Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006) / 한국유방암학회지

Purpose@#In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. @*Methods@#In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3–4, 5–6, and 7–8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. @*Results@#Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8–96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. @*Conclusion@#Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression.

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006) / 한국유방암학회지

Purpose@#In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. @*Methods@#In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3–4, 5–6, and 7–8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. @*Results@#Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8–96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. @*Conclusion@#Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression.

Primary Histiocytic Sarcoma Presenting as a Breast Mass: A Case Report / 한국유방암학회지

Histiocytic sarcoma is a rare hematologic malignancy, with very few cases of primary histiocytic sarcoma of the breast described in English scientific literature. Herein, we describe a case of primary histiocytic sarcoma of the breast in a 75-year-old woman, with no clinical history of malignant tumors, who presented with a palpable solitary breast mass. Microscopically, the resected breast mass showed large pleomorphic cells, some multinucleated giant cells, and admixed inflammatory components. The pleomorphic tumor cells further showed a diffuse, noncohesive growth pattern, an abundant eosinophilic cytoplasm, and strong and diffuse immunoreactivity for cluster of differentiation (CD) 68 and CD163. Furthermore, a whole-body positron-emission tomography/computed tomography using deoxy-2-[¹⁸F]fluoro-D-glucose performed after surgery showed no other masses or lesions. After surgical excision, the patient was followed up, and no evidence of tumor recurrence or metastasis was noted.

Clinicopathological Significance of SMAD4 Expression in Breast Cancer

PURPOSE@#SMAD4 is a member of the SMAD family and acts as a central mediator of transforming growth factor beta signaling. Little is known about SMAD4 expression and its prognostic significance in breast cancer. We evaluated the clinicopathological and prognostic significance of SMAD4 expression in breast cancer.@*METHODS@#Two hundred and fifty-five patients with invasive ductal carcinoma of the breast from 2000 to 2008 were retrospectively analyzed. We investigated SMAD4 expression using a tissue microarray-based immunohistochemical assay and evaluated the association between SMAD4 and prognosis of breast cancer.@*RESULTS@#High SMAD4 expression was positively associated with early stage (p=0.009), estrogen receptor positivity (p=0.026), and human epidermal growth factor receptor 2 negativity (p=0.001). A significant difference in overall survival (OS) was associated with high SMAD4 expression in patients with T1 stage tumors (hazard ratio: 0.459, p=0.024).@*CONCLUSION@#High SMAD4 expression was correlated with several favorable prognostic factors and was associated with favorable OS in T1 stage breast cancer. SMAD4 in breast cancer has potential prognostic significance, and further investigations and understanding about SMAD4 expression are needed.

Correlation of Semi-Quantitative Breast-Specific Gamma Imaging Findings with Dynamic Contrast-Enhanced MRI Parameters Assessed by a Computer-Aided Evaluation Program for Breast Cancer

PURPOSE@#To investigate whether a correlation exists between the semi-quantitative breast-specific gamma imaging (BSGI) findings and dynamic contrast-enhanced (DCE) MRI parameters assessed by a computer-aided evaluation program.@*MATERIALS AND METHODS@#Semi-quantitative index of the lesion to non-lesion (L/N) ratio in BSGI and DCE-MRI parameters was assessed by a computer-aided evaluation program, where 47 cases of invasive breast cancer were obtained. Correlations between the L/N ratio and DCE-MRI parameters were assessed by a computer-aided evaluation program. Tumor diameter (cm), angio-volume (cc), degree of initial peak enhancement (%), persistent enhancement proportion (%), and washout enhancement proportion (%) were analysed. The relationships between the L/N ratio and DCE-MRI parameters were evaluated by a univariate and multivariate regression analysis.@*RESULTS@#The mean L/N ratio of the 47 tumors was 3.63 ± 2.19 (range: 1–13.1). The L/N ratio was higher in tumors with larger diameters (p < 0.001), increased angio-volume (p < 0.001), higher degree of initial peak enhancement (p = 0.005) and increased washout enhancement proportion (p = 0.004). In the multivariate regression analysis, angio-volume (cc) and washout enhancement proportion (%) were associated with L/N ratio (p = 0.007 and p = 0.024, respectively).@*CONCLUSION@#There was a correlation between the semi-quantitative L/N ratio in BSGI and DCE-MRI parameters assessed by a computer-aided evaluation program for breast cancer.

