An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer.

PURPOSE: Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. MATERIALS AND METHODS: This was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. RESULTS: Pegfilgrastim administration reduced FN by 11.8-1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. CONCLUSION: The use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

Single Cell Analysis of Human Thyroid Reveals the Transcriptional Signatures of Aging.

The thyroid gland plays a critical role in the maintenance of whole-body metabolism. However, aging frequently impairs homeostatic maintenance by thyroid hormones due to increased prevalence of subclinical hypothyroidism associated with mitochondrial dysfunction, inflammation, and fibrosis. To understand the specific aging-related changes of endocrine function in thyroid epithelial cells, we performed single-cell RNA sequencing (RNA-seq) of 54 726 cells derived from pathologically normal thyroid tissues from 7 patients who underwent thyroidectomy. Thyroid endocrine epithelial cells were clustered into 5 distinct subpopulations, and a subset of cells was found to be particularly vulnerable with aging, showing functional deterioration associated with the expression of metallothionein (MT) and major histocompatibility complex class II genes. We further validated that increased expression of MT family genes are highly correlated with thyroid gland aging in bulk RNAseq datasets. This study provides evidence that aging induces specific transcriptomic changes across multiple cell populations in the human thyroid gland.

Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence.

OBJECTIVES: Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. METHODS: This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. RESULTS: Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). CONCLUSION: We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer.

Erratum to: The current status of cancer survivorship care and a consideration of appropriate care model in Korea.

[This corrects the article on p. 110 in vol. 16.].

The current status of cancer survivorship care and a consideration of appropriate care model in Korea.

Purpose: Breast cancer patients with a human epidermal growth factor receptor 2 (HER2) enriched subtype are known to have higher rates of brain metastases (BM) than other patients. This study aimed to evaluate treatment options and survival outcomes. Methods: A total of 115 breast cancer brain metastases (BCBM) patients with nearly complete medical records were retrospectively analyzed. Additionally, 36 patients were HER2 enriched types according to histological subtypes. The BM was found by brain magnetic resonance imaging in patients who had neurologic symptoms or by regular screening. Age, breast tumor size, number of BM, histological subtypes, first treatment of breast cancer, estrogen receptor, and HER2 status, stage, local treatment of BM were analyzed. Median overall survival, 5-year survival were analyzed from the data. Results: The median survival time after BM was 6 months, the mean survival time was 16.3 months, and the 5-year survival after BM was only 8.0%. Factors that significantly affect the survival of BCBM patients include histological subtype, number of BM, use of lapatinib in multivariate analysis. A total of 19 out of 36 HER2 enriched patients were treated with lapatinib or capecitabine. For the treatment of HER2 enriched patients, additional use of blood-brain barrier (BBB) crossing substances, as well as local treatment for BM, significantly improve the survival rate in the Kaplan-Meier method (P=0.001). Conclusion: A combination of local treatment modality for BCBM and the use of substances that cross the BBB for the HER2 enriched patient improved the survival rate.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial.

PURPOSE: The addition of ovarian function suppression (OFS) for 5 years to tamoxifen (TAM) for treatment of premenopausal patients with breast cancer after completion of chemotherapy has beneficial effects on disease-free survival (DFS). This study evaluated the efficacy of adding 2 years of OFS to TAM in patients with hormone receptor-positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. PATIENTS AND METHODS: We enrolled 1,483 premenopausal women (age ≤ 45 years) with estrogen receptor-positive breast cancer treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy. Ovarian function was assessed every 6 months for 2 years since enrollment on the basis of follicular-stimulating hormone levels and vaginal bleeding history. If ovarian function was confirmed to be premenopausal at each visit, the patient was randomly assigned to complete 5 years of TAM alone (TAM-only) group or 5 years of TAM with OFS for 2 years that involved monthly goserelin administration (TAM + OFS) group. DFS was defined from the time of enrollment to the time of the first event. RESULTS: A total of 1,293 patients were randomly assigned, and 1,282 patients were eligible for analysis. The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (hazard ratio, 0.69; 95% CI, 0.48 to 0.97; P = .033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM-only group (hazard ratio, 0.31; 95% CI, 0.10 to 0.94; P = .029). CONCLUSION: The addition of 2 years of OFS to TAM significantly improved DFS compared with TAM alone in patients who remained premenopausal or resumed ovarian function after chemotherapy.

