Inhibition of tamoxifen's therapeutic effects by emodin in estrogen receptor-positive breast cancer cell lines

PURPOSE: This study was aimed to investigate the combination effect of endoxifen and emodin on estrogen receptor (ER) positive breast cancer cell lines and to explain the mechanism of the combination effect. METHODS: We conducted this study on MCF-7 (ER+/human epidermal growth factor receptor-2 [HER2]−), T47D (ER+/HER2−), ZR-75-1 (ER+/HER2+), and BT474 (ER+/HER2+) cell lines, which confirmed combination effect of endoxifen and emodin. Optimal concentrations for combination were determined to study the effects on proliferation of MCF-7 and ZR-75-1 cells. Analysis of the combination effect was carried out in the CompuSyn software. The combination of downstream mechanisms, and combined effects of other similar compounds were tested on the MCF-7 and ZR 75-1 cell lines. Protein expression was confirmed by western blot. RESULTS: The combination of endoxifen and emodin had antagonistic effects on MCF-7 and ZR-75-1cell lines (combination index > 1). We validated the antagonistic effect in T47D and BT474 cell lines. During the combined treatment, the results showed elevated amounts of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK). Analysis of drug interactions showed antagonistic effect between endoxifen and chemical compounds similar to emodin, such as chrysophanol or rhein, in MCF-7 and ZR-75-1 cells. CONCLUSION: Addition of emodin attenuated tamoxifen's treatment effect via cyclin D1 and pERK up-regulation in ER-positive breast cancer cell lines.

Factors Associated with Metastatic Breast Cancer in Patients Who Show Long-Term Stable Disease Status

PURPOSE: This study aimed to analyze the basic clinical characteristics and survival of patients with breast cancer whose disease had been stably maintained for more than 24 months after systemic therapy. METHODS: We retrospectively reviewed the medical records of patients with primary breast cancer who underwent surgery. Among these patients, patients with stage IV disease at diagnosis or those who developed distant metastasis during the follow-up period after surgery were included in this analysis. Patients whose disease remained stable for more than 24 months were classified as the long-term stable disease group. The remaining patients were classified as the control group. RESULTS: A total of 245 patients were eligible for this analysis. Patients in the long-term stable disease group showed a lower rate of histologic type III, a higher rate of hormone receptor positivity, and received less adjuvant chemotherapy. In the long-term stable disease group, the most frequent site of metastasis was the lungs, whereas in the control group, it was the bones. Overall survival was significantly better in the long-term stable disease group than in the control group (p<0.001). In univariate analysis, factors affecting the overall survival rate were the duration from diagnosis to metastasis, the absence of lymphatic infiltration, and the presence of hormone receptors. In multivariate analysis, the duration from diagnosis to metastasis and the absence of lymphatic infiltration were significant factors affecting the overall survival rate. CONCLUSION: Disease progression was observed in many patients even after the disease had been stable for more than 24 months after systemic therapy. Although these patients had better outcomes compared with the others, continuous observation and possible additional treatment might be helpful for some patients.

Clinicopathologic Characteristics of Pregnancy-Associated Breast Cancer: Results of Analysis of a Nationwide Breast Cancer Registry Database / 한국유방암학회지

PURPOSE: This study aimed to evaluate the clinicopathological characteristics of pregnancy-associated breast cancer (PABC) in comparison with non-pregnancy associated breast cancer (non-PABC). METHODS: A total of 344 eligible patients with PABC were identified in the Korean Breast Cancer Society Registry database. PABC was defined as ductal carcinoma in situ, invasive ductal carcinoma, or invasive lobular carcinoma diagnosed during pregnancy or within 1 year after the birth of a child. Patients with non-PABC were selected from the same database using a 1:2 matching method. The matching variables were operation, age, and initial stage. RESULTS: Patients with PABC had significantly lower survival rates than patient with non-PABC (10-year survival rate: PABC, 76.4%; non-PABC, 85.1%; p=0.011). PABC patients had higher histologic grade and were more frequently hormone receptor negative than non-PABC patients. Being overweight (body mass index [BMI], ≥23 kg/m²), early menarche (≤13 years), late age at first childbirth (≥30 years), and a family history of breast cancer were more common in the PABC group than in the non-PABC group. Multivariate analysis showed the following factors to be significantly associated with PABC (vs. non-PABC): early menarche (odds ratio [OR], 2.165; 95% confidence interval [CI], 1.566–2.994; p<0.001), late age at first childbirth (OR, 2.446; 95% CI, 1.722–3.473; p<0.001), and being overweight (OR, 1.389; 95% CI, 1.007–1.917; p=0.045). CONCLUSION: Early menarche, late age at first childbirth, and BMI ≥23 kg/m² were more associated with PABC than non-PABC.

