Search

Objective : To evaluate the value of breast density change of mammography and breast MRI as a predictive marker for a response to postoperative anti-hormone therapy by targeting ER-positive postmenopausal breast cancer patient Methods : Density change of mammography, breast MRI density being taken just before start of anti-hormone therapy, mammography being performed after 6 months, 1 year, 2 years thereafter and breast MRI being performed 1 year after start of therapy will be measured by volpara and 3D-MR method. Molecular profile including ER expression level that has a relation with response rate to anti-hormone therapy will be analyzed and outcome will be evaluated based on disease free survival and overall survival. Recurrence rate of each group was estimated based on the data of the patients in breast center of Seoul National University Hospital, 2006-2011, who underwent surgery of ER-positive breast cancer. Among 1065 persons, 7.5% (80/1065) showed recurrence rate and among these, recurrence rate of patients who took AI was 6.9% (12/175). Among these, based on MDR 5% cutoff, 1.6% vs 9.8% was represented. By designating recurrence rate as 1.5%, 9.5% and assuming dropout rate by refusal to clinical test as 10%, registration goal was set at total 411 persons based on each 137, 274 persons per each group. Results : (this is interim analysis) From 2012, total 156 patients are enrolled, among them, 32 patients were eliminated (affirmative consent, switched to Tamoxifen, recurrence and etc). From now total 124 patients are on-going to this study. Compare with Non AI group, breast density change of AI group is much decreased from base line study and it is statistically significant. (1 year follow up – base line, 2 year follow up– base line ; -12.2%, - 18.6% vs - 7.6%, -15.3% P-value 0.002, 0.009 respectively) Only one patient was relapsed within 5 year and there were no death. Psychological anxiety, medication compliance and side effects analysis were done. Psychological anxiety about disease and medication were improved as time goes by (p Discussion : 70% of breast cancer is ER-positive breast cancer. Endocrine therapy (ET) has been clarified as an effective target therapy in large scale, prospective randomized trial and up to the present, it has been settled down as a standard therapeutic method of ER-positive breast cancer. As a result of 20 years' follow-up after intake of AI (aromatase inhibitor) and 20 years' follow-up after intake of tamoxifen, recurrence was represented as 2-2.5% and at present, clear mechanism of such resistance and predictive biomarker have not been clarified. Due to this resistance, all the ER-positive breast cancer patients are forced to receive anti-hormone therapy for 5 years or 10 years. According to the taking AI, breast density is significantly decreased compare Non AI group. Of course need more follow up data and analysis, but we can confirm a meaning of endocrine responsiveness of breast density change being measured after anti-hormone therapy as predictive surrogate. Citation Format: Kim Y, Lee E, Lee H-B, Kim KE, Ju YW, Jung JG, Moon H-G, Noh D-Y, Han W. Prospective study analyzing value of breast Density change predicting ENdocrine therapy response in postmenopausal women taking adjuvant ARomatase inhibitor [DEAR study] (interim analysis) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-15.

Purpose: Sentinel lymph node biopsy (SLNB) lowers morbidity of lymphedema then axillary lymph node dissection (ALND). However, there has been concern about incidence of lymphedema after SLNB especially when the number of harvested nodes during sentinel node biopsy procedure is more than a few. In this study, we assessed lymphedema incidence and its risk factors including the number excised lymph nodes in patients who underwent SLNB. Methods: Between January, 2011 and April, 2012, the records of 910 consecutive patients who underwent breast surgery with axillary staging (SLNB/ALND) for breast cancer at Seoul National University Hospital were reviewed. Lymphedema was assessed by circumferential upper extremity measurements. The lymphedema was defined as > 1cm for either the upper arm or the forearm. Patients with clinical records of the treatment for lymphedema in the rehabilitation clinic were regarded as having lymphedema. Univariate and multivariate analyses were performed to identify potential risk factors associated with lymphedema. Association of number of excised lymph nodes with lymphedema was analyzed by Spearman rank correlation coefficient. Results: At median follow-up of 69.8 months, 231 patients (25.4%) presented with lymphedema. In univariate analysis, body mass index (BMI) (P Conclusion: The risk of lymphedema is multifactorial in breast cancer surgery and adjuvant treatments. In SLNB alone patients, higher BMI was only significant factor correlated with lymphedema. Excised number of lymph nodes during sentinel biopsy procedure was not associated with lymphedema. Citation Format: Ju YW, Jung JG, Kim KE, Kim Y, Lee E, Lee H-B, Moon H-G, Han W, Noh D-Y. Breast cancer-related lymphedema: Morbidity of sentinel node biopsy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-15.