Therapeutic positioning of secretory acetylated APE1/Ref-1 requirement for suppression of tumor growth in triple-negative breast cancer in vivo.

Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a relatively large proportion of BC-related death. Thus, more effective therapeutic strategies are needed for the management of TNBC. We demonstrated that the stimulation of apoptosis by the binding of secreted acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) to the receptor for advanced glycation end products (RAGE) was essential for TNBC cell death in response to hyperacetylation. The aim of the present study was to assess the potential therapeutic efficacy of secretory Ac-APE1/Ref-1 in orthotopic TNBC xenografts in vivo. We found that hyperacetylation in xenografts caused secretion of Ac-APE1/Ref-1 into the blood, where the factor bound directly to RAGE in hyperacetylated tumor tissues. Hyperacetylation in the TNBC xenografts induced strong inhibition of tumor growth and development, leading to apoptotic cell death, accompanied by increased RAGE expression and generation of reactive oxygen species. Tissues exhibited markedly higher counts of apoptotic bodies, a reduced proliferation index, and reduced neovascularization compared with control tumors. Ac-APE1/Ref-1-stimulated apoptosis was markedly reduced in RAGE-knockdown tumors compared with RAGE-overexpressing tumors, even in the presence of hyperacetylation. The function of secreted Ac-APE1/Ref-1 was confirmed in other hyperacetylated TNBCs xenografts using BT-549 and MDA-MB-468 cells, demonstrating its relevance as an anti-cancer molecule.

The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress.

BACKGROUND: Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy. METHODS: Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event. DISCUSSION: This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00912548 . Registered May 31 2009. Korean Breast Cancer Society Study Group Register KBCSG005 . Registered October 26 2009.

A Phase II Trial of Neoadjuvant Chemotherapy with Genexol® (Paclitaxel) and Epirubicin for Locally Advanced Breast Cancer.

PURPOSE: Neoadjuvant chemotherapy (NC) is yet to be established as the definitive treatment regimen for locally advanced breast cancer (LABC). The aim of this study was to determine the efficacy and toxicity of NC with epirubicin and paclitaxel. METHODS: Between March 2007 and January 2009, 50 patients with LABC were enrolled in an open-label, phase II, multicenter study carried out at five distinct institutions. All patients were scheduled to receive four cycles of 60 mg/m(2) epirubicin and 175 mg/m(2) paclitaxel every 3 weeks, preoperatively, unless they developed profound side effects or disease progression. After curative surgery, two additional cycles of chemotherapy were administered to patients who had shown a positive response to NC. RESULTS: In all, 196 cycles of chemotherapy were administered preoperatively; 47 of the 50 patients (94%) underwent all four cycles of designated treatment. Complete disappearance of invasive foci of the primary tumor, and negative axillary lymph nodes were confirmed in eight patients (16.0%), post operation. The cumulative 5-year disease-free survival rate was 70.0% for patients with complete remission (CR) and partial remission (PR), and 33.3% for patients with stable disease (SD) and progressive disease (PD) (p=0.018). The cumulative 5-year overall survival was 90.0% for patients who achieved CR and PR and 55.6% for patients who had SD and PD (p=0.001). Neutropenia (42.0%) was the most common grade 3/4 toxicity. However, none of the toxicities resulted in cessation of the treatment. CONCLUSION: The encouraging pathologic response observed in the patients treated with epirubicin plus paclitaxel NC in this study suggests that epirubicin could be a substitute for doxorubicin, which is the most cardiotoxic agent.

Oncoplastic reconstruction with superior based lateral breast rotation flap after lower quadrant tumor resection.

