Correlation of breast cancer axillary lymph node metastases with stem cell Mutations

Cory A. Donovan, Rodney Pommier, Robynn Schillace, Steven O'Neill, Patrick Muller, Jennifer L. Alabran, Juliana Hansen, Jennifer A. Murphy, Arpana Naik, John Vetto, Su Ellen Johnson Pommier

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    IMPORTANCE: Mutations in oncogenes AKT1, HRAS, and PIK3CA in breast cancers result in abnormal PI3K/Akt signaling and tumor proliferation. They occur in ductal carcinoma in situ, in breast cancers, and in breast cancer stem and progenitor cells (BCSCs). OBJECTIVES: To determine if variability in clinical presentation at diagnosis correlates with PI3K/Akt mutations in BCSCs and provides an early prognostic indicator of increased progression and metastatic potential. DESIGN, SETTING, AND PARTICIPANTS: Malignant (BCSCs) and benign stem cells were collected from fresh surgical specimens via cell sorting and tested for oncogene mutations in a university hospital surgical oncology research laboratory from 30 invasive ductal breast cancers (stages IA through IIIB). MAINOUTCOMES ANDMEASURES: Presence of AKT1, HRAS, and PIK3CA mutations in BCSCs and their correlation with tumor mutations, pathologic tumor stage, tumor histologic grade, tumor hormone receptor status, lymph node metastases, and patient age and condition at the last follow-up contact. RESULTS: Ten tumors had mutations in their BCSCs. In total, 9 tumors with BCSC mutations and 4 tumors with BCSCs without mutations had associated tumor present in the lymph nodes (P =.001). CONCLUSIONS AND RELEVANCE: Tumors in which BCSCs have defects in PI3K/Akt signaling are significantly more likely to manifest nodal metastases. These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer. Molecular profiling of BCSCs may identify patients who would likely benefit from PI3K/Akt inhibitors, which are being tested in clinical trials.

    Original languageEnglish (US)
    Pages (from-to)873-878
    Number of pages6
    JournalJAMA Surgery
    Volume148
    Issue number9
    DOIs
    StatePublished - Sep 2013

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    Stem Cells
    Lymph Nodes
    Neoplastic Stem Cells
    Breast Neoplasms
    Neoplasm Metastasis
    Mutation
    Neoplasms
    Phosphatidylinositol 3-Kinases
    Oncogenes
    Carcinoma, Intraductal, Noninfiltrating
    Tumor Biomarkers
    Clinical Trials
    Hormones

    ASJC Scopus subject areas

    • Surgery

    Cite this

    Correlation of breast cancer axillary lymph node metastases with stem cell Mutations. / Donovan, Cory A.; Pommier, Rodney; Schillace, Robynn; O'Neill, Steven; Muller, Patrick; Alabran, Jennifer L.; Hansen, Juliana; Murphy, Jennifer A.; Naik, Arpana; Vetto, John; Pommier, Su Ellen Johnson.

    In: JAMA Surgery, Vol. 148, No. 9, 09.2013, p. 873-878.

    Research output: Contribution to journalArticle

    Donovan, Cory A. ; Pommier, Rodney ; Schillace, Robynn ; O'Neill, Steven ; Muller, Patrick ; Alabran, Jennifer L. ; Hansen, Juliana ; Murphy, Jennifer A. ; Naik, Arpana ; Vetto, John ; Pommier, Su Ellen Johnson. / Correlation of breast cancer axillary lymph node metastases with stem cell Mutations. In: JAMA Surgery. 2013 ; Vol. 148, No. 9. pp. 873-878.
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    abstract = "IMPORTANCE: Mutations in oncogenes AKT1, HRAS, and PIK3CA in breast cancers result in abnormal PI3K/Akt signaling and tumor proliferation. They occur in ductal carcinoma in situ, in breast cancers, and in breast cancer stem and progenitor cells (BCSCs). OBJECTIVES: To determine if variability in clinical presentation at diagnosis correlates with PI3K/Akt mutations in BCSCs and provides an early prognostic indicator of increased progression and metastatic potential. DESIGN, SETTING, AND PARTICIPANTS: Malignant (BCSCs) and benign stem cells were collected from fresh surgical specimens via cell sorting and tested for oncogene mutations in a university hospital surgical oncology research laboratory from 30 invasive ductal breast cancers (stages IA through IIIB). MAINOUTCOMES ANDMEASURES: Presence of AKT1, HRAS, and PIK3CA mutations in BCSCs and their correlation with tumor mutations, pathologic tumor stage, tumor histologic grade, tumor hormone receptor status, lymph node metastases, and patient age and condition at the last follow-up contact. RESULTS: Ten tumors had mutations in their BCSCs. In total, 9 tumors with BCSC mutations and 4 tumors with BCSCs without mutations had associated tumor present in the lymph nodes (P =.001). CONCLUSIONS AND RELEVANCE: Tumors in which BCSCs have defects in PI3K/Akt signaling are significantly more likely to manifest nodal metastases. These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer. Molecular profiling of BCSCs may identify patients who would likely benefit from PI3K/Akt inhibitors, which are being tested in clinical trials.",
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    AU - Donovan, Cory A.

