Geumhee Gwak

Topoisomerase II-alpha gene deletion is not frequent as its amplification in breast cancer

SummaryTopoisomerase II-alpha (TOP2A) has been investigated as a potential predictor for the response to doxorubicin-based chemotherapy which is a representative TOP2A inhibitor and one of the most effective chemotherapeutics for the breast cancer treatment. We performed the assay for the TOP2A gene amplification and deletion on a tissue microarray (TMA) of 284 breast tumor samples from the patients treated by doxorubicin-based adjuvant chemotherapy. TOP2A gene was deleted in six patients (2.1%), whereas TOP2A gene was amplified in 20 (7.1%) of 284 tumors. Twenty-four of 26 TOP2A amplifications and deletions were associated with HER2 co-amplification. TOP2A amplification or deletion was not associated with poor clinical outcome. Nine (34.6%) of 26 patients with TOP2A amplification or deletion had recurrent disease. Thirty percent of the patients with TOP2A amplification had systemic recurrence whereas 50% of the patients with TOP2A deletion had systemic recurrence. On multivariate analysis, histologic grade and tumor size were the significant predictors for the disease-free survival and histologic grade was an only significant predictor for the overall survival. Our study indicates that response to the doxorubicin-based chemotherapy might be stratified by TOP2A amplification and deletion. However, relative low frequency of TOP2A genetic changes seems to hamper its clinical utility.

Silver-Enhanced In Situ Hybridization as an Alternative to Fluorescence In Situ Hybridization for Assaying HER2 Amplification in Clinical Breast Cancer

Purpose Valid determination of HER2 status is a prerequisite to establish an adequate treatment strategy for breast cancer patients, regardless of the disease stage. The goal of this study was to examine the feasibility of the newly developed silver-enhanced in situ hybridization (SISH) technique as an alternative to fluorescence in situ hybridization (FISH) for HER2 assay in primary invasive breast cancer. Methods FISH and SISH for HER2 amplification were performed using tissue microarray. Both methods were used in 257 consecutive primary breast cancers. Results HER2 amplification was observed in 62 (23.1%) of a total of 257 breast cancers based on SISH. Of the 257 breast cancers measured using both methods, the results of the two methods were consistent in 248 (concordance, 96.5%; kappa=0.903). When we compared HER2 amplification in the primary tumor with the metastatic lymph nodes of the same patients, HER2 amplification was observed in nine cases (14.0%) out of 64 cases in which HER2 was not amplified in the primary tumors. In contrast, HER2 status was completely preserved in metastatic lymph nodes showing HER2 amplification in the primary tumor. Conclusion These results indicate that SISH can be a feasible alternative to FISH in the clinical setting. In node-positive breast cancer, confirmation of the HER2 status of the metastatic lymph nodes appears to be mandatory, regardless of the HER2 status of the primary tumors.

Analysis of the Potent Prognostic Factors in Luminal-Type Breast Cancer

Purpose Luminal-type breast cancer has a good prognosis compared to other types, such as human epidermal growth factor receptor 2 and triple negative types. Luminal-type breast cancer is classified into luminal A and B, according to the proliferation index. We investigated the clinicopathological factors that affect the prognosis of the luminal-type subgroups. Methods We reviewed the medical records and the pathologic reports of 159 luminal-type breast cancer patients who were treated between February 2005 and November 2007. We divided luminal-type breast cancer into luminal A and B, according to Ki-67 (cutoff value, 14%) and analyzed the clinicopathologic factors, such as age at diagnosis, intensity score of estrogen receptor and progesterone receptor, histologic grade, and Bcl-2. Moreover, we compared the disease-free survival (DFS) of each group. Results In the univariate analysis, age (p=0.004), tumor size (p=0.010), lymph node metastasis (p=0.001), and Bcl-2 (p=0.002) were statistically significant factors in luminal-type breast cancer. In the multivariate analysis, lymph node (p=0.049) and Bcl-2 (p=0.034) were significant relevant factors in luminal-type breast cancer. In the subgroup analysis, the increased Bcl-2 (cutoff value, 33%) was related with a longer DFS in the luminal B group (p=0.004). Conclusion In our study, luminal A breast cancer showed a longer DFS than luminal B breast cancer, further, Bcl-2 may be a potent prognostic factor in luminal-type breast cancer.

Comparison of 6 cycles versus 4 cycles of neoadjuvant epirubicin plus docetaxel chemotherapy in stages II and III breast cancer

BACKGROUND This phase III clinical study was designed to investigate whether 6 cycles of epirubicin plus docetaxel (ED) is more effective than 4 cycles of ED as neoadjuvant chemotherapy (NC) in patients with stage II or III breast cancer. PATIENTS AND METHODS Women with breast cancer that had tumors larger than 3 cm were prospectively randomized to receive 4 or 6 cycles of epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2) every 3 weeks. The primary end point was the clinical response to NC. RESULTS A total of 176 patients were randomly assigned, and 150 patients were assessable for efficacy and toxicity. Groups were well balanced for clinicopathologic parameters. The median age was 42 years (range 30-58). Overall clinical response was observed in 72% with ED4 and 82% with ED6. pCR was observed in 11% with ED4 and in 24% with ED6 (p=0.047). 47% of the ED4 group underwent breast conserving surgery (BCS) whereas 58% of ED6 group underwent BCS. Grade 3/4 neutropenia was observed in 27% in ED4 and 31% in ED6. Febrile neutropenia occurred in 17% with ED4 and 19% with ED6. Grade 3 mucositis was observed in 8% with ED4 and in 6% with ED6. CONCLUSION Six cycles of ED enhanced the rates of pCR and BCS compared with 4 cycles without increasing treatment-related toxicities.

