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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.

Objective To report on the uptake of breast cancer screening strategies in epithelial ovarian cancer patients with BRCA1 or BRCA2 mutation. Methods A retrospective review of the clinico-pathologic data and implementation of breast cancer surveillance was performed on patients who were diagnosed with epithelial ovarian cancer at a single center between 2009 and 2019. If annual mammography or breast MRI was performed, it was considered that breast cancer screening was done following the guidelines. Results A total of 309 women were diagnosed as epithelial ovarian cancer during the study period. Of these, 66 patients (21.4%) carried out BRCA testing. Thirteen patients (19.7%) had BRCA1/2 pathogenic/likely pathogenic variants, 10 of whom with BRCA1 mutation and 3 with BRCA2 mutation. Among the 13 patients with BRCA1/2 mutation, 10 patients received annual mammography with or without breast ultrasonography. Only 1 patient performed breast MRI. During the follow-up period, 1 patient developed breast cancer and another patient was diagnosed with pancreatic cancer. Discussion The uptake of BRCA1/2 testing and breast cancer surveillance among epithelial ovarian cancer patients with BRCA1/2 mutation is still not optimal, and strategies to increase uptake are needed.

Background Aortic stenosis (AS) induces significant pressure overload to the left ventricle (LV) and its burden may increase if there is concomitant LV systolic dysfunction. Severe AS with LV systolic dysfunction is a class I indication for aortic valve replacement (AVR) irrespective of symptoms, however, this recommendation is not well established in those with moderate AS and LV systolic dysfunction. In this study, we sought to investigate the clinical impact of surgical AVR among patients with moderate AS and LV systolic dysfunction. Methods From 2001 to 2017, we retrospectively but consecutively identified patients with moderate AS and LV systolic dysfunction from a single tertiary hospital. Moderate AS was defined as aortic valve area between 1.0 and 1.5cm2 and LV systolic dysfunction as LV ejection fraction less than 50%. The primary outcome was all-cause death and we additionally analyzed cardiac death as a secondary endpoint. The outcomes were compared between those who underwent early surgical AVR at the stage of moderate AS versus those who were followed without AVR at the outpatient clinic. Results Among a total of 257 patients with moderate AS and concomitant LV systolic dysfunction (70.0 ± 11.3 years, 63.4% of male), 34 patients received early AVR. Patients in the AVR group was younger than the observation group (64.2 ± 8.1 vs. 70.9 ± 11.5, respectively), and had a lower prevalence of hypertension and chronic kidney disease. During a mean of 3-year follow up, 112 patients (47.5%) died and the overall death rate was 15.367 per 100 person-year (PY). The AVR group showed a significantly lower rate of all-cause death than the observation group (5.241PY vs. 18.160PY, p-value = 0.002). After multivariable Cox proportional hazard regression adjusting for age, sex, comorbidities and laboratory data, early AVR at the stage of moderate AS significantly reduced the risk of all-cause death (hazard ratio [HR] 0.340, 95% confidence interval [CI] 0.117 - 0.985, p-value = 0.047). However, there was no risk reduction of cardiac death (HR 0.578 95% CI 0.150 - 2.231, p-value = 0.426). Conclusions In patients with moderate AS and LV systolic dysfunction, AVR reduces the risk of all-cause death. A prospective design study is warranted to confirm our findings in the near future. Abstract P1274 Figure. Kaplan-Meier curves for deaths

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.

