Sehsuvar Gokgoz

Response to Neoadjuvant Chemotherapy in Breast Cancer Could be Predictable by Measuring a Novel Serum Apoptosis Product, Caspase-Cleaved Cytokeratin 18: A Prospective Pilot Study

The M30-monoclonal antibody recognizes a neo-epitope of cytokeratin 18 which is formed after caspase-cleavage during apoptosis. Caspase-cleaved cytokeratin 18 is released from apoptotic cells into circulation. The aim of this study was to evaluate the relationship between M30-antigen level and chemotherapy response in neoadjuvant treatment of breast cancer. Forty-two patients with invasive breast carcinoma received 4 cycles of anthracycline based neoadjuvant chemotherapy. Serum samples were obtained for assessment of M30-antigen levels before the administration of first chemotherapy cycle (baseline), and then after 24 and 48 hours for determination of chemotherapy induced apoptosis. M30-antigen levels at 24 and 48 hours were found to be significantly higher than baseline (p < 0.001, p = 0.003, respectively). M30-antigen levels in responders showed statistically significant increases at 24 and 48 hours (p < 0.001; p = 0.004, respectively), while statistically significant increases were not observed in nonresponders. Percentage change of M30-antigen levels was significantly higher in responders than nonresponders at 24 hours (p = 0.020). In conclusion, our study revealed a significant relationship between increases of M30-antigen levels in serum and overall response to therapy.

Factors influencing axillary node metastasis in breast cancer.

Aims and Background The status of the axillary lymph nodes at the time of diagnosis has been accepted as one of the most important prognostic factors for the overall and disease-free survival of patients with breast cancer. The aim of our study was to determine which factors influence axillary node involvement in invasive breast cancer. Methods The data presented here were obtained from 344 patients who were treated for invasive breast cancer at the Department of Radiation Oncology, Uludag University Medical College, Bursa, Turkey. Possible prognostic factors were categorized as patient related and tumor related. The Mann-Whitney U test was used for univariate analysis and logistic regression was used for multivariate analysis. Results In univariate analysis, a familial cancer history (P = 0.0042), age <40 years (P = 0.0276), higher T stage (P <0.0000), nipple involvement (P = 0.0345), skin involvement (P = 0.0270), perineural invasion (P = 0.0231), and lymphatic vessel invasion (P <0.0000) were correlated with increased axillary node involvement. A higher incidence of ≥4 involved lymph nodes was associated with higher T stage (P = 0.0004), nipple involvement (P = 0.0292), presence of an extensive intraductal component (P = 0.0023), skin involvement (P = 0.0008), perineural invasion (P = 0.0523), and lymphatic vessel invasion (P <0.0000) in univariate analysis. In multivariate analysis, age <40 years (P = 0.0454), cancer history within the family (P = 0.0024), higher T stage (P = 0.0339), lymphatic vessel invasion (P = 0.0003), and perineural invasion (P = 0.0408) were found to be independent factors for axillary lymph node positivity. Age <40 years (P = 0.0221), perineural invasion (P = 0.0408), and an extensive intraductal component (P = 0.0132) were associated with an increased incidence of ≥4 involved nodes in the logistic regression analysis. In patients with breast cancer, the incidence of axillary lymph node involvement was independently influenced by age <40 years, presence of cancer history within the family, higher T stage, lymphatic vessel invasion, and perineural invasion. Conclusions In conclusion, absence of familial cancer history, presence of lymphatic vessel invasion, higher T stage, and age below 40 years independently increased the risk of axillary node involvement. Presence of perineural invasion and lymphatic vessel invasion, age below 40, and an extensive intraductal component of more than 25% independently affected the risk of having ≥4 nodes involved. Patients characterized by these factors may be classified into a higher risk group for nodal involvement, but more data are needed to define factors that can help in the decision-making regarding the omission of axillary treatment.

Carcinoma originating from aberrant breast tissue. A case report and review of the literature

Carcinoma arising from ectopic breast tissue, either supernumerary breast or aberrant breast tissue, is extremely rare. Carcinoma occurs more frequently in the ectopic breast tissue of the axilla than in extra-axillary ectopic breast tissue. Here we report a case of an invasive lobular carcinoma arising from extra-axillary ectopic breast tissue and presenting as a subcutaneous nodule.

BRCA1/2 germline mutations and their clinical importance in Turkish breast cancer patients.

BRCA1/BRCA2 genes were screened in 117 patients with breast cancer by sequencing. Fourteen percent of patients tested positive for BRCA1/BRCA2 mutations. Four frame shift mutations, four pathogenic missense mutations, and 25 different sequence variations were detected. BRCA mutation positivity was significantly associated with Ki67 (p = .001). BRCA protein expressions were decreased in the patients harboring important mutations and polymorphisms (BRCA1;P508stop, V1740G, Q1182R, Q1756P and BRCA2;V2466A) related with disease. Our findings contribute significantly to the types of germline BRCA1/BRCA2 mutations and their biological effects in Turkish women. These data could help guide the management of BRCA1/BRCA2 mutation-carrying patients when considering breast-conserving therapy.

