Hy De Lee

Population-based Breast Cancer Statistics in Korea during 1993-2002: Incidence, Mortality, and Survival

In 2002, breast became the most common cancer site in Korean women. Using national breast cancer incidence data during 1993-2002, crude, age-standardized, and age-specific rates for incidence and mortality were calculated. Survival was examined for cases diagnosed during 1993-2002 and followed up to 2004. Observed survival was calculated using the life table method and relative survival using the Ederer II method. Age-standardized incidence rates in female increased from 14.5 in 1993 to 26.2 per 100,000 in 2002. Age-specific incidences showed peaks in women in their forties. Mortality rates increased from 3.7 in 1993 to 4.6 per 100,000 in 2002 and showed peaks in women in their fifties. Five-year relative survival for female breast cancer diagnosed during 1993-2002 was 82.2%. When we examined the secular trends using cases diagnosed 1993-1999 for complete 5-yr follow-up, the 5-yr relative survival increased from 75.2% in 1993 to 83.5% in 1999. The data from this study will provide valuable information to plan and evaluate actions against breast cancer including national breast cancer screening.

Prognostic Factors for Patients with Bone-Only Metastasis in Breast Cancer

Purpose Bone is the most frequent site of metastasis among breast cancer patients. We investigated prognostic factors affecting survival following bone-only metastasis in breast cancer patients. Materials and Methods The medical records of breast cancer patients who were treated and followed at Gangnam Severance Hospital retrospectively reviewed to identify patients with bone-only metastasis. Results The median time from the diagnosis of bone-only metastasis to the last follow-up or death was 55.2 [95% confidence interval (CI), 38.6-71.9] months. The Kaplan-Meier overall survival estimate at 10 years for all patients was 34.9%. In the multivariate Cox regression model, bisphosphonate treatment [hazard ratio=0.18; 95% CI, 0.07-0.43], estrogen receptor positivity (hazard ratio=0.51; 95% CI, 0.28-0.94), and solitary bone metastasis (hazard ratio=0.32; 95% CI, 0.14-0.72) were significantly associated with longer overall survival in the bone-only recurrence group. Among the treatment modalities, only bisphosphonate treatment was identified as a significant prognostic factor. Conclusion Identifying the factors influencing breast cancer mortality after bone-only metastasis will help clarify the clinical course and improve the treatment outcome for patients with breast cancer and bone-only metastasis. Bisphosphonates, as a significant prognostic factor, warrant further investigation.

Does Liver Resection Provide Long-Term Survival Benefits for Breast Cancer Patients with Liver Metastasis? A Single Hospital Experience

Purpose Liver resection with colorectal liver metastasis widely accepted and has been considered safe and effective therapeutic option. However, the role of liver resection in breast cancer with liver metastasis is still controversial. Therefore, we reviewed the outcome of liver resection in breast cancer patients with liver metastases in a single hospital experiences. Materials and Methods Between January 1991 and December 2006, 2176 patients underwent breast cancer surgery in Gangnam Severance Hospital. Among these patients, 110 cases of liver metastases were observed during follow-up and 13 of these patients received liver resection with potential feasibility to achieve an R0 resection. Results The median time interval between initial breast cancer and detection of liver metastasis was 62.5 months (range, 13-121 months). The 1-year and 3-year overall survival rates of the 13 patients with liver resection were 83.1% and 49.2%, respectively. The 1-year and 3-year overall survival rates of patients without extrahepatic metastasis were 83.3% and 66.7% and those of patients with extrahepatic metastasis were 80.0% and 0.0%, respectively (p=0.001). Conclusion Liver resection for metastatic breast cancer results in improved patient survival, particularly in patients with solitary liver metastasis and good general condition.