Introduction/Background To evaluate the clinical implication of preoperative tumor grade results in endometrial cancer with low-risk for lymph node metastasis. Methodology The medical records of 75 women with endometrial cancer were retrospectively reviewed. Women with (1) non-endometrioid type, (2) deep myometrial invasion on magnetic resonance imaging (MRI), (3) enlarged lymph node on MRI, (4) extension beyond the uterine corpus on MRI and (5) serum cancer antigen 125 (CA-125) level >35 IU/ml before surgery were excluded. Pattern of pelvic lymph node dissection (PLND) and clinical course by preoperative tumor grade were compared. Results Median age was 45 (range, 28–83) years and follow-up period was 35 (range, 1–126) months. Grade 1, grade 2-3 and unknown grade were respectively diagnosed in 50 (66.7%), 11 (14.7%) and 14 (18.6%) women before staging surgery by endometrial biopsy. After surgery, 30% of preoperative grade 1 was confirmed to non-grade 1, and 48.0% of preoperative non-grade 1 was confirmed to grade 1 (p=0.063). PLND was similarly performed between the preoperative grade 1 and non-grade 1 groups (44.0% vs. 36.0%, p=0.507). Lymph node metastasis was diagnosed in 1 women with preoperative grade 1 and 1 women with preoperative non-grade 1 (4.5% vs. 11.1%, p=0.503). There was no recurrence in women with preoperative non-grade 1 during follow-up period (0% vs. 6.0%, p=0.546). Conclusion Preoperative tumor grade results occasionally make it difficult to decide PLND omission in low-risk endometrial cancer, however, non-grade 1 tumor seems not to increase the lymph node metastasis and recurrence. Disclosure Nothing to disclose.

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease.

Achieving a clear resection margin in breast conserving surgery (BCS) is an important factor in tumor recurrence in breast cancer. To obtain clear resection margins and reduce re-excision rates, some surgeons obtain intraoperative assessments of the margins of excised specimens, using intraoperative frozen biopsy. But intraoperative frozen biopsy has several problems such as low sensitivity or longer operation time. We have previously reported a nomogram for prediction of positive resection margin by integrating preoperatively available clinical and pathologic information. The factors were the presence of microcalcification, mammographic density, tumor size discrepancy between magnetic resonance imaging and ultrasonography, and the presence of ductal carcinoma in situ or lobular carcinoma in needle biopsy specimens. We conducted a prospective trial to examine the accuracy and clinical benefits of the nomogram in 442 breast cancer patients (nomogram group) who underwent BCS between Dec 2011 and March 2013, and compared the clinical outcome with that of the 253 patients (control group) who underwent BCS between Jan 2011 and Oct 2011. For nomogram group, the intraoperative frozen section biopsy was omitted in patients with low nomogram scores. Applying our nomogram did not increase the rate of reoperation due to resection margin positivity when compared to the control group (6.56% vs. 4.25%, respectively, p = 0.22). In the nomogram group, the reoperation rate in patients with low nomogram score who did not undergo intraoperative frozen biopsy was 3.2%, and this is lower than the reoperation rate in the control group. Additionally, we experienced a significant reduction in operation time by 15 minutes when compared to the control group (p In conclusion, our results show that out nomogram for predicting positive resection margin for patients who receive BCS can significantly reduce the operation time without increasing reoperation rate. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-04.