    AU - Pommier, Rodney

    AU - Schillace, Robynn

    AU - O'Neill, Steven

    AU - Muller, Patrick

    AU - Alabran, Jennifer L.

    AU - Hansen, Juliana

    AU - Murphy, Jennifer A.

    AU - Naik, Arpana

    AU - Vetto, John

    AU - Pommier, Su Ellen Johnson

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    N2 - IMPORTANCE: Mutations in oncogenes AKT1, HRAS, and PIK3CA in breast cancers result in abnormal PI3K/Akt signaling and tumor proliferation. They occur in ductal carcinoma in situ, in breast cancers, and in breast cancer stem and progenitor cells (BCSCs). OBJECTIVES: To determine if variability in clinical presentation at diagnosis correlates with PI3K/Akt mutations in BCSCs and provides an early prognostic indicator of increased progression and metastatic potential. DESIGN, SETTING, AND PARTICIPANTS: Malignant (BCSCs) and benign stem cells were collected from fresh surgical specimens via cell sorting and tested for oncogene mutations in a university hospital surgical oncology research laboratory from 30 invasive ductal breast cancers (stages IA through IIIB). MAINOUTCOMES ANDMEASURES: Presence of AKT1, HRAS, and PIK3CA mutations in BCSCs and their correlation with tumor mutations, pathologic tumor stage, tumor histologic grade, tumor hormone receptor status, lymph node metastases, and patient age and condition at the last follow-up contact. RESULTS: Ten tumors had mutations in their BCSCs. In total, 9 tumors with BCSC mutations and 4 tumors with BCSCs without mutations had associated tumor present in the lymph nodes (P =.001). CONCLUSIONS AND RELEVANCE: Tumors in which BCSCs have defects in PI3K/Akt signaling are significantly more likely to manifest nodal metastases. These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer. Molecular profiling of BCSCs may identify patients who would likely benefit from PI3K/Akt inhibitors, which are being tested in clinical trials.

    AB - IMPORTANCE: Mutations in oncogenes AKT1, HRAS, and PIK3CA in breast cancers result in abnormal PI3K/Akt signaling and tumor proliferation. They occur in ductal carcinoma in situ, in breast cancers, and in breast cancer stem and progenitor cells (BCSCs). OBJECTIVES: To determine if variability in clinical presentation at diagnosis correlates with PI3K/Akt mutations in BCSCs and provides an early prognostic indicator of increased progression and metastatic potential. DESIGN, SETTING, AND PARTICIPANTS: Malignant (BCSCs) and benign stem cells were collected from fresh surgical specimens via cell sorting and tested for oncogene mutations in a university hospital surgical oncology research laboratory from 30 invasive ductal breast cancers (stages IA through IIIB). MAINOUTCOMES ANDMEASURES: Presence of AKT1, HRAS, and PIK3CA mutations in BCSCs and their correlation with tumor mutations, pathologic tumor stage, tumor histologic grade, tumor hormone receptor status, lymph node metastases, and patient age and condition at the last follow-up contact. RESULTS: Ten tumors had mutations in their BCSCs. In total, 9 tumors with BCSC mutations and 4 tumors with BCSCs without mutations had associated tumor present in the lymph nodes (P =.001). CONCLUSIONS AND RELEVANCE: Tumors in which BCSCs have defects in PI3K/Akt signaling are significantly more likely to manifest nodal metastases. These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer. Molecular profiling of BCSCs may identify patients who would likely benefit from PI3K/Akt inhibitors, which are being tested in clinical trials.

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