Phase II Study of Gemcitabine Plus Paclitaxel in Metastatic Breast Cancer Patients with Prior Anthracycline Exposure

Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. Patients and Methods: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m2 was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m2 was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. Results: Objective response rate was 41.7 percent (95 percent CI: 21.9–61.4) with 16.7 percent (95 percent CI: 1.7–31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6–42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3–4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. Conclusion: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.

BRCA mutations cause reduction in miR-200c expression in triple negative breast cancer.

Triple negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer (BC). Over the recent years, miRNA expression studies have been providing certain detailed overview that aberrant expression of miRNAs is associated with TNBC. Although TNBC tumors are strongly connected with loss of function of BRCA genes, there is no knowledge about the effect of BRCA mutation status on miRNA expressions in TNBC cases. The aims of this study were to evaluate the expression profile of miRNAs that plays role in TNBC progression and the role of BRCA mutations in their regulation. The expression level of BC associated 13 miRNAs was analyzed in 7 BRCA mutations positive, 6 BRCA mutations negative TNBC cases and 20 non-tumoral tissues using RT-PCR. According to RT2 Profiler PCR Array Data Analysis, let-7a expression was 4.67 fold reduced in TNBCs as compared to normal tissues (P=0.031). In addition, miR-200c expression was 5.75 fold reduced in BRCA mutation positive TNBC tumors (P=0.005). Analysis revealed a negative correlation between miR-200c and VEGFA expressions (r=-468). Thus, miR-200c may be involved in invasion and metastasis in TNBC cases with BRCA mutation. In this study we provide the knowledge on the first report of association between microRNA-200c and BRCA mutations in TNBC. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for TNBC treatment and new directions for the development of anticancer drugs.

CK19, CK20, EGFR and HER2 status of circulating tumor cells in patients with breast cancer.

AIMS AND BACKGROUND The major cause of death in breast cancer patients is metastasis. Various biomarkers have been used for the early detection of circulating tumor cells in the peripheral blood of breast cancer patients. The aims of the current study were to analyze circulating tumor cells in the blood of breast cancer patients by investigating EGFR, CK19, CK20 and HER2 expression profiles and to evaluate their prognostic importance. METHODS CK19, CK20 and EGFR gene expression profiles were evaluated in the blood samples of 84 female patients with primary invasive ductal breast cancer and 20 healthy female volunteers using SYBR green-based real-time qPCR assays. HER2 expression analyses were conducted in 46 patients who had an HER2-positive primary tumor and in 30 healthy women to determine the cutoff level of positivity. RESULTS The positive rates of CK20, EGFR, CK19 and HER2 mRNA expression in the peripheral blood were 28.57% (24/84), 20.23% (17/84), 5.95% (5/84) and 2.17% (1/46), respectively. The high positive ratio of CK20 mRNA expression in the peripheral blood of breast cancer was identified for the first time in the current study. Significant differences were identified in CK20 expression status and several clinical parameters related with aggressiveness of tumors using a binary logistic regression analysis. Higher CK20-positive levels were observed in patients who had lymph node metastasis and advanced-grade primary tumors, which were estrogen receptor-negative. We have demonstrated that CK20 may be a novel biomarker that is useful to identify circulating tumor cells and predict breast cancer progression. CONCLUSIONS The results suggest that the investigation of CK20 mRNA with other biomarkers in the peripheral blood of breast cancer patients may be useful to monitor the presence of disseminated tumor cells in the blood circulation and to predict the prognosis of breast cancer.

Expression and clinical significance of miRNAs that may be associated with the FHIT gene in breast cancer

The dysregulation of miRNA expression has frequently been observed in breast cancer. Therefore, we investigated the expression profile of miRNAs that may be associated with expression of the FHIT gene in breast cancer and assessed their clinicopathological significance. The expression levels of miR-143, miR-663a, miR-668, miR-922 and FHIT were analyzed in normal and malignant breast tissues from 65 patients with breast cancer. We studied the correlation between the expression of miR-143, miR-663a, miR-668, miR-922 and FHIT and the clinicopathological features presented by the patients. The expression levels of the miRNAs and FHIT were downregulated in breast cancer tissue. The expression levels of miR-143, miR-663a and miR-668 were significantly reduced in FHIT downregulated tumors. miR-668 expression was also significantly altered relative to FHIT down- and up- regulated tumor tissues. Reduced miR-663a expression was statistically associated with high-grade ER/PR (+) status, benign reactive hyperplasia, lymph-node metastasis, in-situ component >25% and Ki 67>15% compared with non-tumor tissues. Additionally, reduced miR-668 expression was significantly different between tumors with and without lymph-node metastasis. miR-668 may play an important role in breast cancer development and progression by regulating the expression of FHIT. Furthermore, miR-668 and miR-663a may be potential prognostic biomarkers for breast cancer.

