Ye Won Jeon

Synergistic effect between celecoxib and luteolin is dependent on estrogen receptor in human breast cancer cells

The anti-cancer effects of celecoxib and luteolin are well known. Although our previous study demonstrated that the combination of celecoxib and luteolin synergistically inhibits breast tumor growth compared with each of the treatments alone, we did not uncover the molecular mechanisms of these effects. The aims of our present study were to compare the effects of a celecoxib and luteolin combination treatment in four different human breast cell lines and to determine the mechanisms of action in vitro and in vivo. The synergistic effects of a celecoxib and luteolin combination treatment yielded significantly greater cell growth inhibition in all four breast cancer cell lines compared with the single agents alone. In particular, combined celecoxib and luteolin treatment significantly decreased the growth of MDA-MB-231 cancer cells in vivo compared with either agent alone. The celecoxib and luteolin combination treatment induced synergistic effects via Akt inactivation and extracellular signal-regulated kinase (ERK) signaling inhibition in MCF-7 and MCF7/HER18 cells and via Akt inactivation and ERK signaling activation in MDA-MB-231 and SkBr3 cells. These results demonstrate the synergistic anti-tumor effect of the celecoxib and luteolin combination treatment in different four breast cancer cell lines, thus introducing the possibility of this combination as a new treatment modality.

Association Between Alterations in the Serum 25-Hydroxyvitamin D Status During Follow-Up and Breast Cancer Patient Prognosis

BACKGROUND Serum vitamin D status can affect the prognosis of breast cancer patients. Our aim was to determine the association between alterations in the 25-hydroxyvitamin D [25(OH)D] status during follow-up and the prognosis of breast cancer patients. Additionally, we evaluated the association between the 25(OH)D status at the time of diagnosis and the prognosis using a detailed age and stage categorization. MATERIALS AND METHODS Four hundred and sixty-nine Korean breast cancer patients were included. We collected patient clinicopathological data, including their serum 25(OH)D concentration at diagnosis and at the annual follow- up until 4 years after diagnosis. The patients were divided according to their 25(OH)D status at diagnosis into a deficient (<20 ng/ml) and a non-deficient (≥20 ng/ml) group. At follow-up, patients were categorized into the four following groups according to 25(OH)D status alterations: persistently deficient, improved, deteriorated and persistently non-deficient. RESULTS At diagnosis, 118 patients were classified into the deficient group and 351 into the non-deficient group. After a median follow-up period of 85.8±31.0 months, the patients with advanced- stage disease or an older age in the non-deficient group showed a significantly better survival compared with the deficient group. Furthermore, at the 1-year follow-up of 25(OH)D status, the persistently non-deficient group and the improved group had better survival compared with the other two groups. CONCLUSIONS Our results suggest that maintaining an optimal 25(OH)D status at diagnosis and during the 1-year follow-up period is important for improving breast cancer patient survival.

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.

The Prognostic Values of Preoperative Tumor Volume and Tumor Diameter in T1N0 Papillary Thyroid Cancer

Purpose The current TNM staging system for papillary thyroid cancer (PTC), which is based on tumor diameter, may not precisely reflect the true tumor burden. Therefore, we investigated whether preoperative tumor volume might more accurately reflect tumor burden and predict prognosis in patients with T1N0 PTC than preoperative tumor diameter. Materials and Methods We retrospectively reviewed data from 1,659 patients with T1N0 PTC, and after exclusion, a total of 1,081 patients were ultimately included. Tumor volume (V) was calculated for all patients using preoperative ultrasonography, and patients were grouped according to tumor diameter (T1a vs. T1b) and tumor volume (V1a vs. V1b). The recurrence-free survival (RFS) rates were then compared for these groups. Results The mean follow-up time was 66.12±28.75 months, and 97.2% of the cohort experienced RFS. The optimal volume cut-off was defined as 0.545 cm3. There were no differences in RFS rates between T1a/T1b groups (all ages) and V1a/V1b groups (< 45 years of age). However, ≥ 45-year-old patients in the V1b group had a significantly poorer RFS rate than those in the V1a group. These results were confirmed by multivariate analysis. Conclusion Our results indicate that preoperative tumor volume may be more useful for predicting prognosis than tumor diameter in ≥ 45-year-old patients with T1N0 PTC.