A large proportion of breast cancer patients receive hormonal therapy as their adjuvant treatment options. For postmenopausal women, the initial choice for the hormonal therapy is aromatase inhibitor (AI), and tamoxifen (TM) is reserved for women experiencing severe side effects against AI or having low bone density. An important but unresolved clinical question regarding the use of AI in postmenopausal women is the safety of AI regarding the risk cardiovascular events. Studies have shown inconsistent results over the cardiovascular safety of AI and TM. In this study, we investigated the risk of developing cardiovascular and cerebrovascular events in women with breast cancer who receive hormonal therapy using AI, TM, or both. To this end, we used the National Health Insurance Sharing Service in Korea which is provided by National Health Insurance Service. The database provides anonymized insurance data for research purposes after the approval of the review committee. In the database, we identified 47,569 women with the age older than 55 who were diagnosed with breast cancer. Patients were classified as no hormonal treatment group (n=18,807), AI group (n=19,584), TM group (n=7,081), or Switch group (n=2,097). The Switch group was defined as the women with history of both AI and TM prescriptions. During the studied period, a total of 2,032 cardiovascular or cerebrovascular events (CVE) were recorded. Overall, the women prescribed with TM had significantly less hazard ratio for developing CVE when compared to the women who did not receive any hormonal treatment (HR 0.809 95% C.I. 0.706-0.928). However, this protective effect of tamoxifen was not observed in either AI or Switch group (HR 0.917 95% C.I. 0.833-1.010, and HR 0.856 95% C.I. 0.695-1.053, respectively). The protective effect of TM was also similar in women older than 60 (HR 0.808 95% C.I. 0.696-0.938). The cardiovascular and cerebrovascular protective effects of tamoxifen was also substantial in high risk women defined by their family history of cardiovascular diseases and the diagnosis of hypertension or diabetes. Our results suggest that the use of TM is associated with a substantial protective effect against developing cardiovascular or cerebrovascular events in women with breast cancer. However, the protective effect was not observed for women receiving AI. Our data suggest the potential tailored approach in hormonal treatment in breast cancer patients who are at high risk of cardiovascular of cerebrovascular events. Citation Format: Moon H-G, Choi SH, Park Y, Jung JG, Ju YW, Kim KE, Kim Y, Lee E, Lee H-B, Han W, Noh D-Y, Yoon H-J. A nationwide data on the cardiovascular protective effect of tamoxifen and aromatase inhibitor in postmenopausal women with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-09.

This abstract was not presented at the conference. Citation Format: Lee H-B, Kim KE, Ju YW, Jung J-G, Ryu H-S, Lee SB, Lee JW, Lee HJ, Kim M-S, Kwon S, Kim J, Kim C, Moon H-G, Noh D-Y, Ahn S-H, Park I-A, Kim S, Yoon S, Kim A, Han W. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-10.

Introduction: Estrogen receptor is expressed in 75% of breast cancers and is related to a relatively indolent phenotype. Yet, up to 25% of these tumors develop resistance to endocrine therapy. Alternative splicing events are observed in almost every hallmarks of cancer, implying that dysregulation of splicing and cancer progression are closely related. The purpose of this study was to detect splice variants related to endocrine resistance in hormone receptor(HR)-positive breast cancer. Methods: RNA sequencing data of 455 HR-positive patients with documented endocrine treatment from The Cancer Genome Atlas (TCGA) database was used for analysis. Splice variants of 96 ESR1 pathway-related genes were detected using a data-mining algorithm recognizing spliceomic heterogeneity. A differential analysis of splice variants between 48 endocrine therapy-resistant and 407 endocrine therapy-responsive patients was performed to discover isoforms frequently detected in endocrine-resistant tumors. Isoforms related to endocrine resistance was further analyzed using whole transcriptome sequencing data from 59 HR-positive invasive breast cancer patients (24 endocrine therapy-resistant, 35 endocrine therapy-responsive who underwent operation at Seoul National University Hospital. Results: Of 96 ESR1 pathway-related genes, 17 genes showed statistically different splice variant isoforms frequencies (AKT1, ATF2, ATF4, CALM2, CALM3, CREB1, EGFR, ESR1, ESR2, GRM1, HRAS, HSP90AA1, OPRM1, PIK3R3, PRKACB, SHC1, and SHC4). A differential analysis of these isoforms using SNUH data confirmed a predominant isoform of HRAS (64.47% vs 57.14%, p-value 0.0037) and a minor isoform of SHC1 (25.53% vs 32.33%, p-value 0.0456) in endocrine therapy-resistant HR-positive patients. In the same analysis using HR-negative patients, the mean isoform percentage was similar between patients with distant recurrence and no recurrence. Potential Spliceomic Signatures Reproduced From Seoul National University Hospital Data Hormone Receptor Positive Hormone Receptor negative GeneMean Isoform % in Resistant SpecimensMean Isoform % in Responsive Specimensp-valueMean Isoform % in Resistant SpecimensMean Isoform % in Responsive Specimensp-valueHRAS64.4757.140.003757.9758.850.8413SHC125.5332.330.045628.3632.580.2551 Conclusions: Phenotype-specific splice variants can be detected using transcriptome sequencing data. Splice variants in HRAS and SHC1 are potential spliceomic signatures that may be used to predict endocrine therapy-resistant breast cancer. Further investigation is warranted to explore the biological role of these isoforms and identify the role of splice variants as a biomarker for endocrine resistance. Citation Format: Lee H-B, Kim M-S, Rhu J, Park JH, Kim KE, Ju YW, Lee E-S, Moon H-G, Noh D-Y, Kim S, Han W. Detection of splice variants related to endocrine resistant hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-05-13.

