Vocila and Julia Wulfkuhle and Guido Gambara and Gallagher, {Rosa I.} and Bryant Dunetz and Nicholas Hoke and Ting Dong and Craig, {David W.} and Massimo Cristofanilli and Brian Leyland-Jones and Liotta, {Lance A.} and O'Shaughnessy, {Joyce A.} and Carpten, {John D.} and Petricoin, {Emanuel F.}",
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T1 - Enrichment of PI3K-AKT–mTOR pathway activation in hepatic metastases from breast cancer

AU - Pierobon, Mariaelena

AU - Ramos, Corinne

AU - Wong, Shukmei

AU - Hodge, K. Alex

AU - Aldrich, Jessica

AU - Byron, Sara

AU - Anthony, Stephen P.

AU - Robert, Nicholas J.

AU - Northfelt, Donald W

AU - Jahanzeb, Mohammad

AU - Vocila, Linda

AU - Wulfkuhle, Julia

AU - Gambara, Guido

AU - Gallagher, Rosa I.

AU - Dunetz, Bryant

AU - Hoke, Nicholas

AU - Dong, Ting

AU - Craig, David W.

AU - Cristofanilli, Massimo

AU - Leyland-Jones, Brian

AU - Liotta, Lance A.

AU - O'Shaughnessy, Joyce A.

AU - Carpten, John D.

AU - Petricoin, Emanuel F.

PY - 2017/8/15

Y1 - 2017/8/15

N2 - 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.

AB - 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.

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