Eunshin Lee

In Vivo Tumor Growth Rate Measured by US in Preoperative Period and Long Term Disease Outcome in Breast Cancer Patients

Objective The aim of our study was to evaluate the effect of tumor growth rate, calculated from tumor size measurements by US, on breast cancer patients’ outcome. Patients and Methods Breast cancer patients who received at least two serial breast ultrasonographies (US) in our institution during preoperative period and were surgically treated between 2002 and 2010 were reviewed. Tumor growth rate was determined by specific growth rate (SGR) using the two time point tumor sizes by US. Results A total of 957 patients were analyzed. The median duration between initial and second US was 28 days (range, 8–140). The median initial tumor size was 1.7cm (range, 0.4–7.0) and median second size was 1.9cm (range, 0.3–7.2). 523(54.6%) cases had increase in size. The median SGR(x10-2) was 0.59 (range, -11.90~31.49) and mean tumor doubling time was 14.51 days. Tumor growth rate was higher when initial tumor size was smaller. Lymphovascular invasion, axillary lymph node metastasis, and higher histologic grade were significantly associated with higher SGR. SGR was significantly associated with disease-free survival (DFS) in a univariate analysis (p = 0.04), but not in a multivariate Cox analysis (p>0.05). High SGR was significantly associated with worse DFS in a subgroup of initial tumor size >2cm (p = 0.018), but not in those with tumor size <2cm (p>0.05). Conclusion Our results showed that tumor growth rate measured by US in a relatively short time interval was associated with other worse prognostic factors and DFS, but it was not an independent prognostic factor in breast cancer patients.

Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation

ABSTRACT While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling.

Can We Skip Intraoperative Evaluation of Sentinel Lymph Nodes? Nomogram Predicting Involvement of Three or More Axillary Lymph Nodes before Breast Cancer Surgery

Purpose The American College of Surgeons Oncology Group Z0011 trial reported that complete dissection of axillary lymph nodes (ALNs) may not be warranted in women with clinical T1-T2 tumors and one or two involved ALNs who were undergoing lumpectomy plus radiation followed by systemic therapy. The present study was conducted to identify preoperative imaging predictors of ≥ 3 ALNs. Materials and Methods The training set consisted of 1,917 patients with clinical T1-T2 and node negative invasive breast cancer. Factors associated with ≥ 3 involved ALNs were evaluated by logistic regression analysis. The validation set consisted of 378 independent patients. The nomogram was applied prospectively to 512 patients who met the Z0011 criteria. Results Of the 1,917 patients, 204 (10.6%) had ≥ 3 positive nodes. Multivariate analysis showed that involvement of ≥ 3 nodes was significantly associated with ultrasonographic and chest computed tomography findings of suspicious ALNs (p < 0.001 each). These two imaging criteria, plus patient age, were used to develop a nomogram calculating the probability of involvement of ≥ 3 ALNs. The areas under the receiver operating characteristic curve of the nomogram were 0.852 (95% confidence interval [CI], 0.820 to 0.883) for the training set and 0.896 (95% CI, 0.836 to 0.957) for the validation set. Prospective application of the nomogram showed that 60 of 512 patients (11.7%) had scores above the cut-off. Application of the nomogram reduced operation time and cost, with a very low re-operation rate (1.6%). Conclusion Patients likely to have ≥ 3 positive ALNs could be identified by preoperative imaging. The nomogram was helpful in selective intraoperative examination of sentinel lymph nodes.

Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer

Purpose Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. Materials and Methods This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. Results A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. Conclusion Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

AB0622 Clinical Characteristics of Systemic Sclerosis Patients with Interstitial Lung Disease Who do not Require Immunosuppressive Treatment

