The likelihood of nodal metastases is increased in breast cancer patients whose tumors have breast cancer stem and progenitor cells with defects in PI3/Akt signaling.
The findings, drawn from an analysis of surgical specimens, "support embarking on a new way of approaching breast cancer diagnosis and treatment planning" and have potential implications for targeted treatment with PI3/Akt inhibitors currently being tested in clinical trials, Dr. Cory A. Donovan and his colleagues at the Oregon Health and Science University, Portland reported online July 24 in JAMA Surgery.
The researchers evaluated malignant and benign stem cells from 30 fresh surgical specimens of ductal breast cancers. Nine of the 10 specimens with mutations in breast cancer stem and progenitor cells (BCSCs) were associated with axillary lymph node micro- or macrometastases. Just 4 of the 20 tumors without mutations were associated with axillary lymph node metastases, the investigators said (JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028]).
The tumor specimens were collected from patients with stage IA through IIIB cancers via cell sorting and were subjected to whole genomic amplification and subsequent screening for oncogene mutations. The 10 tumors with BCSC defects had AKT1, HRAS, or PIK3CA mutations.
"Three different mutations (E545k, N345k, and H1047R) were detected in PIK3CA, a single mutation was detected in AKT1, and a single mutation was detected in HRAS," the investigators wrote.
No difference in CD44 positivity was observed between BCSCs with and without mutations.
"When the presence of any BCSC mutation correlated with patient and breast cancer characteristics, no statistically significant correlations were found with patient age at diagnosis, tumor size, tumor histologic grade, estrogen receptor expression, progesterone receptor expression, or ERBB2 status. However, a statistically significant correlation was observed between the presence of BCSC mutations and axillary lymph node metastases. This significance was more pronounced when micrometastatic disease was included," they said.
At a mean follow-up of 29 months, disease had progressed after treatment in 3 of the 10 patients with BCSC mutations. Two patients died of disease; one had brain metastases. Conversely, there was no evidence of disease at a mean follow-up of 19 months in the patients with BCSCs without mutations.
Since 20% of patients without BCSC mutations had axillary lymph node metastases, it appears that a PI3K/Akt mutation in BCSC is not a requirement for metastases, but the link between PI3K and metastatic potential demonstrated in this study suggests that "micrometastases harboring PI3K/Akt mutations may carry a different risk for distant metastatic disease," Dr. Donovan and his associates noted.
"Longer patient follow-up periods and a larger sample size will determine if this subset of patients demonstrates an increased risk and may benefit from specifically designed use of adjuvant chemotherapy," the researchers added.
The existing evidence regarding the prognostic significance of specific PI3K/Akt signaling pathway mutations is conflicting, likely because of the variability of the mutations, the heterogeneity of the tumors, and the complexity of the pathway. Although the findings in BCSCs in the current study are consistent with others showing that PIK3CA and AKT mutations in breast cancers are associated with factors that may indicate poor prognosis and decreased survival, other studies have demonstrated improved survival, lower tumor grades, and increased rates of estrogen receptor positivity in patients with tumors that have PIK3CA mutations, they said.
"Our study findings indicate that the answer to this controversy may lie in identifying mutations in BCSCs, as well as mutations in the tumor as a whole," they said, adding that the findings support an evaluation of BCSCs along with overall breast cancer assessment.
"The analysis of BCSCs can generate specific information about tumor growth and metastatic potential that may not be obtained from analysis of the tumor progeny cells alone. Simultaneous molecular analyses of both the tumor and BCSCs may better identify patients who are likely to benefit from specific therapeutic regimens. Similarly, simultaneous BCSC and tumor analysis may increase the number of patients who might benefit from treatment but be missed by tumor analysis alone," Dr. Donovan and his coworkers said.
P13K/Akt signaling pathway inhibitors are currently being evaluated in clinical trials and could prove useful for the treatment of patients with BCSC mutations, they noted, adding that this may be true even in cases without PIK/Akt mutation.
"The use of BCSC-specific and tumor-targeted chemotherapeutic agents may prove to be synergistic with each other, providing a novel therapeutic approach," they said.
This study was supported by a grant from the Janet E. Bowen Foundation. The authors reported having no disclosures.