Correlations between Tumor to Background Ratio on Breast-Specific Gamma Imaging and Prognostic Factors in Breast Cancer

The purpose of this study was to investigate the correlations between tumor-to-background ratio (TBR) obtained from breast-specific gamma imaging (BSGI) and the prognostic factors of breast cancer. Sixty-seven patients with invasive ductal carcinoma who underwent preoperative BSGI were enrolled. The BSGI images were visually scored from 1 to 5 according to a breast imaging reporting and data system (BIRADS). The TBR results obtained from positive BSGI images were compared according to the following prognostic factors: tumor size; axillary lymph node metastasis; nuclear grade (NG); histologic grade (HG); subtype; Ki-67; and the expression profile of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Among 67 images, 60 were classified as a positive finding (sensitivity 89.6%). A higher TBR value was significantly correlated with tumor size ≥ 2 cm (P = 0.001), axillary lymph node metastasis (P = 0.007), high HG (P = 0.029), negative PR status (P = 0.036), and Ki-67 ≥ 14% (P = 0.007). The TBR showed a significant difference between the luminal A and non-luminal A subtypes (P = 0.007). On multivariate analysis, TBR had a high correlation with tumor size ≥ 2 cm, axillary lymph node metastasis, and negative PR status (P = 0.003, 0.048, and 0.030, respectively). A high TBR on BSGI was significantly correlated with poor prognostic factors of breast cancer. Luminal A subtype, a breast cancer subtype with more favorable prognosis, was associated with a low TBR on BSGI.

Wnt7a Deficiency Could Predict Worse Disease-Free and Overall Survival in Estrogen Receptor-Positive Breast Cancer / 한국유방암학회지

PURPOSE: Wnt7a is a glycoprotein involved in embryonic development and the progression of different types of malignant tumors. This study aimed to detect the level of Wnt7a expression in breast cancer and explore its role in the disease progression and prognosis. METHODS: A total of 258 patients diagnosed with invasive ductal carcinoma of the breast were included in this study. Using tissue microarray and immunohistochemical staining, we evaluated the association between Wnt7a expression and clinicopathological parameters, and the prognostic value of Wnt7a. RESULTS: Wnt7a expression was significantly correlated with estrogen receptor (ER) expression (odds ratio, 3.95; 95% confidence interval [CI], 1.99–7.80; p < 0.001). On univariate and multivariate analyses, loss of Wnt7a expression was associated with poor disease-free survival (DFS) (multivariate hazard ratio [HR], 9.12; 95% CI, 1.80–46.09; p=0.008), but not with poor overall survival (OS). In the ER-positive group (n=114), loss of Wnt7a expression was an independent prognostic factor for shorter DFS (multivariate HR, 13.54; 95% CI, 1.11–165.73; p=0.042) and OS (multivariate HR, 4.76; 95% CI, 1.29–17.61; p=0.019) on univariate and multivariate analyses. However, in the ER-negative group, there was no significant difference in DFS and OS according to Wnt7a expression. CONCLUSION: The loss of Wnt7a expression might be a meaningful factor in assessing DFS and OS, especially in ER-positive breast cancer.