Background Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs. Although interstitial lung disease (ILD) is a major cause of death in this disease, pulmonary function remains stable in a subset of SSc patients with ILD without any treatment. However, clinical characteristics in this subset of patients are not well characterized. Objectives To investigate clinical characteristics of SSc patients with ILD who do not require additional immunosuppressive treatment for ILD. Methods A total of 151 SSc patients with ILD who received medical care at Seoul National University Hospital between 1978 and 2013 were enrolled in this study. ILD was diagnosed based on chest computed tomography (CT) and the extent of ILD was semi-quantitatively graded into 1-4 (grade 1, <25%; grade 2, 25–50%; grade 3, 50–75%; grade 4, >75% of lung involvement). Detailed baseline clinical characteristics were obtained from medical record review. Mortality was ascertained from medical record review and data from the Statistics Korea. After confirming survival benefit of untreated group versus treated group with Kaplan Meier analysis, clinical characteristics of untreated group were defined by comparison with treated group (chi-square test or Student t-test). Sensitivity test was performed by proving survival benefit of patients with the defined characteristics in the untreated group (log-rank test). Results The mean (standard deviation) age at diagnosis of 151 patients was 48.7 (12.9) years and 88.7% were women. Eighty (52.9%) patients did not receive immunosuppressive treatment for ILD, while 71 (47.0%) patients required immunosuppressive treatment, which includes cyclophosphamide (n=46), azathioprine (n=8), glucocorticoids (n=14) and others (n=3). Interestingly, median survival of non-treatment group was significantly better than treatment group during the follow-up of 1300.80 person-years (p=0.029 by log-rank test). Compared with treatment group, non-treatment group had higher baseline predicted % of forced vital capacity (FVC, 79.2±16.8% vs. 68.0±18.2, p<0.001), predicted % of diffusion capacity of carbon monoxide (DLCO, 66.4±20.5 vs. 52.0±17.9, p<0.001), lower CT grade (Grade 1: 89.6% vs. 54.7%, p<0.001), absence of pulmonary arterial hypertension (83.8% vs. 64.8%, p=0.013) and absence of gastrointestinal involvement (60.0% vs. 39.0%). Other baseline characteristics were not different, which include age at diagnosis, duration of disease, skin subset, profile of autoantibodies, involvement of heart or kidney and subtypes of ILD on CT. Among the non-treatment group, patients with the defined characteristics showed significant survival benefit than those without the characteristics (p=0.0047 by log-rank test). Conclusions Watch and wait approach may be applied to patients with SSc-associated ILD with minimal pulmonary infiltrates on CT scan and absence of pulmonary arterial hypertension at ILD diagnosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3686

S100A8/A9 mediate the reprograming of normal mammary epithelial cells induced by dynamic cell-cell interactions with adjacent breast cancer cells.

To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.

Endocrine Treatment-Related Symptoms and Patient Outcomes in Breast Cancer: A Meta-Analysis

Purpose An association between endocrine treatment-related symptoms and breast cancer recurrence has been suggested previously; however, conflicting results have been reported. We performed a meta-analysis of published studies to clarify this relationship. Methods We systematically searched PubMed, Embase, Scopus, and the Cochrane database for studies investigating the association between endocrine treatment-related symptoms and patient survival. Random-effects meta-analysis was conducted with recurrence rate as the primary outcome. Results Out of 7,713 retrieved articles, six studies were included. In patients who received endocrine treatment, the presence of any endocrine treatment-related symptom was found to be associated with a lower recurrence rate in comparison to an absence of any symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66–0.87). This relationship persisted in patients presenting with only vasomotor or only musculoskeletal symptoms (HR, 0.74, 95% CI, 0.63–0.87; HR, 0.69, 95% CI, 0.55–0.86, respectively). At both time-points of symptom evaluation (3 months and 12 months), patients with endocrine treatment-related symptoms had a lower recurrence rate (HR, 0.74, 95% CI, 0.66–0.84; HR, 0.79, 95% CI, 0.69–0.90, respectively). This association was also significant in pooled studies including patients with and without baseline symptoms (HR, 0.73, 95% CI, 0.54–0.99; HR, 0.76, 95% CI, 0.69–0.85, respectively). Conclusion Endocrine treatment-related symptoms are significantly predictive of lower recurrence rate in breast cancer patients, regardless of the type of symptoms, time-point of evaluation, or inclusion of baseline symptoms. These symptoms could be biomarkers for the prediction of long-term responses to endocrine treatment in patients with breast cancer.

The treatment outcomes and the use of adjuvant therapies in breast cancer patients with severe co-morbidities

Purpose Studies have suggested a potential role of patient’s co-morbidity in determining the survival outcomes of breast cancer. In this study, we examined the long-term oncologic outcomes in breast cancer patients who underwent curative surgery according to their pre-existing comorbid conditions and analyzed the association between the co-morbidity and the use of adjuvant therapies. Methods The medical records of 2,501 patients who underwent surgery for primary breast cancer from June 2006 to June 2010 were reviewed retrospectively. The patients were classified into three groups according to preoperative ASA status determined by the anesthesiologists. Clinico-pathologic characteristics and survival outcomes of the patients were compared among the different co-morbidity groups. Results There were 1,792 (71.6%), 665 (26.6%), and 44 (1.8%) patients in ASA I, II, and III, respectively. Total 95 (3.8%) deaths and 269 (10.8%) recurrences (loco-regional and distant) occurred during the median follow-up period of 71 months. Patients with high comorbidity showed significantly higher rate of deaths (51 (2.8%), 38 (5.7%) and 6 (13.6%) deaths in ASA I, II and III group, respectively, p<0.001). The ASA 3 patients also showed significantly higher rate of breast cancer recurrence when compared to other groups (180 (10.0%), 80 (12.0%) and 9 (20.5%) in ASA I, II, and III, respectively, p = 0.041). Significantly fewer patients in the high co-morbidity group received adjuvant therapies (77 (4.3%), 44 (6.6%) and 8 (18.2%) in ASA I, II, and III, respectively, p<0.001). The increased recurrence of breast cancer in the high morbidity group was mostly seen in patients who did not receive adjuvant therapies. The incidence of serious adverse effect during the adjuvant therapy did not differ according to the co-morbidity conditions. Conclusions In this study, high comorbidity was related to increased risk of death and recurrence in breast cancer. The increased risk of recurrence in high co-morbidity group was mostly seen in patients who did not receive adjuvant therapies. Considering the relatively low rates of serious adverse effects in high co-morbidity patients who received adjuvant therapies, active use of adjuvant therapies in selected patients may improve survival outcomes in breast cancer patients with severe co-morbidities.

