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Objective: Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial. Methods: HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes. Results: The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer. Conclusion: Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Identifying factors that predispose patients to central nervous system (CNS) metastases may hasten disease detection and improve treatment outcomes. Methods: We reviewed the records of patients who were diagnosed with clinical stage I-III primary breast cancer at the National Cancer Center Hospital East from 2003 to 2005. Cox proportional hazard models were fitted to reveal risk factors for CNS metastases. Results: The median follow-up period after the operation was 53.5 months. Among the 591 identified patients with breast cancer, 76 experienced a relapse. Seventeen patients developed CNS metastases. Multivariate analysis indicated that the triple negative (TN) subtype (hazard ratio = 5.5) and a high Ki67 labeling index (LI; hazard ratio = 3.9) were associated with a higher risk for CNS metastases. At 4 years, the TN subtype was associated with significantly worse overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with hormone receptor-positive/ human epidermal growth factor receptor-2-negative tumors. Breast cancers with a Ki67 LI ≥30% were also associated with lower overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with cancers with a Ki67 LI <30%. Conclusion: TN or Ki67-overexpressing breast cancer produced earlier CNS metastases and lower disease-free and overall survival rates. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Ki-67 overexpression has been reported to be related to a poor prognosis for early stage breast cancer. We analyzed whether Ki-67 has a prognostic impact on risk subgroups based on the recommendations at St. Gallen in 2007. Methods: To determine the impact of Ki-67 on each risk group, a retrospective analysis was performed in patients with breast cancer who underwent curative surgery. Ki-67 was examined by immunohistochemistry with a predefined cutoff level of 10%. Results: A total of 1,166 patients were eligible for this analysis. During the follow-up period, distant metastasis was observed in 164 patients (14.1%), and 80 patients (6.9%) died. Ki-67 overexpression (Ki-67 ≥10%) was identified as an independent prognostic factor for distant-metastatic-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis. In the intermediate-risk group, the difference between Ki-67 overexpression and no overexpression was statistically significant in 5-year DFS (90.9 vs. 83.4%, p = 0.002) and OS (98.1 vs. 95.8%, p = 0.002). However, in both the low- and high-risk groups, Ki-67 overexpression was not an independent prognostic factor for either 5-year DFS or OS. Conclusions: Ki-67 overexpression indicates an unfavorable prognostic impact for DFS and OS. However, this impact is restricted only to those patients classified at intermediate risk. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]