An extremely rare cause of gastric outlet: breast lobular carcinoma metastases to stomach.

A 47-year-old female was admitted with complaints of epigastric abdominal pain, nausea, vomiting, and weight loss that started 3 months ago. Gastroscopy evaluation revealed gastric outlet obstruction due to chronic ulceration in the pyloric region. Endoscopic biopsy samples reported chronic active inflammation. Her physical examination revealed a mobile and solid mass about 2 9 2 cm in size on the upper-outer quadrant of the left breast, and a palpable lymph node of 1.5 cm in diameter on the left axilla. Computerized contrast tomographic imaging revealed a focal density area over the upper-middle of the left breast, about 2.5 cm in diameter, and lymph nodes in the left axilla. Circumferential wall thickening at the pyloric level with distention was observed in abdominopelvic computerized tomography. Patient was operated with antrectomy-truncal vagotomy-gastroenterostomy procedure. A pathologic evaluation reported massive tumoral mass at the distal gastric localization with infiltration to periserosal adipose tissue (T3) and the local invasion pattern was similar to gastric carcinoma with primary neuroendocrine differentiation. Immunohistochemistry showed that carcinoma cells were positive for CK7, ER, PR, GCDFP-15 and Ecadherin was negative (Fig. 1). The patient underwent mastectomy operation in the same hospitalization period after she had clinically stabilized from the first operation. Modified radical mastectomy operation was performed. Pathologic evaluation demonstrated a 3 9 2 9 1.2 cm mass, which histopathologic findings correlated as lobular carcinoma. Immunohistochemical staining was positive for ER, PR, GCDFP-15, and negative for E-cadherin and cerbB2 (Fig. 2). Thirty-one metastatic lymph nodes and one benign lymph node were obtained on axillary dissection. Postoperative follow-ups were all normal and the patient was discharged at the end of the first month. Surgical oncology council opted for the patient to take chemotherapy and hormonotherapy in the postoperative period. Gastrointestinal metastases generally emerge after several years in patients with breast cancers. This period ranged from 5 to 20 years and even 30 years, after the diagnosis of primary breast cancer (26). Symptoms are generally nonspecific in patients with gastric metastasis. Metastases of lobular breast carcinoma are generally characterized by diffuse infiltration of stomach, and radiologic imaging studies may reveal linitis plastica pattern (12,13,14). Metastatic infiltration of the stomach is generally limited to the submucosa or seromuscular layer. Because of this, histopathologic diagnosis must include deep biopsies. Immunohistochemical staining of metastatic breast carcinomas is generally CK7-, GCDFP-15-, CEA-, estrogen receptor (ER)and progesterone receptor (PR)-positive, and CK-20-negative. Among gastrointestinal malignancies, only those of the gastric, colorectal, pancreatic, and transitional cell carcinomas are CK-20 positive, unlike breast carcinomas, which are all are CK-20-positive (17). Survival rates for gastrointestinal metastases of the breast are generally lower than 2 years in most patients (26). The survival rate was better in patients after Address correspondence and reprint requests to: Pinar Sarkut, MD, Department of General Surgery, Uludag University School of Medicine, 16059 Gorukle, Bursa, Turkey, or e-mail: pinartasar@gmail.com

The effect of distance on the postoperative follow-up of patients with breast carcinoma.

Abstract Purpose : To assess the effect of in or out of city residence of patients with breast carcinoma, where breast surgery unit treatment and follow-up is made postoperatively. Method : 234 patients operated on for breast carcinoma at the Breast Surgery Unit were retrospectively studied. Patients were divided into two groups; patients living in the major city where the Breast Surgery Centre is located and patients living in smaller cities, districts, towns and villages out of the city. The distance of patients’ residences from the Breast Centre has also been determined in kilometres. The number of patients and the frequency of check-up visits were compared in both groups. Results : The number of patients residing in the city centre where the Breast Unit is located was 156 (66.7%). Comparing the frequency of patients’ visits for check-up during the postoperative period, there were no differences between the two groups during the first four years. However, the patients living out of the city did not visit the Breast Unit for check-ups during the fifth postoperative year. Moreover, when the patients were classified into two groups with known and unknown outcomes, it was observed that those patients with unknown outcomes lived further away from the city where the Breast Surgery Unit was located compared to those with known outcomes (p = 0.002). Discussion : Living within or out of the major city centre where the Breast Surgery Unit is located does not have any effect on the frequency of follow-up visits or the number of patients applying for check ups during the first four years postoperatively. However, there were gradual decreases over the course of time in both groups and these differences became apparent during the 5th year. In addition to this, the distance was also found to be an important factor for patients with unknown outcomes in the present study. The combination of living outside the city where The Breast Unit was located and the distance may have a negative effect on follow-ups. There is a need for new, larger scale, studies with longer follow-ups to show how this difference will change over a longer time period.