Background In patients with fine needle aspiration (FNA)-proven axillary lymph node metastasis at diagnosis (cN+), the current standard surgical procedure is axillary lymph node dissection (ALND) at definitive surgery after neoadjuvant chemotherapy (NAC). However, growing evidences suggest that SLNB after NAC is feasible and may demonstrate acceptable performance in selected patients. We performed sentinel lymph node biopsy in patients treated with cytologically-confirmed axillary lymph nodes metastases at presentation, who converted to a clinically negative axillary status after NAC (ycN0). Patients and methods We retrospectively evaluated 240 patients with invasive breast cancer with ultrasound-guided FNA-proven axillary nodal metastases at the time of diagnosis. All patients received NAC and underwent surgery at Samsung medical center between October 2007 and May 2013. Among these patients, 75 patients underwent SLNB. These patients converted to clinically node-negative disease (ycN0) after NAC on breast MRI or PET/CT scan. A combined detection technique was used with radioisotope and blue dye for the detection of SLN. Patients with negative SLN on frozen pathology and low clinical suspicion of metastasis during operation were not performed further ALND. Results The detection rate of SLNB was 93.3% (70/75), and median number of retrieved sentinel lymph nodes was 3.0 (range 1-8). False negative rate was 6.7% (1/15). Of these 75 patients, 35 (46.6%) patients had positive sentinel lymph nodes (ypN+) and underwent ALND. Thirty-five (46.6%) patients had tumor-free sentinel lymph nodes (ypN0sn) and 20 patients of them were followed without subsequent ALND. In these SLN-negative patients without further ALND, 9 patients were HER2-enriched subtypes and 9 patients, TNBC subtypes. Only two of them were Luminal B subtypes. The median follow-up period was 12.0 months (range 0-26 months) with 2 events; 1 regional recurrence in ipsilateral supraclavicular node and 1 systemic recurrence in brain on postoperative 7 months and 5 months, respectively. There has not occurred an ipsilateral axillary recurrence so far. Conclusions Although the follow-up was not long enough to conclude, this study tried to demonstrate that SLNB after NAC was feasible and further ALND may not be necessary in patients with SLN-negative disease (ypN0sn). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-04.

Background: The downstaging of the primary tumor and the increase in breast conservation rates seems to be the only clinical benefit of Neoadjuvant systemic therapy(NST) in breast cancer treatment, given that several studies failed to demonstrate an improvement of overall survival compared with postoperative adjuvant chemotherapy. In Europe, S6 trial showed better early outcome in survival in favour of the neoadjuvant chemotherapy group compared to adjuvant chemotherapy group in premenopausal patients without significantly modifying long-term event rates. The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy in young age breast cancer patients. Methods: Between January 2001 and December 2008, 1169 consecutive patients with breast cancer aged under 40 underwent adjuvant chemotherapy before or after surgery. Prospectively collected medical records for all patients were reviewed retrospectively. For the comparison of survival between neoadjuvant versus adjuvant chemotherapy group, cinically T2 and node positive patients were retrieved. Survival curves were derived from Kaplan-Meier estimates and compared by log-rank test. Results: Of the 1169 patients, 203(17.3%) patients were treated with neoadjuvant chemotherapy, and they were grouped as ‘NST’ and ‘non-NST’ according to initial treatment. About 47% patients in each group were clinically T2 patients. (99(47.8%) in NST group, 453(46.9%) in non-NST group) Among them, clinically T2 and node positive patients were 188, 97 patients in NST group, 91 patients in non-NST group each. The median age was 35.11±3.9 years old and HER2 amplification was observed as 23.5%, and they were not different between two groups.(p = 0.146 and 0.941 each) Significant lower hormone receptor expression rate and higher Ki-67 level were observed in NST group(p = 0.03 and Conclusion: A potential advantage of primary over adjuvant chemotherapy in young age breast cancer patients’ survival might be proposed by this results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-20.

The effect of carbon nanotube (CNT) integration in polymer matrixes (two-phase) and fibre reinforced composites (three-phase) was studied. Simulations for CNT/polymer composites (nanocomposites) and CNT/fibre/polymer composites (multiscale) were carried out by combining micromechanical theories applied to nanoscale and woven fibre micromechanic theories. The mechanical properties (Young’s modulus, Poisson’s ratio and shear modulus) of a multiscale composite were predicted. The relationships between the mechanical properties of nano- and multiscale composite systems for various CNT aspect ratios were studied. A comparison was made between a multiscale system with CNTs infused throughout and one with nanotubes excluded from the fabric tows. The mechanical properties of the composites improved with increased CNT loading. The influence of CNT aspect ratio on the mechanical properties was more pronounced in the nanocomposites than in the multiscale composites. Composites with CNTs in the fibre strands ...

