This article is more than 5 years old. Information may no longer be current.
Stem cell mutations in breast cancer tumors associated with nodal metastases
Click Here to Manage Email Alerts
Patients whose tumors contain breast cancer stem and progenitor cells with defects in PI3K/Akt signaling are significantly more likely to develop lymph node metastases, according to study results.
Besides being responsible for breast cancer initiation and metastases, breast cancer stem and progenitor cells (BCSCs) also may direct dormancy and disease recurrence, according to researcher SuEllen Pommier, PhD, research associate professor in the division of surgical oncology, department of surgery, at Oregon Health & Science University’s Knight Cancer Institute.
“The key to understanding how these cells accomplish these abnormal functions may be through identifying their genetic defects,” Pommier told HemOnc Today. “PI3K/Akt signaling pathway defects have been previously reported in breast cancer, but incidence and clinical outcomes data vary. The results of this study, in which it was shown that that patients with PI3K/Akt mutations in their stem/progenitor cells were more likely to have axillary lymph node involvement, help explain the variability in clinical response to treatment.”
Mutations in the AKT1, HRAS and PIK3CA oncogenes occur in breast cancer, ductal carcinoma in situ and BCSCs. The mutations lead to abnormal PI3K/Akt signaling and tumor proliferation, according to background information in the study.
Pommier and colleagues conducted the investigation to determine whether variability in clinical presentation at diagnosis is associated with PI3K/Akt mutations in BCSCs and could serve as a prognostic indicator of disease progression or metastatic potential.
The researchers collected malignant and benign stem cells from 30 patients with stage IA to stage IIIB invasive ductal breast cancers. The investigators tested the stem cells for mutations in the AKT1, HRAS and PIK3CA oncogenes.
The presence of those mutations in BCSCs — as well as their correlation with several factors, including lymph node metastases, patient age and condition at last follow-up, and tumor stage, grade and hormone receptor status — served as the primary outcome measures.
Researchers determined that 10 (33%) of the tumors had BCSCs with AKT1, HRAS or PIK3CA mutations. Nine of the 10 tumors with BCSC mutations, as well as four of 20 tumors with BCSCs that did not have mutations, demonstrated lymph node metastases (P=.001).
“Because four of 20 patients without BCSC mutations had axillary lymph node metastases, a PI3K/Akt mutation in BCSCs may not be a requirement for axillary lymph node metastases,” the researchers wrote. “However, a significant correlation was found between the two factors.”
The oncogenic defects, which are markers of more aggressive breast cancer, may not always be identified through tumor analysis alone, according to researchers.
“Breast cancer stem/progenitor cells make up only a small portion of the total number of cells within a breast cancer and can be missed in whole tumor testing,” Pommier told HemOnc Today. “They, however, as this study demonstrated, provide crucial prognostic and treatment information and thus should be independently tested along with whole tumor analyses. Through further investigation of breast cancers and their stem/progenitor cells, our intention is to provide an improved prognostic tool, as well as to develop more effective breast cancer treatment strategies.”
Perspective
Back to TopDouglas Yee, MD
Donovan and colleagues evaluated the presence of mutations in the PI3K signaling pathway in primary breast cancer specimens after sorting to define BCSCs. In this small study, they show that 10 of 30 tumors had detectable mutations of this pathway in the BCSCs. The authors also demonstrate that axillary lymph node metastases were more frequently associated with the mutation-containing tumors.
Although demonstrating that PI3K mutations may occur very early in a stem cell population, they do not show the results for the nonprogenitor cells. Presumably, because BCSCs give rise to the bulk of the tumor, these mutations should be detectable in the nonprogenitor population as well, and hopefully would not be missed by mutation analysis of the primary tumor.
An important finding is the increased metastatic potential of the mutation-bearing primary breast cancers as reflected by the high rate of positive lymph node deposits. Although it is tempting to speculate that this increased metastatic potential is due to the presence of specific mutations in oncogenes, it must be a higher intrinsic mutational potential (Burns MB. Nat Genet. 2013;doi:10.1038/ng.2701) in BCSCs might lead to biologically more aggressive tumors because of accumulated mutations in multiple pathways. Certainly, mutation and activation of molecules in the PI3K and other oncogenic pathways need to be evaluated as both prognostic and predictive factors in primary breast cancer.
Click Here to Manage Email Alerts