Background The identification of individuals at elevated risk for hereditary cancers has allowed the development of consensus recommendations for cancer screening and prevention. The introduction of multigene panels may identify more individuals with breast cancer gene mutations than does testing for BRCA1/2 alone. Therefore, the multigenerational panel increase the need for genetic counseling suggesting preventive approach or cancer-specific screening to patients and family members. The rapid clinical introduction of multigene panel testing, however, have several issues such as low- to moderate-risk gene mutations and clinical recommendations. We collect the mutation results and clinical recommendations after testing with multigene panel and giving genetic counseling. Methods We had developed multigene panel consisted of 64 genes related to hereditary cancer through previous study and prospectively enrolled 104 individuals who were appropriate candidates for hereditary breast cancer evaluation. The patients were tested with 64-gene panel(Celemics) and results were provided by us 4˜10 weeks later. We checked the family history of cancer and made a pedigree before testing. Result Among 104 participants, 26 patients harbored deleterious mutations, most commonly in high to moderate-risk breast/ovarian cancer genes (BRCA1/2, BRIP, RAD51 and RAD51D), Lynch syndrome gene(MSH6) and other genes(FH, SPINK1). We recommended the cancer-specific screening and/or preventive approach for mutation-positive patients and suggested additional genetic test for the family members. Among them, 6 (23%) patients received Risk reducing procedures (Prophylactic mastectomy or oophorectomy) and most of them(19 patients(73%)) received cancer specific screening. Conclusion We demonstrate the use of multigene panel testing for hereditary breast cancer and will suggest the process of the genetic counseling including indication and results analysis with multigene panel testing. Citation Format: Lee E-S, Han W, Kim Y, Rhu J, Park JH, Kim K-E, Ju YW, Kim R, Lee H-B, Moon H-G, Noh D-Y. Clinical application of multigene panel testing and genetic counseling for hereditary/familial breast cancer risk assessment: Prospective single center study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-18.

Stage-Gate® is a widely used product innovation process for managing portfolios of new product development projects. The process enables companies to minimize uncertainty by helping them identify—at various stages or gates—the “wrong” projects before too many resources are invested. The present research looks at the question of whether using Stage-Gate® may lead companies also to jettison some “right” projects (i.e., those that could have become successful). The specific context of this research involves projects characterized by asymmetrical uncertainty: where workload is usually underestimated at the start (because new development tasks or new customer requirements are discovered after the project begins) and where the development team's size is often overestimated (because assembling a productive team takes more time than anticipated). Software development projects are a perfect example. In the context of an underestimated workload and an understaffed team, the Stage-Gate® philosophy of low investment at the start may set off a negative dynamic: low investments in the beginning lead to massive schedule pressure, which increases turnover in an already understaffed team and results in the team missing schedules for the first stage. This delay cascades into the second stage and eventually leads management to conclude that the project is not viable and should be abandoned. However, this paper shows how, with slightly more flexible thinking (i.e., initial Stage-Gate® investments that are slightly less lean), some of the ostensibly “wrong” projects can actually become the “right” projects to pursue. Principal conclusions of the analysis are as follows: (1) adhering strictly to the Stage-Gate® philosophy may well kill off viable projects and damage the firm's bottom line; (2) slightly relaxing the initial investment constraint can improve the dynamics of project execution; and (3) during a project's first stages, managers should focus more on ramping up their project team than on containing project costs.