PURPOSE: Poor cosmetic outcome have been reported as a result of breast cancer operation due to lower quadrant breast tumors; this is particularly true for women with small, firm breasts. Herein, we report here on the use of superior based lateral breast rotation flap reconstruction to improve cosmetic outcome in patients with lower quadrant breast cancer. METHODS: We enrolled 33 patients with invasive breast cancer located in the lower quadrant of the breast, which were located more than 2 cm apart from the nipple. After completing a quadrantectomy, a single S-shaped or reverse S-shaped incision was made from axilla to tumor site. Two triangular skin islands, one on the axilla and one overlying the tumor were marked for excision. Once the fibroglandular tissues and the additional fatty tissue of the lateral chest wall were appropriately mobilized, the breast defect was closed at the mid-point of the parenchymal thickness in order to keep the natural position of the infra mammary fold. RESULTS: Median tumor size was 2.3 cm (range, 0.7-3.5 cm) and median resected volume was 35.5 g (range, 27.0-51.0 g). With a mean follow-up of 24.5 months (range, 9.0-33.5 months), cosmetic outcomes were good (94.0%) to fair (6.0%) at 6 months after the procedure, and there was no local or systemic recurrence during the short term follow-up period. CONCLUSION: Clearly, this type of rotation flap reconstruction is an oncologically safe and a cosmetically sound procedure. Hopefully this rotation flap reconstruction technique will become more widely available and perhaps a standard procedure for lower quadrant breast tumors, especially for cosmetic treatment of small to medium-sized breasts.

Immediate extended latissimus dorsi flap reconstruction after skin-sparing mastectomy for breast cancer associated with paraffinoma: report of a case.

Paraffin oil injection into the breast, which had been used for breast augmentation in the past, can cause various complications. Complete removal of paraffinoma lesions with immediate breast reconstruction using autogenous tissue is a very satisfactory treatment option. However, diffuse random distribution of paraffin oil through the subdermal layer makes it impossible to remove all of the lesions with overlying skin without resulting in a shortage of available skin and poor cosmesis. We herein report the case of a patient with breast cancer associated with paraffinoma, treated with skinsparing mastectomy and axillary node dissection with immediate extended latissimus dorsi flap reconstruction, resulting in good cosmetic outcome, and showing no complications during the wound-healing process.

Prognostic Factors in Patients with Stage II/III Breast Cancer Treated with Adjuvant Extension of Neoadjuvant Chemotherapy: A Retrospective Cohort Study with Ten-Years of Follow-Up Data.

PURPOSE: The aim of this retrospective study was to identify the reliable long term prognostic factors in patients with stage II/III breast cancer who were treated with an adjuvant extension of neoadjuvant chemotherapy (NC). METHODS: Women under the age of 70-years, with previously untreated clinical stage II and III breast cancer, were treated with NC, which was comprised of three cycles of FEC (5-FU, epirubicin, and cyclophosphamide every 3 weeks) or MMM (methotrexate, mitoxantrone, and mitomycin-C every 3 weeks) with an adjuvant extension of three cycles of the same regimen. RESULTS: Cumulative 10-years disease-free survival (DFS) was 87.3% for patients with a good response and 55.5% for patients with no response (p=0.032); 92.9% for node negative patients, 75.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). Cumulative 10-years overall survival (OS) was 89.1% for patients with good response and 55.5% for patients with no response (p=0.024); 95.2% for node negative patients, 80.0% for 1-3 positive nodes, 50.0% for 4-9 positive nodes and no survival for 10 or more positive nodes (p<0.001). No significant difference was observed in DFS and OS between the FEC and MMM treated groups. CONCLUSION: Based on a review of data with a long follow-up, only the clinical response to NC and the absolute number of metastatic axillary lymph node identified at surgical staging were independent predictors of both DFS and OS in patients with stage II/III breast cancer patients treated with adjuvant extension of NC.

Selective Sentinel Node Plus Additional Non-Sentinel Node Biopsy Based on an FDG-PET/CT Scan in Early Breast Cancer Patients: Single Institutional Experience.