Breast conserving therapy in stage I & II breast cancer in Korea

A randomized clinical study of 187 patients with T1, T2 breast cancer was performed, in order to compare the effects of modified radical mastectomy (MRM) and breast conserving therapy (BCT) on breast recurrence, overall survival, and disease-free survival. One hundred eighty seven patients with T1, T2 breast cancer, admitted at Yongdong Severance Hospital from April 1991 to August 1994, were randomized into two different treatment groups. Of the 187 patients, 111 patients had received MRM and 76 had received BCT. In any of the variables considered with the exceptions of age and menopausal status, patient characteristics such as tumor size, incidence of axillary lymph node metastasis, histologic grading, and estrogen and progesterone receptor positive rate were not significantly different between the two groups (p > 0.05). Using the Kaplan-Meier Product-limit method and log-rank test, the difference of locoregional recurrence, and overall and disease-free survival, between these comparable groups was analyzed. Average follow-up period was 37.6 months. Two out of 111 MRM patients and two out of 76 BCT patients had locoregional recurrence. Only one patient who had MRM was found to have a recurrence in her opposite breast. The overall survival rates in MRM and BCT patients were, respectively, 93.7% and 94.1%. Furthermore, the disease-free survival rates were, respectively, 89.2% and 93.9%. This result indicates that there were no significant differences between two groups in locoregional recurrence, and overall and disease-free survival. Having gained a better cosmetic appearance, the conservative treatment group was satisfied with the BCT. In this study, we conclude that BCT is a good alternative surgical treatment modality for T1, T2 Korean breast cancer patients, which could substitute for the more traditional MRM. However, further follow-up will be needed for long-term results.

Long-Term Survival Analysis of Korean Breast Cancer Patients at a Single Center: Improving Outcome Over Time

Purpose The prognosis of breast cancer has been consistently improving. We analyzed our cohort of breast cancer patients with a long-term follow up at a single center over time. Materials and Methods A total of 1889 patients with known cancer stages were recruited and analyzed between January 1991 and December 2005. Patients were classified according to the time periods (1991-1995; 1996-2000; 2001-2005). To determine intrinsic subtypes, 858 patients whose human epidermal growth receptor-2 status and Ki67 were reported between April 2004 and December 2008 were also analyzed. Results At a median follow up of 9.1 years, the 10-year overall survival (OS) rate was 80.5% for the entire cohort. On multivariate analysis for OS and recurrence-free survival (RFS), the time period was demonstrated to be a significant factor independent of conventional prognostic markers. In the survival analysis performed for each stage (I to III), OS and RFS significantly improved according to the time periods. Adoption of new agents in adjuvant chemotherapy and endocrine therapy was increased according to the elapsed time. In the patients with known subtypes, OS and RFS significantly differed among the subtypes, and the triple-negative subtype showed the worst outcome in stages II and III. Conclusion In the Korean breast cancer cohort with a long-term follow up, our data show an improved prognosis over the past decades, and harbor the contribution of advances in adjuvant treatment. Moreover, we provided new insight regarding comparison of the prognostic impact between the tumor burden and subtypes.

Preventive Effects of Zoledronic Acid on Bone Metastasis in Mice Injected with Human Breast Cancer Cells

Bisphosphonates are used routinely to reduce bone-related events in breast cancer patients with bone metastasis. We evaluated the effects of zoledronic acid, a third generation, nitrogen-containing bisphosphonate, to prevent bone metastasis in breast cancer. Zoledronic acid or vehicle alone was administered to nude mice either simultaneously or after intracardiac injection of human breast cancer MDA-MB-231 cells. Nude mice treated with zoledronic acid at early time points showed a lower incidence of bone metastases than did vehicle-treated nude mice, but these differences were not statistically significant. Only 37.5% of mice treated with zoledronic acid at the time of tumor cell inoculation developed bone metastases compared to over 51.8% of mice receiving vehicle alone (P = 0.304). Cell count of apoptosis confirmed by immunohistochemical staining in metastatic bone tissue significantly increased in the zoledronic acid-treated groups compared to non-treated group (1,018.3 vs 282.0; P = 0.046). However, metastatic tumor cells, which invade soft tissue around the bone, did not show extensive apoptosis; there were no differences between the zoledronic acid-treated and control groups. These results suggest that zoledronic acid increases apoptosis of metastatic breast tumor cells in the bone and could therefore reduce metastatic tumor burden. These results support the use of zoledronic acid to reduce the incidence of bone metastasis in breast cancer.