Background: According to the American College of Surgeons Oncology Group Z0011 trial, complete axillary lymph node dissection (ALND) did not affect survival of patients with clinical T1-T2 invasive breast cancer and one to two sentinel lymph nodes (SLNs) metastases treated with lumpectomy, adjuvant systemic therapy, and radiation therapy. A significant proportion of breast cancer patients may not require ALND, in whom intraoperative analysis of SLNs can be omitted reducing operation time and cost. The aim of this study was to develop a nomogram predicting three or more axillary lymph nodes (ALNs) metastases based on preoperative imaging and clinicopathological factors. Methods: The training set consisted of 1030 patients with clinical T1-T2 invasive breast cancer and clinically negative ALN who received surgery at Seoul National University Hospital (SNUH) between January 2010 and December 2013. Preoperative imaging techniques including ultrasonography (US), computed tomography (CT), positron emission tomography (PET), and clinicopathological features associated with three or more ALN metastases were evaluated by logistic regression analysis. A nomogram predicting three or more ALNs was developed with statistically significant factors. The validation set consisted of 781 independent patients who received surgery at SNUH between January 2014 and December 2015. Results: Of the 1030 patients, 89 (8.6%) had three or more ALN metastases. Multivariate analysis showed that three or more ALN metastases was independently associated with tumor size (cm) by US (p Conclusion: Patients with a strong possibility of three or more ALNs metastases can be identified using preoperative imaging methods including US, CT, and PET. The nomogram measuring this prospect may be valuable in skipping intraoperative analysis of SLNs with advantage of reduced operation time and cost. Citation Format: Park JH, Ju YW, Kim KE, Rhu J, Kim Y, Lee E, Lee H-B, Moon H-G, Noh D-Y, Han W. Nomogram predicting axillary lymph node metastases to skip intraoperative analysis of sentinel lymph nodes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-14.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is useful for breast cancer diagnosis and treatment planning. Nevertheless, due to the multi-temporal nature of DCE-MRI data, the assessment of early stage breast cancer is a challenging task. In this study, we applied an unsupervised clustering approach and cluster validation technique to the analysis of malignant intral-tumoral kinetic curves in DCE-MRI. K-means cluster analysis was performed from real world malignant tumor cases and the data were transformed into an optimal number of reference patterns representative each cluster. The optimal number of clusters was estimated by a cluster validation index, which was calculated with the ratio of inter-class scatter to intra-class scatter. This technique then classifies tumor specific patterns from a given MRI data by measuring the vector distances from the reference pattern set, and compared the result from the k- means clustering with that from three-time-points (3TP) method, which represents a clinical standard protocol for analysis of tumor kinetics. The evaluation of twenty five cases indicates that optimal k-means clustering reflects partitioning intra-tumoral kinetic patterns better than the 3TP technique. This method will greatly enhance the capability of radiologists to identify and characterize internal kinetic heterogeneity and vascular change of a tumor in breast DCE-MRI.

Mice lacking the Gadd45a gene are susceptible to ionizing radiation-induced tumors. Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA. Because cells deficient in Gadd45a were shown to have a partial defect in the global genomic repair component of the nucleotide excision repair pathway of UV-induced photoproducts, dimethylbenzanthracene (DMBA) carcinogenesis was investigated because this agent produces bulky adducts in DNA that are also repaired by nucleotide excision repair. Wild-type mice and mice deficient for Gadd45a were injected with a single i.p. dose of DMBA at 10-14 days of age. The latency for spontaneous deaths was slightly decreased for Gadd45a-null mice compared with wild-type mice. At 17 months, all surviving animals were killed, and similar percentages of each genotype were found to have tumors. However, nearly twice as many Gadd45a-null than wild-type mice had multiple tumors, and three times as many had multiple malignant tumors. The predominant tumor types in wild-type mice were lymphoma and tumors of the intestines and liver. In Gadd45a-null mice, there was a dramatic increase in female ovarian tumors, male hepatocellular tumors, and in vascular tumors in both sexes. In wild-type mice, this dose of DMBA induced a5-fold increase in Gadd45a transcript in the spleen and ovary, whereas the increase in liver was20-fold. Nucleotide excision repair, which repairs both UV- and DMBA-induced DNA lesions, was substantially reduced in Gadd45a-null lymphoblasts. Mutation frequency after DMBA treatment was threefold higher in Gadd45a-null liver compared with wild-type liver. Therefore, lack of basal and DMBA-induced Gadd45a may result in enhanced tumorigenesis because of decreased DNA repair and increased mutation frequency. Genomic instability, decreased cell cycle checkpoints, and partial loss of normal growth control in cells from Gadd45a-null mice may also contribute to this process.

In today’s network economy, multi-echelon supply networks have become the dominant life form. The question of how to coordinate goods flows in such multi-echelon settings has become paramount. This study investigates the effectiveness of collaboration and information sharing in a three-echelon supply network, whereas academic research so far has focused on collaboration in two-echelon supply chains. The starting point for this study is a published and prize-winning real-world case of collaborative planning (CP) in the high-clockspeed industry of electronics. In particular, this research zooms in on the role played by the middle echelon, that of the contract manufacturers (CM), whose strategic interests typically are less aligned with the OEM than those of the key component suppliers. A system dynamics simulation model is developed and calibrated from this three-echelon supply network setting. Simulation analysis suggests that, when the CM is actively engaged in the joint CP process, the benefits are higher for all three echelons involved. On the other hand, if the CM does not collaborate, then collaboration between the two other echelons still yields significant benefits for all supply network members. In short, in goods flow information sharing in three-echelon supply network settings, “three is not a crowd”, but “two is company”.