BACKGROUND: This study was designed to determine whether a preoperative fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with computed tomography (CT) (FDG-PET/CT) could be used as a guide for axillary node dissection (AND) or sentinel lymph node biopsy (SNB) in breast cancer patients. METHODS: Between February 2007 and April 2008, we performed FDG-PET/CT scans in 137 biopsy-proven breast cancer patients planning to have an SNB to select patients for either AND (PET/CT N+) or SNB (PET/CT N0). In performing SNB, we also performed additional non-SNB (ADD), which was enlarged at the lower axilla. RESULTS: Twenty-seven patients with positive scans underwent complete AND as a primary procedure, and 110 patients with negative scans underwent SNB + ADD. There were 8 cases of false negative scans, and no case of false positive scan. The overall sensitivity, specificity, positive predictive value, and overall accuracy of FDG-PET/CT in predicting axillary metastasis were 77.1%, 100%, 100%, and 94.2%, respectively. In a subset of 110 patients with SNB + ADD, 104 patients had histologically negative SN, and 6 patients had positive SN in frozen section. Among 110 SNB + ADD cases, there were only 8 cases (7.3%) of positive axillary basins in permanent biopsy, including two cases of late positives that had micrometastases in the SN only. Through selective SNB + ADD based on an FDG-PET/CT, we have spared 27 unnecessary SNBs (true positive scans). CONCLUSIONS: FDG-PET/CT is a specific imaging modality for predicting axillary node metastasis, and allows for a selective approach to either AND or SNB. A selective SNB + ADD based on an FDG-PET/CT reduced both unnecessary SNBs and positive axillary basins, enhancing the identification rates of SN and the accuracy of SNB.

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.

Diagnostic value of pyrosequencing for the BRAF V600E mutation in ultrasound-guided fine-needle aspiration biopsy samples of thyroid incidentalomas.

CONTEXT: Dideoxy sequencing is the most commonly used method for detecting the BRAF(V600E) mutation in thyroid cancer and melanoma. However, this gold standard method often makes less definite results in detecting the BRAF(V600E) mutation when there are relatively low amounts of the mutant template in biopsy specimens, which are invariably contaminated with normal tissues. Pyrosequencing, which measures the incorporation of each of the four nucleotides at each template position and indicates the amounts of mutant template present, may be more useful in such situations. OBJECTIVE: To investigate the diagnostic efficiency of pyrosequencing for the mutant BRAF allele in ultrasound (US)-guided fine needle aspiration biopsies (FNABs) of thyroid incidentalomas. DESIGN, SETTING AND SUBJECTS: A total of 101 thyroid incidentaloma cases were included prospectively. Cytological diagnoses of the FNAB samples were made according to the American Thyroid Association (ATA) guidelines, 2006. The presence of the BRAF(V600E) mutation was investigated by pyrosequencing and dideoxy sequencing. RESULTS: On the basis of cytological analysis, the thyroid incidentalomas were classified into benign (n = 43), malignant (n = 30), indeterminate or suspicious neoplasm (n = 24), and nondiagnostic (n = 4) categories. Pyrosequencing detected the BRAF(V600E) mutation in 30 cases: 22 malignant cases, 7 indeterminate cases, and 1 nondiagnostic case. Dideoxy sequencing also detected the BRAF(V600E) mutation in 28 of the same cases but failed to clearly distinguish the mutant allele from the wild-type allele in one indeterminate case and one nondiagnostic case. Histopathological analysis ascertained that all BRAF(V600E)-positive cases were papillary thyroid carcinomas. CONCLUSIONS: Pyrosequencing may be suitable for detecting the BRAF(V600E) mutation in thyroid incidentaloma and may be superior to dideoxy sequencing when low amounts of the mutant template are present in the biopsy.

A phase II study of neoadjuvant docetaxel plus doxorubicin (KBCS-01) in stage II, III breast cancer.

BACKGROUND: This multicenter phase II study was conducted to evaluate the response and safety of a combination of docetaxel plus doxorubicin as neoadjuvant therapy for stage II, III breast cancer. METHODS: Patients with stage II or III breast cancer underwent three cycles of neoadjuvant chemotherapy with doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 3 weeks followed by curative surgery. Prophylactic GCSF was not used. RESULTS: Ninety patients were enrolled in the study and 86 were evaluable for efficacy. The median age was 43 years (range, 30-69). The mean relative dose intensity was 0.98 for docetaxel and 0.98 for doxorubicin. Breast-conserving surgery was performed in 12 (13.7%) patients. The clinical overall response rate was 86% and pathologic complete response was 10.5%. Grade 3/4 neutropenia was observed in 26% of total 258 cycles and febrile neutropenia was observed in 15.8%. Pneumonia was observed in one patient and grade 3 mucositis was observed in three patients. CONCLUSION: Docetaxel and doxorubicin was an effective and well-tolerated neoadjuvant chemotherapy for stage II and III breast cancer. Clinical benefit of this treatment will be confirmed by survival data with long term follow up.