The Molecular Subtype Dependent Effect of Concurrent Radiotherapy and Systemic Therapy on Breast Cancer: Analysis of a Human In Vivo Model of Metastatic Brain Lesions

PURPOSE: The molecular subtype of breast cancer is an important predictive factor. Therefore, we investigated the effects of concurrent or serial radiotherapy and systemic therapy on metastatic brain lesions according to the molecular subtype of breast cancer. METHODS: The present retrospective study examined data from 66 patients with breast cancer and metastatic brain lesions, who were treated using radiotherapy between January 1990 and July 2014. Patients were classified into the following three subtypes based on their hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status: HR+/HER2− (luminal A, 13 patients), HR+/HER2+ (luminal B, 21 patients), HR−/HER2+ (HER2, 22 patients), or HR−/HER2− (triple negative, 10 patients). The brain lesions and their responses to treatment were evaluated using brain computed tomography or magnetic resonance imaging. Progression of brain disease was defined by a ≥20% increase in the sum of the lesion's diameters or the development of a new brain lesion. Progression-free survival was calculated from the initiation of radiotherapy to the first instance of brain disease progression or last follow-up. RESULTS: Patients in the HER2 group who had received concur-rent radiotherapy and systemic therapy (mainly HER2-targeted therapy) exhibited significantly better progression-free survival than did patients who had received radiotherapy followed by systemic therapy (p=0.037). However, concurrent radiotherapy and systemic therapy did not significantly improve progression-free survival in the luminal A (p=0.527), luminal B (p=0.462), or triple negative (p=0.558) groups. CONCLUSION: Concurrent radiotherapy and mainly HER2-targeted systemic therapy significantly prolonged progression-free survival in the HER2 group.

Risk Factors Associated with Distant Metastasis and Survival Outcomes in Breast Cancer Patients with Locoregional Recurrence / 한국유방암학회지

PURPOSE: To decide the optimal treatment for breast cancer patients with locoregional recurrence (LRR), it is important to determine which group has the highest risk of subsequent distant metastasis (DM). We aimed to investigate the factors associated with DM in patients with LRR. METHODS: We reviewed the data of 208 patients with LRR as the first event after primary surgery for breast cancer at our institution between 1997 and 2010, to identify significant factors associated with DM. Subsequently, Kaplan-Meier curves and the Cox regression method were used to analyze the correlation between clinical factors and survival. RESULTS: DM occurred in 33.2% (68/208) of LRR patients. The median DM-free interval was 23 months. Some clinical factors were associated with DM in univariate analysis, including the type of primary surgery (p=0.026), tumor size (p=0.005), nodal status (p=0.011), and administration of initial adjuvant chemotherapy (p=0.001). In addition, regional rather than local recurrence and a disease-free interval (DFI; duration between primary surgery and LRR) < or =30 months were also significant (p<0.001 for both). However, only a shorter DFI reached significance in multiple logistic regression analysis. Cox regression analysis of DM-free survival showed that both a shorter DFI and regional recurrence were significant factors with hazard ratios of 2.1 (95% confidence interval [CI], 1.21-3.65) and 1.85 (95% CI, 1.04-3.28), respectively. CONCLUSION: DFI was the most important factor associated with subsequent DM in patients with LRR as a first event of failure.