Displacement of Surgical Clips during Postoperative Radiotherapy in Breast Cancer Patients Who Received Breast-Conserving Surgery.

Purpose Surgical clips are used as a target for postoperative breast radiotherapy, and displacement of surgical clips would result in inaccurate delivery of radiation. We investigated the displacement range of surgical clips in the breast during postoperative radiotherapy following breast-conserving surgery. Methods A total of 178 patients who received breast-conserving surgery and postoperative radiation of 59.4 Gy in 33 fractions to the involved breast for 6.5 weeks were included. Surgical clips were used to mark the lumpectomy cavity during breast-conserving surgery. Patients undertook planning computed tomography (CT) scan for whole breast irradiation. Five weeks after beginning radiation, when the irradiation dose was 45 Gy, planning CT scan was performed again for a boost radiotherapy plan in all patients. The surgical clips were defined in both CT images and compared in lateromedial (X), anteroposterior (Y), superoinferior (Z), and three-dimensional directions. Results The 90th percentile of displacement of surgical clips was 5.31 mm (range, 0.0–22.2 mm) in the lateromedial direction, 7.1 mm (range, 0.0–14.2 mm) in the anteroposterior direction, and 6.0 mm (range, 0.0–10.0 mm) in the superoinferior direction. The 90th percentile of three-dimensional displacement distance was 9.8 mm (range, 0.0–28.2 mm). On the multivariate analysis, seroma ≥15 mL was the only independent factor associated with the displacement of surgical clips. In patients with seroma ≥15 mL, the 90th percentile of displacement of surgical clips was 15.1 mm in the lateromedial direction, 12.7 mm in the anteroposterior direction, 10.0 mm in the superoinferior direction, and 21.8 mm in the three-dimensional distance. Conclusion A target volume expansion of 10 mm from surgical clips may be sufficient to compensate for the displacement of clips during postoperative radiotherapy after breast-conserving surgery. For patients who had a seroma, a replanning CT scan for a boost radiation should be considered to ensure exact postoperative radiotherapy in breast cancer.

Early-Onset Breast Cancer in a Family with Neurofibromatosis Type 1 Associated with a Germline Mutation in BRCA1

Neurofibromatosis type 1 (NF1), which may occur as an autosom-al dominant disorder, is caused by the absence of neurofibromin protein due to somatic mutations in the NF1 gene, and it has been associated with an increased risk of breast cancer. Herein we describe a family with two women affected by both NF1 and early-onset breast cancer. We evaluated whether the concomitance of NF1 and early-onset breast cancer could be due to disease-causing mutations in both NF1 and BRCA1 gene in a Korean family with clinical features of both NF1 and hereditary breast cancer. Mutation analyses identified nonsense mutations in NF1 and BRCA1 genes. Our findings indicate that an awareness of the possible concomitance of NF1 and BRCA1 gene mutations is important for identifying the genetic origin of early-onset breast cancer in patients with NF1 to achieve early detection of cancers and decrease breast cancer-associated morbidity and mortality in these patients.

Synergistic anticancer effects of ruxolitinib and calcitriol in estrogen receptor‑positive, human epidermal growth factor receptor 2‑positive breast cancer cells