Prospective Evaluation of the Feasibility of Sentinel Lymph Node Biopsy in Breast Cancer Patients with Negative Axillary Conversion after Neoadjuvant Chemotherapy

Purpose Tumor response to neoadjuvant chemotherapy (NAC) may adversely affect the identification and accuracy rate of sentinel lymph node biopsy (SLNB). This study was conducted to evaluate the feasibility of SLNB in node-positive breast cancer patients with negative axillary conversion after NAC. Materials and Methods Ninety-six patients with positive nodes at presentation were prospectively enrolled. 18Fluorodeoxyglucose-positron emission tomography (18F-FDG PET) and ultrasonography were performed before and after NAC. A metastatic axillary lymph node was defined as positive if it was positive upon both 18F-FDG PET and ultrasonography, while it was considered negative if it was negative upon both 18F-FDG PET and ultrasonography. Results After NAC, 55 cases (57.3%) became clinically node-negative, while 41 cases (42.7%) remained node-positive. In the entire cohort, the sentinel lymph node (SLN) identification and false-negative rates were 84.3% (81/96) and 18.4% (9/49), respectively. In the negative axillary conversion group, the results of SLNB showed an 85.7% (48/55) identification rate and 16.7% (4/24) false-negative rate. Conclusion For breast cancer patients with clinically positive nodes at presentation, it is difficult to conclude whether the SLN accurately represents the metastatic status of all axillary lymph nodes, even after clinically negative node conversion following NAC.

Abstract A68: The role of estrogen‐responsive finger protein (Efp) and 14‐3‐3 sigma (σ) in breast carcinogenesis and their prognostic implication

Background: 14‐3‐3 sigma (σ) is a negative regulator of the cell cycle and contributes to G2/M arrest. In many malignant tumors, the 14‐3‐3 σ is considered to be an important tumor suppressor of which the decreased expression has been reported. The level of the 14‐3‐3 σ was reported to be decreased either by hypermethylation at its promoter site or ubiquitin‐mediated proteolysis by the estrogen‐responsive ring finger protein (Efp). In this study, we tried to investigate which mechanism plays more important role in the 14‐3‐3 σ regulation, how the change of the 14‐3‐3 σ expression affect the biology of human breast cancer, and hence to extend our understanding of the role of the 14‐3‐3 σ in human breast cancer. Materials and Methods: In order to examine the role of ubiquitin‐associated proteolysis by the Efp, we examined the change of the level of 14‐3‐3 σ protein after Efp silencing using siRNA in MCF‐7 breast cancer cell line. We also examined the Efp and 14‐3‐3 σ expression in 220 human breast carcinoma tissues by immunohistochemistry. To investigate the role of methylation in regulation of 14‐3‐3 σ, we examined the methylation status of 14‐3‐3 σ promoter in human breast carcinoma tissue by methylation‐specific polymerase chain reaction. Other clinicopathological variables were also evaluated together with the follow‐up data to assess the prognostic significance of those two molecules. Results: Silencing of the Efp with siRNA in a MCF‐7 breast cancer cell line resulted in increased expression of the 14‐3‐3 σ. Expression of the Efp and 14‐3‐3 σ in human breast cancer tissue was not very common with 19.8% and 20.7% of the total cases being positive, respectively. The Efp‐positive cases were more frequently 14‐3‐3 sigma‐negative. Hypermethylation of the 14‐3‐3 σ was common in breast cancer (64.9%) and had a tendency of negative association with the 14‐3‐3 σ positivity. The Efp expression was negatively associated with axillary lymph node metastasis (p=0.021) or positive p53 status (p=0.009). The 14‐3‐3 σ expression was positively associated with increasing histologic and nuclear grade (p=0.012 and p=0.033), and positive p53 (p=0.001). The 14‐3‐3 σ was negatively correlated with ER or PR expression (p=0.020 and p=0.032) and hypermethylation (p=0.072). Positive 14‐3‐3 σ expression was significantly correlated with poor prognosis. A multivariate analyses of disease‐free survival (p=0.008) and disease‐specific survival (p=0.009) showed that the 14‐3‐3 σ was a independent prognostic marker. Conclusion: Our data clearly demonstrated that 14‐3‐3 σ expression was negatively correlated with Efp expression in vitro and excised breast cancer tissues demonstrated similar tendency. 14‐3‐3 σ was also negatively correlated with hypermethylation in human breast cancer tissue. These results suggest that 14‐3‐3 σ may be regulated by both mechanisms i.e. ubiquitin‐mediated proteolysis by Efp and down‐regulation by hypermethylation in human breast cancers. Interestingly, 14‐3‐3 σ turned out to be a significant poor prognostic indicator in breast cancer, suggesting a hither to unrecognized role of 14‐3‐3 σ in breast cancer in addition to a well established role as tumor suppressor. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A68.