Research article
Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases
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* Corresponding authors: C R Miller rmiller@med.unc.edu - Carey K Anders carey_anders@med.unc.edu
- † Equal contributors
1 Department of Medicine, Division of Hematology-Oncology, CB 7305, University of North Carolina, Chapel Hill, NC 27599, USA
2 Department of Human Pathology, Integrated Therapies in Oncology Unit, University of Messina, Messina 98125, Italy
3 Lineberger Comprehensive Cancer Center, 170 Manning Drive, CB 7350, University of North Carolina, Chapel Hill, NC 27599, USA
4 Department of Biostatistics and Clinical Data Management, Lineberger Comprehensive Cancer Center, Manning Drive, CB 7350, University of North Carolina, Chapel Hill, NC 27599, USA
5 Department of Pathology, Duke University Medical Center, Box 3712, Durham, NC 27710, USA
6 Department of Medicine, Division of Hematology-Oncology, 382 Hanes Building, Duke University Medical Center, Box 102382, Durham, NC 27710, USA
7 Department of Pathology, Carolinas Medical Center, P.O. Box 32187, Charlotte, NC 28232, USA
8 Department of Pathology, Mayo Clinic, 13400 East Shea Boulevard, Rochester, MN 85259, USA
9 Department of Genetics, 120 Mason Farm Road, CB#7264, University of North Carolina, Chapel Hill, NC 27599, USA
10 Department of Pathology & Laboratory Medicine, CB#7525, University of North Carolina, Chapel Hill, NC 27599, USA
11 Department of Neurosurgery, CB 7250, University of North Carolina, Chapel Hill, NC 27599, USA
Breast Cancer Research 2011, 13:R125 doi:10.1186/bcr3071
Published: 1 December 2011Abstract
Introduction
Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs.
Methods
p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method.
Results
Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival.
Conclusions
The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.