Functional Comparison of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells as Sources of Hepatocyte-Like Cells

Pluripotent stem cells can differentiate into many cell types including mature hepatocytes, and can be used in the development of new drugs, treatment of diseases, and in basic research. In this study, we established a protocol leading to efficient hepatic differentiation, and compared the capacity to differentiate into the hepatocyte lineage of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Optimal combinations of cytokines and growth factors were added to embryoid bodies produced by both types of cell. Differentiation of the cells was assessed with optical and electron microscopes, and hepatic-specific transcripts and proteins were detected by quantitative reverse transcription polymerase chain reaction and immunocytochemistry, respectively. Both types of embryoid body produced polygonal hepatocyte-like cells accompanied by time-dependent up regulation of genes for α-fetoprotein, albumin (ALB), asialoglycoprotein1, CK8, CK18, CK19, CYP1A2, and CYP3A4, which are expressed in fetal and adult hepatocytes. Both types of cell displayed functions characteristic of mature hepatocytes such as accumulation of glycogen, secretion of ALB, and uptake of indocyanine green. And these cells are transplanted into mouse model. Our findings indicate that hESCs and hiPSCs have similar abilities to differentiate into hepatocyte in vitro using the protocol developed here, and these cells are transplantable into damaged liver.

Clinicopathological Significance of Dual-Specificity Protein Phosphatase 4 Expression in Invasive Ductal Carcinoma of the Breast / 한국유방암학회지

PURPOSE: Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen-activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. METHODS: We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. RESULTS: Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. CONCLUSION: DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer.

Increased Expression of Forkhead Box M1 Is Associated with Aggressive Phenotype and Poor Prognosis in Estrogen Receptor-Positive Breast Cancer

Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy.

High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer / 한국유방암학회지

PURPOSE: Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. METHODS: The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. RESULTS: High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. CONCLUSION: Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes.

The Glycolytic Phenotype is Correlated with Aggressiveness and Poor Prognosis in Invasive Ductal Carcinomas / 한국유방암학회지

PURPOSE: Glucose uptake and glycolytic metabolism are enhanced in cancer cells, and increased expression of glucose transporter 1 (GLUT1) has also been reported. The aim of this study was to investigate GLUT1 expression in human breast tissues and invasive ductal carcinomas. METHODS: We used tissue microarrays consisting of normal breast tissue, ductal hyperplasia, ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastases. We examined GLUT1 expression in the microarrays by immunohistochemistry, reviewed the medical records and performed a clinicopathological analysis. RESULTS: Membranous GLUT1 expression was observed in normal and tumor cells. GLUT1 expression was higher in ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastasis than in normal tissue and ductal hyperplasia (p=0.002). Of 276 invasive ductal carcinomas, 106 (38.4%) showed GLUT1 expression. GLUT1 expression was correlated with higher histologic grade (p<0.001), larger tumor size (p=0.025), absence of estrogen receptor (p<0.001), absence of progesterone receptor (p<0.001), and triple-negative phenotype (p<0.001). In univariate survival analysis, patients with GLUT1 expression had poorer overall survival and disease-free survival (p=0.017 and p=0.021, respectively, log-rank test). In multivariate survival analysis with the Cox proportional hazards model, GLUT1 expression was an independent prognostic factor of poorer overall survival and disease-free survival (p=0.017 and p=0.019, respectively). CONCLUSION: GLUT1 expression seems to play an important role in malignant transformation, and the glycolytic phenotype in invasive ductal carcinoma may indicate aggressive biological behavior and a worse prognosis.

Expression of Cyclin D1 and bcl-2 in Infiltrative Ductal Carcinoma of the Breast: Their Correlations and Clinical implications / 한국유방암학회지

PURPOSE: Cyclin D1 and bcl-2 are involved in cell proliferation and apoptosis in tumor development and are commonly expressed in breast cancer. But there are few clinical reports on the correlation between cyclin D1 and bcl-2 expression. This study was designed to analyze the correlations of cyclin D1 and bcl-2 and their clinical implications in breast cancer. METHODS: Immunohistochemical expression of cyclin D1 and bcl-2 were studied in 342 infiltrative ductal carcinoma cases and were compared with clinicopathologic parameters such as age, tumor size, histologic grade, lymph node status, p53, c-erbB2 and hormone receptors. RESULTS: Cyclin D1 expression was found in 86 of 342 cases (25.1%). Bcl-2 was positive in 227 of 342 cases (66.4%). Bcl-2 overexpression was associated with the high expression of cyclin D1 (p=0.001). Correlation was detected between both cyclin D1 and bcl-2 and hormone receptor positivity (p<0.001). There was a reverse correlation between bcl-2 and histologic grade, p53, c-erbB2. And the bcl-2 overexpression group showed better disease free survival rates at 3-year follow up. CONCLUSION: Higher expression of cyclin D1 was associated with bcl-2 overexpression. Positive estrogen receptor expression was associated with high cyclin D1 and bcl-2 expression. Bcl-2 tends to correlate with a positive clinical outcome.