Prognostic Significance of a Micropapillary Pattern in Pure Mucinous Carcinoma of the Breast: Comparative Analysis with Micropapillary Carcinoma

Background Mucinous carcinoma of the breast is an indolent tumors with a favorable prognosis; however, micropapillary features tend to lead to aggressive behavior. Thus, mucinous carcinoma and micropapillary carcinoma exhibit contrasting biologic behaviors. Here, we review invasive mucinous carcinoma with a focus on micropapillary features and correlations with clinicopathological factors. Methods A total of 64 patients with invasive breast cancer with mucinous or micropapillary features were enrolled in the study. Of 36 pure mucinous carcinomas, 17 (47.2%) had micropapillary features and were termed mucinous carcinoma with micropapillary features (MUMPC), and 19 (52.8%) had no micropapillary features and were termed mucinous carcinoma without micropapillary features. MUMPC were compared with 15 invasive micropapillary carcinomas (IMPC) and 13 invasive ductal and micropapillary carcinomas (IDMPC). Results The clinicopathological factors of pure mucinous carcinoma and MUMPC were not significantly different. In contrast to IMPC and IDMPC, MUMPC had a low nuclear grade, lower mitotic rate, higher expression of hormone receptors, negative human epidermal growth factor receptor 2 (HER2) status, lower Ki-67 proliferating index, and less frequent lymph node metastasis (p < .05). According to univariate analyses, progesterone receptor, HER2, T-stage, and lymph node metastasis were significant risk factors for overall survival; however, only T-stage remained significant in a multivariate analysis (p < .05). Conclusions In contrast to IMPC and IDMPC, the micropapillary pattern in mucinous carcinoma does not contribute to aggressive behavior. However, further analysis of a larger series of patients is required to clarify the prognostic significance of micropapillary patterns in mucinous carcinoma of the breast.

Different Effects of Orbital Shear Stress on Vascular Endothelial Cells: Comparison with the Results of In Vivo Study with Rats

Purpose: An attempt was made to characterize the orbital shear stress by comparing the effects of orbital shear stress on vascular endothelial cells (ECs) with the results of animal experiments. Materials and Methods: In the laboratory study, cultured ECs of well were distinguished by center and periphery then exposed to orbital shear stress using an orbital shaker. In the animal study, arteriovenous (AV) fistulas were made at the right femoral arteries of Sprague-Dawley rats to increase the effect of the laminar flow. The condition of the stenosis was given on the left femoral arteries. The protein expression of inducible nitric oxide synthase (iNOS) and Akt phosphorylation were observed and compared. Results: Under orbital shear stress, ECs showed an increase in iNOS protein expression and phosphorylation of Akt but most of the protein expressions derived from the periphery. When compared to the animal study, the increased expression of iNOS protein and phosphorylation of Akt were observed in the sample of AV fistula conditions and the iNOS protein expression was decreased in the stenosis conditions. Conclusion: Orbital shear stress did not show the characteristics of a pure turbulent shear force. By comparing the observation with the morphological changes of vascular ECs and site-specific protein expression on the results of animal experiments, uniform directional lamina shear stress forces were expressed at the periphery.

Comparison of Doxorubicin Plus Docetaxel Neoadjuvant Chemotherapy with Doxorubicin Plus Vinorelbine in Primary Breast Cancer

Purpose This study was performed to compare the therapeutic efficacy and toxicity of doxorubicin plus docetaxel neoadjuvant chemotherapy (NC) with doxorubicin plus vinorelbine NC. Methods Fifty-three patients underwent 4 cycles of NC consisted of intravenous injection of doxorubicin (50 mg/m2) plus docetaxel (75 mg/m2) administered every 3 weeks (AD), while 49 patients underwent 4 cycles of NC consisted of intravenous injection of doxorubicin (50 mg/m2) and vinorelbine (25 mg/m2) administered every 3 weeks (AN). Response rate and treatment-related toxicities were analyzed by administered chemotherapeutics. Response to NC was also analyzed according to clinicobiological characteristics of the primary tumors. Results Clinical response was observed in 66% with AN and 81.6% with AD chemotherapy. A complete pathologic response (pCR) was confirmed in 6 patients (11.3%) with AN and in 7 patients (14.3%) with AD after the surgery. Response rate was significantly higher in AD compared with AN (p=0.038), but there was no significant difference between the two group regard to pCR rate. Breast conserving surgery (BCS) was performed in 35.8% of AN group, whereas 20 patients (40.8%) of AD group underwent BCS. The patients with HER2-amplified tumor showed significantly increased response to both types of NC. Pathologic complete response was confirmed in 9 (39.1%) out of 23 HER2-amplified tumors, whereas only 4 (5.1%) of 79 HER2-nonamplified tumors showed pathologic complete response. Febrile neutropenia occurred in 22.6% of total 212 cycles in AN and 38.8% of total 196 cycles in AD. Grade 3/4 neutropenia was observed in 39.6% in AN and 43.9% in AD. Grade 3 mucositis was observed in 26.4% with AN and in 40.8% with AD. Conclusion There was no significant increase of pCR by AD compared with AN. Long-term follow-up results of our study indicate that clinical outcome after NC was significantly associated with initial response to NC regardless of therapeutic regimens.