The Janus kinase (JAK)1 and JAK2 inhibitor, ruxolitinib, and the active form of vitamin D (calcitriol) were previously reported to possess anticancer effects in breast cancer. The present study investigated the combined effects of ruxolitinib and calcitriol on an estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, breast cancer cell line. The ER and HER2-positive MCF7-HER18 breast cancer cell line was used to investigate the combination effect of ruxolitinib and calcitriol. A bromodeoxyuridine (BrdU) assay was used to investigate cell growth inhibition. The synergism of this combination therapy was examined using the Chou-Talalay method. Cell cycle analysis was performed by flow cytometry, and apoptosis was evaluated by flow cytometry following Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining. Alterations in protein expression levels were analyzed by western blotting. The BrdU assay indicated that combination treatment using ruxolitinib and calcitriol produced a synergistic anti-proliferative effect in MCF7-HER18 breast cancer cells. Annexin V-FITC/PI staining and cell cycle analysis identified a synergistic increase in apoptosis and sub-G1 arrest in the presence of ruxolitinib and calcitriol. Western blot analysis revealed that these synergistic effects of ruxolitinib and calcitriol were associated with reduced protein levels of JAK2, phosphorylated JAK2, c-Myc proto oncogene protein, cyclin-D1, apoptosis regulator Bcl-2 and Bcl-2-like protein 1, and with increased levels of caspase-3 and Bcl-2-associated agonist of cell death proteins. The results of the present study demonstrated the synergistic anticancer effects of ruxolitinib and calcitriol in ER and HER2-positive MCF7-HER18 breast cancer cells. Based on these findings, ruxolitinib and calcitriol may have potential as a combination therapy for patients with ER and HER2-positive breast cancer.

The effect of adjuvant chemotherapy on survival in Korean patients with node negative T1c, triple negative breast cancer

Background The present study investigated the prognostic role of adjuvant systemic chemotherapy in patients with node negative, T1c triple negative breast cancer (TNBC) from a nationwide cohort. In addition, the prognostic effect between 3 different chemotherapy regimens were compared in node-negative T1c TNBC patients by subgroup analysis. Methods From the Korean breast cancer registry database, 1,151 T1c node negative TNBC patients were included in this study. Patients were categorized into four treatment groups according to chemotherapy regimen: (1) no chemotherapy, (2) adriamycin plus cyclophosphamide (AC), (3) adriamycin/epirubicin plus cyclophosphamide plus 5-FU (FAC/FEC), and (4) cyclophosphamide plus 5-FU plus methotrexate (CMF). Overall survival (OS) was evaluated between each patient group. Results Of the 1,151 T1c node negative TNBC patients, 1,006 received adjuvant chemotherapy, while 145 received no chemotherapy. Among the patients receiving adjuvant chemotherapy the distribution of regimens was: 586 AC, 168 FAC/FEC (126 FAC, 42 FEC), and 252 CMF. The mean follow-up time of the full study cohort was 87.98 ± 33.56 months (range = 6–192 months). Patients in the no chemotherapy group showed significantly worse OS compared to each chemotherapy regimen group. However, when OS was compared between each chemotherapy regimen, no significant difference was found. Conclusions This study showed that adjuvant systemic chemotherapy improved OS in T1c node negative TNBC patients, regardless of chemotherapy between AC, FAC/FEC, and CMF regimens.

A Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Docetaxel and Gemcitabine in Locally Advanced Breast Cancer

Purpose The current multicenter phase II study was conducted to evaluate the efficacy and safety of the combination of docetaxel and gemcitabine as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer. Methods A total of 98 patients with stage II–III breast cancer were enrolled. The primary endpoint was pathological complete response (pCR) rate of invasive cancer after the completion of the fourth cycle of NAC. The secondary endpoints included response rate (RR), rate of breast-conserving surgery, toxicity, and disease-free survival (DFS). This study is registered with ClinicalTrials.gov (NCT01352494). Results pCR in the breast and the axillary lymph node was observed in seven of the 98 enrolled patients (7.1%). The overall clinical RR, including partial responses, was 65.3%. Breast-conserving surgery was performed in 75 of the 98 assessable patients (76.5%). Neutropenia was frequent and was observed in 92 of the 98 patients (93.9%), including grade 3 and 4 in 24 patients (24.5%) and 63 patients (64.3%), respectively. Dose reductions were required for 30 of the 92 patients (32.6%). After a median follow-up of 24 months, the overall DFS of the group was 86.7%. Conclusion The combination of docetaxel and gemcitabine did not improve pCR. However, this regimen has shown potential as a NAC by producing a reasonable rate of breast-conserving surgery and favorable responses in patients with locally advanced breast cancer. The therapeutic efficacy of this regimen will be determined in additional trials to overcome the limitations of the current study.