Byung Kyun Ko

Tumor suppressor p53 plays a key role in induction of both tristetraprolin and let-7 in human cancer cells

Tristetraprolin (TTP) and let-7 microRNA exhibit suppressive effects on cell growth through down-regulation of oncogenes. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. However, the precise mechanism of this repression is unknown. We here demonstrate that p53 stimulated by the DNA-damaging agent doxorubicin (DOX) induced the expression of TTP in cancer cells. TTP in turn increased let-7 levels through down-regulation of Lin28a. Correspondingly, cancer cells with mutations or inhibition of p53 failed to induce the expression of both TTP and let-7 on treatment with DOX. Down-regulation of TTP by small interfering RNAs attenuated the inhibitory effect of DOX on let-7 expression and cell growth. Therefore, TTP provides an important link between p53 activation induced by DNA damage and let-7 biogenesis. These novel findings provide a mechanism for the widespread decrease in TTP and let-7 and chemoresistance observed in human cancers.

Combination Chemotherapy with 5-Fluorouracil and Heptaplatin as First-line Treatment in Patients with Advanced Gastric Cancer

Heptaplatin is a recently developed platinum derivative. This agent has been reported to have a response rate of 17% as a single agent, and tolerable toxicity in the treatment of advanced gastric cancer. The aim of this study was to evaluate the efficacy and toxicity of a combination of 5-fluorouracil (5-FU) and heptaplatin in patients with advanced gastric cancer. Forty-seven chemotherapy-naive patients with advanced or recurred gastric cancer were recruited. 5-FU was administered over 120 hr by continuous intravenous infusion from day 1 to 5, at a daily dose of 1,000 mg/m2 and heptaplatin was administered over 1 hr by intravenous infusion on day 1 at 400 mg/m2, and this cycle was repeated every 4 weeks. The response rate was 21%, median progression-free survival was 1.9 months (95% CI, 1.6 to 2.2 months). Median overall survival was 6.2 months (95% CI, 4 to 8.4 months) and the 1-yr survival rate was 29% for all patients. The most frequent toxicity was proteinuria. Toxicities were generally mild and reversible. This study demonstrates that the combination of 5-FU/heptaplatin combination is less active but tolerated in patients with advance gastric cancer.

Effect of Axillary Lymph Node Dissection after Sentinel Lymph Node Biopsy on Overall Survival in Patients with T1 or T2 Node-positive Breast Cancer: Report from the Korean Breast Cancer Society

BackgroundThe effect of axillary lymph node dissection (ALND) after sentinel lymph node biopsy (SLNB) in patients with clinically node-negative patients in preoperative evaluations on overall survival (OS) is uncertain. The study aimed to evaluate the difference of survival between node-positive patients who underwent SLNB alone and those who received ALND after SLNB using the Korean Breast Cancer Society registry.MethodsWe enrolled 2,581 patients who met the eligibility criteria. All enrolled patients had T1 or T2 breast cancer, and received mastectomy or breast-conserving treatment followed by documented adjuvant systemic therapy.ResultsThere were 197 patients with SLNB alone and 2,384 patients with ALND after SLNB. Smaller tumor size, lower number of nodal metastasis, and higher proportion of breast-conserving surgery were found in patients with SLNB alone than in those with ALND after SLNB. There was no significant difference in OS between the two groups by the log-rank test. ALND after SLNB showed no significant improvement in OS in multivariate analysis.ConclusionsALND in patients with sentinel metastasis who have T1 or T2 breast cancer receiving adjuvant systemic therapy may not have improved OS.

A comparison of the clinical outcomes of patients with invasive lobular carcinoma and invasive ductal carcinoma of the breast according to molecular subtype in a Korean population

BackgroundTo investigate the clinicopathological characteristics and the survival outcomes of invasive lobular carcinoma (ILC) patients compared to invasive ductal carcinoma (IDC) patients according to their molecular subtype.MethodsWe compared the clinicopathological characteristics, breast cancer-specific survival (BCSS) and overall survival (OS) between patients with IDC (n = 14,547) and ILC (n = 528).ResultsThe ILC presented with a larger tumor size, more advanced cancer stage, increased rate of hormonal receptor positivity, human epidermal growth factor 2 (HER2) negativity and mastectomy than the IDC. The ILC patients more frequently presented with the luminal A subtype, whereas the IDC patients more frequently presented with the luminal B, HER2-overexpression, or triple negative subtype. The BCSS and OS were not significantly different between the IDC and ILC for each molecular subtype.ConclusionsSimilar to IDC patients, molecular subtype should be considered when determining the prognosis and treatment regimen for ILC patients.

TTP mediates cisplatin-induced apoptosis of head and neck cancer cells by down-regulating the expression of Bcl-2

Abstract The chemotherapeutic agent cisplatin is widely used for treatment of head and neck squamous cell carcinoma (HNSCC). B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein that is overexpressed in cancer cells and confers resistance to cisplatin. Thus, inhibition of Bcl-2 expression may enhance the cisplatin sensitivity of cancer cells. In this study, we report that the AU-rich element (ARE) binding protein tristetraprolin (TTP) inhibits the expression of Bcl-2 and enhances cisplatin sensitivity of HNSCC cells. Cisplatin-sensitive HNSCC cells express high levels of TTP and low levels of Bcl-2, while cisplatin-resistant HNSCC cells have low levels of TTP and high levels of Bcl-2. Inhibition of TTP expression using siRNA increases levels of Bcl-2 and decreases cisplatin sensitivity in HNSCC cells. On the contrary, overexpression of TTP decreases Bcl-2 expression and increases sensitivity to cisplatin. Together, the results of the present study suggest that TTP expression enhances cisplatin sensitivity in HNSCC cells by reducing levels of Bcl-2.