Multiwalled carbon nanotube (MWNT) reinforced epoxy resin composites were fabricated and characterised. Several process variables were investigated using design of experiments. The MWNTs (0·5 wt-%) were dispersed in Epon 862 epoxy resin under various sonication conditions. Young’s modulus, energy to failure, glass transition temperature Tg and storage modulus E′ were assessed. The first three were selected in a design of experiment optimisation study. The results indicated that as the sonication intensity and the duration of sonication were increased, the material response of the MWNT/epoxy composite, specifically Young’s modulus, energy and Tg, was enhanced. The fracture surfaces of the composites were examined using scanning electron microscopy. Improved dispersion was observed in samples fabricated with increased sonication intensities. The Mori–Tanaka model was used to predict the mechanical properties of the MWNT/epoxy composites and was found to be in reasonable agreement with experimental d...

Background: Breast cancer rarely occurs in very young women(age Patients and Methods: A total of 551 consecutive patients were evaluated, received preoperative chemotherapy and referred to surgery at the Seoul National University Hospital from January 2001 to December 2010. The clinicopathologic factors and the response to neoadjuvant chemotherapy between the very young age group and the older age group were retrospectively compared. A pCR was defined as the absence of residual invasive carcinoma in the breast. Results: Among the 551 patients who received neoadjuvant chemotherapy, 297 patients revealed HR-positive. The median age of all patients was 42 (range, 24∼67)years and very young age group accounted for 17.2%(51/297). Of 297 patients, 262 (88.2%) received taxane-containing regimen pre-operatively, and there's no difference of chemotherapeutic regimen between two age groups. There were no differences noted between two age groups about clinicopathologic characteristics. The univariate and multivariate analysis of variables related to ORR(CR+PR vs SD+PD) to neoadjuvant chemotherapy showed that very young age at diagnosis was independent predictive factor for poor neoadjuvant chemotherapeutic response.(p = 0.043, OR = 0.528) And this tendency was observed more significantly in age under 30.(p = 0.001, OR = 0.147) Only thirteen patients(4.4%) achieved pCR, which is relatively lower rate, reflective poor chemotherapeutic response in HR-positive group, and there was no relations between pCR rate and the two age groups(p = 0.861) in this study. Taxane-containing regimen(p = 0.004) and Ki67 level(p = 0.005) were related to pCR statistically significantly. Breast conservation rate is not significantly different between two age groups.(age35= 51.2% vs 41.3%, p = 0.150) Conclusions: The very young age group showed lower ORR(CR+PR) to neoadjuvant chemotherapy, although there was no significant difference in pCR rate between the two age groups in HR-positive breast cancer patients. We might have to consider and revalue the chemotherapeutic role as neoadjuvant therapy in very young age, HR-positive group, since they had lower survival rate than others. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-16.

This research presents an experimental and theoretical investigation on the effects of carbon nanotube (CNT) integration within neat epoxy resin (nanocomposites) and a carbon fabric–epoxy composite (multiscale composites). An approach is presented for the prediction of mechanical properties of multiscale composites. This approach combines woven fibre micromechanics (MESOTEX) with the Mori-Tanaka model which was used for the prediction of mechanical properties of nanocomposites in this research. Nanocomposite and multiscale composite samples were manufactured using cast moulding, resin infusion, and hand lay-up process. The CNT concentrations in the composite samples were from 0 to 5 wt-%. The samples were characterised using tensile, shear and flexural tests. The discrepancy between the theoretical predictions and the experimental observations was hypothesised to be due to dispersion and bonding issues and SEM images are presented in support of the hypothesis.