Survival Improvement in Korean Breast Cancer Patients Due to Increases in Early-Stage Cancers and Hormone Receptor Positive/HER2 Negative Subtypes: A Nationwide Registry-Based Study / 한국유방암학회지

PURPOSE: The aim of this study was to investigate whether the observed changes over time in the survival rates vary according to the intrinsic subtypes of breast cancer diagnosed. METHODS: Data from 46,320 breast cancer patients in the Korean Breast Cancer Registry who underwent surgery between 1999 and 2006 were reviewed. Among them, results from 25,887 patients with available data about the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were analyzed. Patients were classified into two cohorts according to the year in which they underwent surgery: 1999-2002 and 2003-2006. RESULTS: The patients treated in the latter time period showed significantly better overall survival (OS) compared with those in the former period when adjusted for follow-up duration. The proportion of hormone receptor+/HER2-subtype and stage I breast cancer were significantly higher in the latter period (47.4% vs. 54.6%, p<0.001; 31.0% vs. 39.6%, p<0.001, respectively). Improvement in OS between the former and latter periods was seen in all subtypes of breast cancer, including triple-negative cancers (all p-values <0.001 in univariate and multivariate analyses). CONCLUSION: Improvement in survival in Korean breast cancer patients over the study years is being observed in all subtypes of breast cancer, implying that increases in both early-stage detection and the proportion of less aggressive cancers contribute to this improvement.

Effects of Screening on Gastric Cancer Management: Comparative Analysis of the Results in 2006 and in 2011

PURPOSE: This study aimed to analyze the effect of screening by using endoscopy on the diagnosis and treatment of gastric cancer. MATERIALS AND METHODS: The clinicopathologic characteristics of gastric cancer were compared in individuals who underwent an endoscopy because of symptoms (non-screening group) or for screening purposes (screening group). The distributions of gastric cancer stages and treatment modalities in 2006 and 2011 were compared. RESULTS: The proportion of patients in the screening group increased from 45.1% in 2006 to 65.4% in 2011 (P<0.001). The proportion of stage I cancers in the entire patient sample also increased (from 60.5% in 2006 to 70.6% in 2011; P=0.029). In 2011, the percentages of patients with cancer stages I, II, III, and IV were 79.9%, 8.2%, 10.9%, and 1.1%, respectively, in the screening group, and 47.9%, 10.8%, 29.8%, and 11.5%, respectively, in the non-screening group. The proportion of laparoscopic and robotic surgeries increased from 9.6% in 2006 to 48.3% in 2011 (P<0.001), and endoscopic submucosal dissection increased from 9.8% in 2006 to 19.1% 2011 (P<0.001). CONCLUSIONS: The proportion of patients diagnosed with gastric cancer by using the screening program increased between 2006 and 2011. This increase was associated with a high proportion of early-stage cancer diagnoses and increased use of minimally invasive treatments.

Right Paraesophageal Lymph Node Metastasis in Papillary Thyroid Cancer and Prophylactic Dissection: A Retrospective Study / 대한내분비외과학회지

PURPOSE: The purpose of this study is to determine the status of nodal disease, including the right paraesophageal node, in papillary thyroid carcinoma (PTC). METHODS: A total of 116 patients with PTC underwent total thyroidectomy and prophylactic central node dissection, including right paraesophageal lymph nodes (RPE LNs). Metastases to RPELNs were analyzed by site and clinicopathologic variables. Recurrence rate and post-operative complications were also evaluated by comparing the right paraesophageal lymph node dissection (RPE LND) with the non-RPE LND group. RESULTS: Central node metastases were detected in 57 (49.1%) patients; paratracheal and pre-tracheal lymph node metastases, total RPE LN metastases, and metastases only in RPE LN occurred in 50 (43.1%), 18 (15.5%), and 5 (4.3%) patients, respectively. Age, tumor size, tumor longitudinal location, extrathyroidal extension, and multicentricity were insignificant in RPE LN metastasis (P>.05). Although there was no significant statistical difference, tumors with lymphatic invasion and larger tumors (>1 cm) had more frequent RPE LN metastases. RPE LN metastases were frequent in deeply located tumors instead of superficially located tumors (P=0.015). Compared with the non-RPE LND group, the incidence of post-operative complications (transient hypocalcemia and vocal cord palsy) was not significantly different and there was no recurrence in both groups during the follow up period. CONCLUSION: The metastatic rate of the right paraesophageal lymph nodes was 15.5%; 83.3% of these were macrometastatic. Prophylactic RPE dissection compared with the non-RPE LND group, however, did not show a survival difference for 5 years.