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Original Investigation | Pacific Coast Surgical Association

Correlation of Breast Cancer Axillary Lymph Node Metastases With Stem Cell Mutations

Cory A. Donovan, MD1; Rodney F. Pommier, MD1; Robynn Schillace, PhD1; Steven O’Neill, BM1; Patrick Muller, BS1; Jennifer L. Alabran, MS1; Juliana E. Hansen, MD2; Jennifer A. Murphy, MD2; Arpana M. Naik, MD1; John T. Vetto, MD1; SuEllen J. Pommier, PhD1
[+] Author Affiliations
1Division of Surgical Oncology, Department of Surgery, Oregon Health & Science University, Portland
2Division of Plastic Surgery, Department of Surgery, Oregon Health & Science University, Portland
JAMA Surg. 2013;148(9):873-878. doi:10.1001/jamasurg.2013.3028.
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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).

Main Outcomes and Measures  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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Figure 1.
PI3K/Akt Signaling Pathway, With Downstream Results

Extracellular signaling molecules interact with surface g-proteins, resulting in activation of PI3K, which phosphorylates phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt. Activation of Akt initiates several intracellular processes related to cell survival, protein synthesis, proliferation, and glucose metabolism. PTEN acts as a negative feedback mechanism on PIP3.

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Figure 2.
Axillary Lymph Node Metastases and Breast Cancer Stem Cell Mutations

Lymph node metastases are significantly increased in patients having breast cancer stem and progenitor cell (BCSC) mutations compared with patients not having BCSC mutations (P = .001).

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