The Efficacy of Enoxaparin for the Prevention of a Pulmonary Thromboembolism in a Skin-sparing Mastectomy with Immediate Reconstruction in Breast Cancer / 한국유방암학회지

PURPOSE: Performance of a skin-sparing mastectomy with immediate reconstruction provides psychological satisfaction and good cosmetic outcome for patients with breast cancer. However, this is a lengthy procedure to perform, and there is increased risk of pulmonary thromboembolism (PTE). The purpose of this study was to evaluate the efficiency of the use of low molecular weight heparins (enoxaparin) for prophylaxis against a pulmomary thromboembolism followed by mastectomy with an immediate transverse rectus abdominis myocutaneous flap (TRAM) in breast cancer. METHODS: A total of 123 patients underwent a skin-sparing mastectomy with an immediate TRAM. The "non-enoxaparin group" wore compression stockings for PTE prophylaxis and the "enoxaparin group" received enoxaparin (40 mg SC injection, once daily starting 2 hr before surgery and continuing for 6 days postoperatively) in conjunction with the use of compression stockings. Lung perfusion, inhalation scans, and serum D-dimer assays were performed on postoperative day 3. If findings were clinically suspicious or intermediate to high probability of a PTE in a lungs scan, embolism computed tomography was performed. Patients were prospectively investigated according to the clinicopathological data. We compared the incidence of PTE and hemorrhagic complications between the two groups. RESULTS: There were no significant clinicopathological differences between the two groups. Eleven patients developed a PTE (nine patients in the non-enoxaparin group and two patients in the enoxaparin group). The prevalence rate of a PTE was 17.3% and 3.2% for each group, respectively (p=0.01). One patient in the non-enoxaparin group required a second operation for bleeding control and three patients in the enoxaparin group needed transfusions. There were minor hemorrhagic complications in the enoxaparin group that improved after supportive management. CONCLUSION: Although there were minor hemorrhagic complications, enoxaparin is safe and effective in a preventing PTE in patients that undergo immediate reconstruction after a skin-sparing mastectomy.

Surgical Treatment of Mirizzi Syndrome / 한국간담췌외과학회지

BACKGROUND/AIMS: Mirizzi syndrome is a rare complication of longstanding gallstone disease which resulting in obstructive Jaundice. It is benign stricture of common hepatic duct because of stone impacted with in the cystic duct or Hartmann pouch of the gallbladder. The aim of this study is to evaluate our experience of Mirizzi syndrome and consider its surgical treatment. METHODS: During the years 1994 to 2001 at Asan medical center, 23 cases of Mirizzi syndrome were diagnosed on the basis of preoperative and postoperative findings and they were retrospectively reviewed. RESULTS: There were 12 patients with Csendes type I, 6 patients with type II, and 5 patients with Type III. Average age was 61 years (range: 31 to 83 years) For preoperative evaluation Endoscopic retrograde cholangiopancreatography (ERCP) and Ultrasonography were performed in all cases. Laparoscopic cholecystectomy was tried in 7 type I cases. 5 were successfully treated and 2 conversions were reported, all because of unclear anatomy. In 6 type II cases open cholecystrctomy, CHD repair and T tube insertion were performed. 5 patients with type III were required hepaticojejunostomy. CONCLUSIONS: High index of suspicion is required for diagnosis of Mirizzi syndrome and laparoscopic approach is permissible in specialized center especially in the case of suspected Mirizzi type I, under the recognition of biliary anatomy through preoperative imaging studies. If there is fistula or unclear anatomy, we recommend open operative techniques for the safety and the efficiency.