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

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.

Characterization of Korean Male Breast Cancer Using an Online Nationwide Breast-Cancer Database: Matched-Pair Analysis of Patients With Female Breast Cancer

AbstractThe aim of this study is to review the characteristics and the survival rate in male breast cancer (MBC) patients in Korea over a 31-year period. Additionally, we analyzed the overall survival (OS) rate of a group of MBC matched to females with breast cancer.We retrospectively analyzed the data from 400 Korean patients who were treated for MBC from 1978 to 2009. Patient demographics and clinical information were routinely documented throughout the study period. Survival and prognostic factors were evaluated. Each MBC patient was matched with 5 female breast cancer (FBC) patients based on 7 characteristics and we compared the OS rates between the 2 groups.For MBC cases, the median follow-up was 72 months and the 5-year OS rate was 85.9%. In univariate analyses, the prognostic factors influencing OS were age (more than 60 years, P <0.001), tumor size (>2 cm, P = 0.007), and having a negative progesterone receptor (PR) status (P = 0.042). Only the age (P = 0.028) and tumor size (P = 0.024) were significant prognostic factors for OS in multivariate analysis. After matching, we had 260 male patients matched to 1300 female patients for analysis. Compared with cases among females, the rate of mastectomy was higher among MBC cases and tumors, which were almost invasive ductal carcinomas (IDCs), were more likely to be located in the central part of the breast. For MBC cases, the percentage of adjuvant radiation therapy was low compared with female cases. The primary hormone therapy agent used was tamoxifen. The 5-year OS rates were similar in MBC compared with FBC (91.0% vs. 92.6%, P = 0.300).We found that only the age (more than 60 years) and tumor size were independent prognostic factors of survival in MBC. The prognosis for MBC is similar to that for FBC given similar stage and hormone-receptor status.

Triple Negative Breast Cancer Has a Worse Prognosis within 3 Years after Treatment Compared to Non-Triple Negative Breast Cancer.

Background Triple negative breast cancers (TNBC) become known as poor prognosis generally. Our purpose was to compare the clinical features and outcomes for TNBC with other subtypes of breast cancers in Korea. Methods We included 2,907 patients who diagnosed breast cancer and treated at Asan Medical Center from 2003 to 2005. Clinical and pathologic parameters, disease-free survival (DFS) and overall survival (OS) were compared between patients with TNBC and non-TNBC. All features were reviewed throughout medical records retrospectively. Results 622 patients (21.4%) had TNBC. TNBC patients was associated with younger age, larger size, positive nodal involvement, overweight, family history, elevation of CaAg15-3, high tumor grade, positive p53 compared non-TNBC. The patients were followed for a median of 54 months (range 1-76 months). Relapse-free survival was 86.3% and 92.6% for TNBC and non-TNBC, respectively, with significant difference (P Conclusions TNBC has a worse prognosis than non-TNBC patients, but this effect is limited within 3 years after diagnosis. The most competent prognostic factor of recurrence and death for TNBC is a nodal status. We plan that perform analysis for prognosis according to hormone receptor and HER-2 receptor status sooner. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4044.

Spindle epithelial tumor with thymus-like differentiation of the thyroid in a 70-year-old man

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland mostly occurring in young patients. The imaging findings of SETTLE tumors are yet to be defined. However, they are usually described as well-defined heterogeneously enhanced masses on CT scan. The current case has the potential growth as compared with a 2009 chest radiography. We took into account the possibility of SETTLE in the case of a bulky mass in patients over 70 years old, particularly in the lower neck. Herein, we report a case of the oldest patient so far. The patient underwent a right lobectomy of the thyroid and mass excision. Follow-up CT scans after 6 months revealed no local recurrence. Surgery is the gold standard treatment for SETTLE. Chemotherapy and radiotherapy could be another possible option for patients with advanced stage SETTLE.

Clinical implication of subcategorizing T2 category into T2a and T2b in TNM staging of breast cancer

Regarding TNM staging in breast cancer, T2 category is currently not divided into subcategories even though it covers a wider range of tumor sizes than T1 category. Using Korean Breast Cancer Registry database, data of 41 071 women diagnosed as non‐metastatic T2 breast cancer between 2001 and 2014 were analyzed. Cutoff value for optimal tumor size was approximated by receiver operating characteristic (ROC) curve to subcategorize T2 tumors. Overall survival (OS) was compared between two subcategories. Median follow‐up period was 65 months. Of 41 071 patients, 4504 (11.0%) died. Based on ROC curve analysis, 3.0 cm was selected as the cutoff value. Five‐year OS rate was 91% in patients with breast tumors ≤3.0 cm (T2a) and 86% in patients with breast tumors >3.0 cm (T2b) (log‐rank P < 0.001). T2b subcategory showed worse OS than T2a subcategory regardless of node status (log‐rank P < 0.001 for all node categories). Within every subgroup defined by primary OS analysis covariates, T2b subcategory consistently showed worse outcome compared to T2a subcategory. By multivariate analysis, T2b subcategory was a significant independent prognostic factor of OS (hazard ratio: 1.26, 95% CI = 1.18‐1.34). T2 category of breast cancer could be subcategorized into T2a and T2b with a cutoff value of 3 cm. These subcategories definitely showed different OSs even after adjusted for known prognostic factors. Subcategorization of T2 category might be useful for predicting prognosis more accurately and tailoring adjuvant therapy.