Background: The identification of prognostic factors for hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative breast cancer is an important issue for the accurate determination of the indications for chemotherapy. The progesterone receptor(PgR) is a downstream molecule induced by transcriptional activation of estrogen signaling. In recent report, quantitatively low PgR expression was significantly associated with a poorer prognosis for patients treated with anastrozole and/or tamoxifen. These findings seem to suggest that the clinically used Ki-67-based IHC classification of luminal subtypes is inaccurate and that semiquantitative measurement of PgR expression can improve the IHC-based classification. Method: 1327 consecutive patients with ER and/or PgR-positive HER2-negative invasive breast cancer treated with surgery and adjuvant treatment at the Seoul National University Hospital from January 2009 to December 2011 were reviewed. All patients had been pathologically diagnosed with breast cancer, and patients who had received chemotherapy or endocrine therapy before surgery were included. ER, PgR, HER2, and Ki-67 were determined from surgically resected, formalin-fixed, paraffin-embedded tumor tissue. The RFS and OS in Kaplan-Meier plots for the PgR high and low expression groups was compared using the log-rank test. Univariate and multivariate analyses of DFS and OS in relation to various factors were performed with a Cox proportional hazards model, which yielded the HR and 95% of CI for each variable. Results: Based on pathology data of semiquantitative measurement of the percentage of PgR-positive cells, patients were separated into two groups with PgR percentage cutoff 20%. Among 1372 patients, 665(48.5%) showed high PgR expression, 707(51.5%) showed low PgR expression. PgR expression was relatively high in younger age( Conclusion: We were able to demonstrate that high PgR expression is associated with a better prognosis for luminal type breast cancer. The semiquantitative determination of PgR expression might thus improve the accuracy of the IHC-based classification of luminal A and luminal B breast cancer, especially for premenopausal patients. Citation Format: Kim MK, Han W. Prognostic effect of semiquantitative measurement of PgR in luminal type breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-05.

Introduction Fusions genes and it's products are widely applied as biomarker and therapeutic target in hematopoietic cancers. It's role as a “driver” of oncogenic pathway have also been proved in several epithelial solid cancers including prostate, lung and breast cancer. We performed high throughput next generation sequencing technique (RNA-Seq) to identify the novel fusion transcript(FT) in a large set of primary breast cancer samples. Materials and Method Total RNA was prepared using the Illumina® TrueSeq™ RNA sample Preparation Kit and TrueSeq mRNA library was constructed. Clustering was done with HiSeq 2000 and Solexa's sequencing was performed. We used tissues extracted from previously collected 100 fresh-frozen primary breast cancer samples obtained after surgical resection. Among 100 samples, 1 failed to pass the process of RNA sequencing and no expression of fusion transcripts were observed in 7 samples resulting in 92 samples with mRNA-Seq data of fusion transcripts. Fourteen(15.2%) samples were cases with distant metastasis during follow up. Estrogen receptor(ER) was positive in 40(43.5%) samples and 23(25%) were triple negative breast cancer. Results and discussion We detected 958 fusion transcripts among 92 tumors and 58 were chosen for tumor-specific fusion transcript candidate (Fragments per kilo-base of exon per million fragments mapped, FPKM>500 and 3 times higher than average, probability>0.6). Most of the fusion transcripts were “private”, expressed only in one sample. Estrogen receptor(ER) positive breast cancer samples had 29 fusion transcripts and ER negative had 25 fusion transcripts among the 58 tumor-specific candidates. HER2 negative samples exhibited 29 fusion transcripts while 15 were identified in HER2 negative samples. Triple negative sample showed 4 TF candidates. Among the 17 recurrence samples 190 fusion transcripts were identified. Of the 190 fusion transcripts in recurred samples, 24 candidates of recurrence-specific FTs were chosen by it's high expression level (FPKM>300 and 2 times higher than average, probability>0.5). Eight were expressed both in recurred, non-recurred samples and 16 were exclusively expressed in recurred samples. No fusion transcript matched directly with the currently known actionable gene-list owing to the limited number while majority is unexploited. Further validation and functional pathway analysis is under progress to ascertain the role of highly suspected fusion transcripts with oncogenic property. Considering the high incidence of breast cancer world-wide, identification of TF expressed even in only a minor percentage among the whole breast cancer population, if druggable, it can be applicable to large number of patients. Conclusion We performed a whole-transcriptome sequencing with a large set of primary breast cancer samples and detected abundant fusion transcripts. The majority of breast cancer(92.9%, 92/99) had at least one fusion transcript suggesting it's role during the tumorigenesis and progression process. With scarce evidence and confirmed data of actionable fusion gene and it's product, data interpretation for it's clinical utility is rather complicated. Accumulation of these large set data of fusion transcript must serve as a groundwork for future work. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-07.