Predictors of Recurrent Ductal Carcinoma In Situ after Breast-Conserving Surgery

Purpose Local recurrence is a major concern in patients who have undergone surgery for ductal carcinoma in situ (DCIS). The present study assessed whether the expression levels of hormone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as resection margin status, tumor grade, age at diagnosis, and adjuvant hormonal therapy and radiotherapy (RT) are associated with recurrence in women with DCIS. Methods In total, 111 patients with DCIS were included in the present study. The invasive and noninvasive recurrence events were recorded. The clinicopathological features; resection margins; administration of hormonal therapy and RT; expression statuses of estrogen receptor (ER), progesterone receptor (PR), and HER2; Ki-67 expression; and molecular subtypes were evaluated. Logistic regression analysis was performed to examine the risk factors for recurrence. Results Recurrence was noted in 27 of 111 cases (24.3%). Involvement of resection margins, low tumor grade, high Ki-67 expression, and RT were independently associated with an increase in the recurrence rate (p<0.05, Pearson chi-square test). The recurrence rate was not significantly associated with patient age; ER, PR, and HER2 statuses; molecular subtype; and hormonal therapy. Conclusion The results of the present study suggested that the involvement of resection margins, low tumor grade, high Ki-67 index, and the absence of adjuvant RT were independently associated with increased recurrence in patients with DCIS. Future studies should be conducted in a larger cohort of patients to further improve the identification of patients at high-risk for DCIS recurrence.

Comparison of Compliance of Adjuvant Chemotherapy Between Laparoscopic and Open Surgery in Patients With Colon Cancer

Purpose Many studies have shown that the completion of adjuvant chemotherapy improves the survival rate. Recently, laparoscopic surgery has been used to treat patients with colon cancer. We analyzed the relationship between the completion of adjuvant chemotherapy and the operation method. Methods We retrospectively analyzed the medical records of 147 patients diagnosed with colon cancer from January 1, 2009, to May 31, 2012. The numbers of patients who underwent laparoscopic and open surgery were 91 and 56, respectively. We analyzed the relationship between the operation method and various factors such as the completion rate of chemotherapy, the patients age, gender, and physical activity, the postoperative hospital stay, the start time of chemotherapy, and the patients body mass index (BMI), TNM stage, and type of health insurance. Results In the laparoscopic surgery group, the postoperative hospital stay (13.5 ± 14.82 days vs. 19.6 ± 11.38 days, P = 0.001) and start time of chemotherapy (17.7 ± 17.48 days vs. 23.0 ± 15.00 days, P = 0.044) were shorter, but the percent complete of chemotherapy (71/91 [78.0%] vs. 38/56 [67.8%], P = 0.121), and survival rate (88/91 [96.7%], 47/56 [83.9%], P = 0.007) were higher than they were in the open surgery group. Patients who were elderly, had a low BMI, and a high American Society of Anesthesiologists score were less likely to complete adjuvant chemotherapy than other patients were. Conclusion Laparoscopic surgery shows a shorter postoperative hospital stay, a shorter start time of chemotherapy, and a higher survival rate. Laparoscopic surgery may be expected to increase compliance of chemotherapy and to improve survival rate.

Risk Factors of a Pulmonary Thromboembolism After Colorectal Surgery

Purpose Previous studies have revealed that predictors and risk factors of pulmonary thromboembolism (PTE) are malignancy, immobilization, diabetes, and obesity in the postoperative patients. However, in patients undergoing colorectal cancer, studies of PTE have not been enough. Thus, we investigated the risk factors of PTE related to colorectal surgery. Methods From January 2009 to October 2014, 312 patients received colorectal surgery without other organ resection. The postoperative patients with PTE were 14 (4.5%), and they were classified by sex, age, and stage as a 1:3 paired match to the control group. A multiple logistic regression was performed to identify which factors were associated with PTE. Results One patient was in stage I, 3 in stage II, 9 in stage III, and 1 in stage IV. In the binary logistic regression analysis, history of diabetes mellitus (odds ratio, 6.498; P = 0.031) and being overweight (odds ratio, 10.018; P = 0.014) were independent risk factors for PTE in patients undergoing colorectal cancer. Conclusion A history of diabetes mellitus and being overweight were independent risk factors of PTE after colorectal cancer.