Nomograms to Predict Positive Resection Margin and to Predict Three or More Positive Lymph Nodes

A nomogram is a graphical calculating device, a two-dimensional diagram designed to allow the approximate graphical computation of a function. Nomograms have been developed for various purposes in clinical use of cancer managements. We will introduce some good examples of useful nomograms for breast cancer surgeons.

SAT0014 Association of Hla Genes in Systemic Sclerosis with Interstitial Lung Disease

Background Interstitial lung disease (ILD) is associated with a significant morbidity and mortality in systemic sclerosis (SSc). Many studies have reported the association between human leukocyte antigen (HLA) alleles and increased risk of SSc, but the associated between ILD in SSc and HLA alleles remains unclear. Objectives The aim of this study was to investigate the association of HLA class I and HLA class II with ILD in Korean SSc cohort. Methods A total of 170 SSc patient (105 SSc patients with ILD and 65 SSc patients without ILD) were enrolled at Seoul National University Hospital from 1988 to 2014. Two hundred one healthy participants from Korean Marrow Donor Program (KMDP) were recruited as controls. Demographic information, clinical skin subset (limited vs. diffuse), SSc-specific autoantibodies (anti-topoisomerase I (ATA), anti-centromere (ACA), anti-ribonucleoprotein (RNP)), and internal organ involvement (ILD, pulmonary arterial hypertension, gastrointestinal, renal involvement) of the enrolled patients were characterized. ILD were diagnosed based on the findings of the chest computed tomography. HLA-A, -B, -C,-DQB1,-DRB1, and -DPB1 typing were performed PCR amplification with directly sequencing from extracted genomic DNA. Results HLA-B*52:01, C*12:02, DRB1*15:02, DPB1*09:01, and DPB1*13:01 alleles were more frequent in SSc patients with ILD than healthy controls. However, the frequencies of these genes did not differ between SSc patients with and without ILD (Table). ATA positive SSc was associated with HLA-B*52:01, C*12:02, DRB1*15:02, DPB1*09:01, and DPB1*13:01 alleles compared to ATA negative SSc and DPB1*09:01 showed the highest odds ratio for ATA (OR =23.08).Table 1. HLA frequencies in patient with systemic sclerosis with ILD and without ILD compared to healthy controls HLA alleles SSc_Total ILD(+)SSc ILD(−)SSc Control SSc Total vs. Control ILD(+)SSc vs. Control ILD(−)SSc vs. Control (N=170) (n=105) (n=65) (N=201) Pc Pc Pc B*52:01 23 (13.5) 20 (19.0) 3 (4.6) 9 (4.5) 0.076 <0.001 1.000 C*12:02 23 (13.5) 20 (19.0) 3 (4.6) 9 (4.5) 0.046 <0.001 1.000 DRB1* 15:02 29 (17.1) 24 (22.9) 5 (7.7) 14 (7.0) 0.074 <0.001 1.000 DPB1* 09:01 22 (12.9) 18 (17.1) 4 (6.2) 9 (4.5) 0.045 <0.001 1.000 DPB1* 13:01 52 (30.6) 38 (36.2) 14 (21.5) 25 (12.4) <0.001 <0.001 1.000 Abbreviation: HLA, human leukocyte antigen; SSc, systemic sclerosis; ILD, interstitial lung disease; OR, odds ratio; Pc, corrected P by Bonferroni correction. Pc of ILD(+)SSc vs. ILD(−)SSc: HLA-B*52:01 (Pc=0.304), C*12:02 (Pc=0.184), DRB1*15:02 (Pc=0.407), DPB1*09:01 (Pc=0.570), DPB1*13:01 (Pc=0.660). Conclusions SSc patients with ILD have several specific HLA genes compared with healthy controls and the frequencies of these HLA genes were significantly higher in ATA-positive SSc as well. Therefore, ATA positivity and ILD are associated with ceratin HLA class I and II in SSc patients. References Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK, et al. HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum 2009;60:3807–14. Disclosure of Interest None declared