Background and Aims Infants with renal cortical defect due to acute pyelonephritis (APN) may be associated with an increased risk of progressive kidney damage. Neutrophil gelatinase-associated lipocalin (NGAL) is produced and secreted by renal tubule cells at low levels, but the amount produced and secreted increases dramatically after ischemic, septic, or nephrotoxic injury of the kidneys. To investigate the usefulness of a rapid blood NGAL assay as a diagnostic marker of cortical defect in infant with febrile UTI at the bedside. Methods Sixty-three infants with suspected febrile UTI were divided into a documented UTI group(n=49) and a non UTI group(n=14). UTI group were divided into cortical defect (UTI-D) group(n=26) and non cortical defect (UTI-N) group(n=23) according to the result of DMSA scan. Blood NGAL concentrations were analyzed using a commercial kit (Triage NGAL test) by fluorescence immunoassay. Results NGAL concentrations were significantly higher in UTI-D group (68.0[60.0–172.5] mg/mL) than in UTI-N group (60.0[60.0–86.5] mg/mL) and in non UTI group (60.0[60.0–60.0] mg/mL). In UTI-D groupin, NGAL concentrations were significantly decreased after antibiotic therapy (60.0[60.0–71.2] mg/mL). The area under the ROC curve of NGAL for the detection of cortical defect was 0.74 (p=0.004). The best cutoff NGAL concentrations for the detection of cortical defect was found to be 61.5 mg/mL (sensitivity: 69.2%; specificity 78.2%). Conclusions Although it is not a stand-alone test, the rapid determination of blood NGAL concentration provides valuable information quickly, concerning the distinction between APN and lower UTI, for determining the clinical course of infant with febrile UTI.

Fcgamma receptors convey to phagocytic cells the ability to recognize, bind, and internalize IgG-coated cells and microorganisms. The present study demonstrates the use of adenovirus (Ad)-mediated gene transfer of human Fcgamma receptor IIA cDNA to convert normally nonphagocytic cells (hepatocytes) into functional equivalents of phagocytic cells. Ad vector in vitro transfer and expression of FcgammaRIIA cDNA in primary rat hepatocytes was confirmed by flow cytometry anti-FcgammaRIIA immunodetection, and the function of the receptor was demonstrated by enhanced binding and phagocytosis of (51)Cr-labeled IgG-opsonized erythrocytes. After in vivo gene transfer to rats, expression of FcgammaRIIA cDNA in hepatocytes was confirmed by Northern analysis and immunohistochemistry. Rats infected with the Ad vector carrying the FcgammaRIIA cDNA demonstrated enhanced clearance of opsonized erythrocytes, but not nonopsonized erythrocytes, from the circulation with increased sequestration within the liver. Together, these data demonstrate that Ad-mediated FcgammaRIIA gene transfer can convert normally IgG-nonphagocytic cells into phagocytic cells capable of recognizing, binding, and ingesting an opsonized particulate antigen, suggesting that gene transfer strategies might be used to transiently augment host defense by enhancing the clearance of immune complexes.

Previous studies on the issue of the prognostic importance of treatment delay in breast cancer have shown inconsistent results. Furthermore, the association between the impact of treatment delay and molecular characteristics of tumors has not been adequately addressed. The purpose of this study is to examine the prognostic impact of initial surgical treatment delay after biopsy-proven cancer diagnosis in breast cancer patients. A total of 1,393 consecutive invasive breast cancer patients, treated in Seoul National University Hospital, Seoul, Korea, between July 2006 and June 2008, were included in this study. Patients with in situ or metastatic carcinoma at the time of diagnosis and patients in whom the dates of the initial pathologic diagnosis were unknown were excluded. The median time from biopsy-confirmed cancer diagnosis to initial surgical treatment was 25 days (range 0-134). When the patients were classified according to their treatment delay days (0 to 29, 30 to 59, and ≥60days), there was no difference in survival between ‘0-29days’ group and ‘30-59days’ group. However, for patients who experienced more than 60 days of initial delay in surgical treatment, the survival was significantly worse when compared to other groups (p = 0.034). The association between the treatment delay and poor outcome was only seen in patients with ER and PR negative tumors (p = 0.018) while patients with hormone-responsive tumors showed no such association. Patients with ER and PR negative tumors developed more recurrence and had shorter disease-free survival if they had treatment delay of more than 60 days. The prognostic importance of treatment delay of more than 60 days remained significant in predicting disease-free survival after adjusting for other known prognostic factors such as age, tumor size, nodal status, cancer stage, nuclear grade and Ki-67 expression (HR 5.127; 95% CI, 1.350 to 19.472; p = 0.016). Our results suggest that having treatment delay of more than 60 days is associated with poor treatment outcome in patients with ER and PR negative breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-08.

Introduction Recent studies of next generation sequencing (NGS) have highlighted the extensive transcriptional heterogeneity of cancer cells. Alternative splicing is one of the evolutionary process by which cells and tissues achieve their specificity within central dogma. Also it is highly assumed to contribute to oncogenesis and thought to be a critical mechanism how cancer cells gain resistance to therapeutic agents and adapt to various circumstances. Relevance of differential splicing in breast cancer biology is mostly unknown. We performed whole transcriptome sequencing (RNA-Seq) to reveal novel splicing alterations among 120 primary breast cancer samples. Materials and Method Total RNA was prepared using the Illumina TrueSeq™ RNA sample Preparation Kit and TrueSeq mRNA library was constructed. Clustering and sequencing was done using Illumina HiSeq 2000. RNA-Seq reads were aligned to human reference genome(hg19) using TopHat software and expression was measured using cufflinks software. We used tissues extracted from previously collected 120 fresh-frozen primary breast cancer samples obtained after surgical resection whose clinicopathological data are available. Patients undergone neoadjuvant systemic therapies or stage lV disease at diagnosis were excluded. Thirty-six(30%) cases occurred distant metastasis during follow up. Hormone receptor(HR) was positive in 61(50.8%) samples, 20(16.7%) had HER2 oncogene overexpression and 36(30%) were triple negative breast cancer. Results and discussion Total 11345 novel isoforms were detected among 120 tumors. Isoforms of pseudo-genes and exon skipping of the ‘non-coding exon’ were excluded. Splice variants detected in normal reference were sorted out as well. 4045 were in-frame exon skipping and 4960 were off-frame exon skipping which may lead to protein truncation. 5036 were private exon skipping and 3969 isoforms were detected recurrently in more than 2 samples. To minimize false positivity we confined ‘exon skipping’ analysis to those with the expression level (Fragments per kilo-base of exon per million fragments mapped, FPKM) of the skipped exon below 0.1 compared to the adjacent exons. Mean number of exon skipping events per sample was 196.8 (range 75-299, SD 35.9). There were no differences in numbers of exon skipping event among breast cancer subtypes nor distant metastasis. We have identified novel exon skipping in ESR1, CHEK2, EIF3E, FGFR, MAP2K, PIK3R2, TERT, VAV3 genes which is strongly suspected to be novel driver isoforms and is under validation process. Conclusion We performed whole-transcriptome sequencing with a large set of primary breast cancer samples and revealed extensive transcriptional heterogeneity by isoform profiling. As distinguishing the natural transcriptomic dynamics from oncogenic ‘driver’ isoform is a major challenge, validation and functional studies are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-09.

Introduction: Many somatic mutations, structural alterations, and gene expression changes are causally implicated in oncogenesis and tumor progression, and as a result, affect clinical outcome. Although majority of breast cancer patients have benefits from therapeutics targeting tumor biology, such as estrogen receptor and HER-2, still many patients suffer from disease recurrence and metastasis. More kind of specific target therapies are needed, especially for hormone-resistant tumor and triple-negative breast cancer. Materials and Method: To find novel therapeutic target in breast cancer, here we examine the both whole exome and whole transcriptome of fresh-frozen primary breast cancer tissues from 120 patients whose clinical, pathological, and survival data are available. Patients with Stage IV disease or who received neoadjuvant chemotherapy were excluded. 36 patients had distant metastasis within 5 years from surgery, and 84 patients were NED at least 5 years. RNA and DNA were extracted and qualities were assessed in all samples. Exome and transcriptome sequencing were done using NGS technology (Illumina HiSeq 2000). As a control, exome sequencing was done for 93 normal DNA from matched patients. Single nucleotide variations (SNV) identified in cancer samples on exonic region, nonsynonymous SNV or stop gain/loss, whose quality ≥20, and not found in 93 normal samples were included. SNVs registered in dbSNP135_common or 1000 genome allele frequency >0.001 were excluded.Results and Discussion: We identified 11,684 putative somatic mutations in 7,373 genes. Of them, 6,547 were deleterious or damaging mutation by Provean or SIFT analysis. Mutations were found in potential drug target genes, such as PIK3CA(25), PTEN(3), AKT1(3), ALK(3), ROS1(2), FGFR4(3), FGFR3(2), ERBB2(2), and IDH1(1) etc. In a pathway analysis, mutations in insulin signaling pathway were most dominant. We hypothesized that driver gene and therapeutic target has to have recurrent mutation and gene expression at least more than average expression. We calculated expression “Volume” according to the median normalized FPKM value of individual gene's RNA-seq data. With a cut-off of 3 or more mutations in each gene, 1,116 genes were selected. After the filtering of Volume Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD4-2.

BACKGROUND: Completion axillary lymph node dissection (ALND) is currently the standard of care in the event of a positive sentinel lymph node biopsy (SLNB). However, result from Z0011 indicate that women with a one or two involved axillary nodes and clinical T1-T2 tumors undergoing lumpectomy with radiation therapy followed by systemic therapy do not benefit from completion of ALND in terms of survival. As a result, the use of intraoperative frozen section during SLNB will be declined. OBJECTIVE: To define possible predictors of having two or less involved axillary node using preoperative image study to provide information for surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph node. METHODS: We reviewed the records of 1214 patients with clinical T1-T2 and clinical node negative invasive breast cancer. None of these patients were in situ cancer on initial gun biopsy nor received neoadjuvant chemotherapy. Factors associated with having three or more involved axillary nodes were evaluated by univariate and multivariate logistic regression analysis. RESULTS: Among 1214 patients, 203 patients (16.7%) had three or more positive nodes. On a multivariate analysis, having three or more positive nodes was associated with primary tumor size by breast US, axillary LN grade according to cortical thickness by US and presence of axillary LN enlargement on chest CT. The area under ROC curve corresponding to the multivariate logistic regression model applied to dataset of 1214 patients was 0.827 (95% CI: 0.793–0.860). When applied to a validation dataset of 378 patients, it was 0.899 (95% CI: 0.841–0.957). A nomogram to predict the probability of having two or less axillary nodes involvement based on patients' age and preoperative image findings was developed from the multivariate logistic regression model. CONCLUSION: Patients with a low probability of having three or more positive nodes can be identified from preoperative image finding. The nomogram developed will be helpful to surgeons making decision about sparing intraoperative frozen section analysis of sentinel lymph. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-08.