Nan Song

Preoperative serum levels of matrix metalloproteinase-2 (MMP-2) and survival of breast cancer among Korean women

Background: Matrix metalloproteinase-2 (MMP-2) has been thought of as a predictor of recurrence or metastasis risk or prognostic markers in cancer. We evaluated whether preoperative serum levels of MMP-2 work as a prognostic biomarker in breast cancer prognosis. Methods: Preoperative serum levels of MMP-2 were measured with ELISA in 303 patients with histologically confirmed breast cancer. The median follow-up time for all patients was 4.24 years. The relationship of MMP-2 to survival was investigated using Cox proportional hazard regression model adjusted for the tumor–node–metastasis (TNM) stage and estrogen receptor (ER) status. Results: In the multivariate analysis, disease-free survival (DFS) was worse among patients with the third tertile of MMP-2 level than with the first tertile of MMP-2 level [hazard ratio, 1.80; 95% confidence interval (CI), 1.04–3.11; P = 0.04]. However, when the patients were stratified by age, ER status, histologic grade, and nuclear grade, inverse correlation was shown between serum MMP-2 levels and prognostic factors, and the associations between MMP-2 and DFS were only significant among patients with poor prognostic factors (HR, 2.75; 95% CI, 1.32–5.73 in ER-negative; HR, 2.90; 95% CI, 1.42–5.92 in histologic grade III; and HR, 2.61; 95% CI, 1.26–5.39 in nuclear grade III). Conclusions: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival in patients with breast cancer in ER-negative, higher histologic grade, or higher nuclear grade breast cancers. Impact: Our results indicate that serum levels of MMP-2 may play a role as prognostic biomarker in breast cancer survival. Cancer Epidemiol Biomarkers Prev; 21(8); 1371–80. ©2012 AACR.

Genetic variants in interleukin-2 and risk of lymphoma among children in Korea.

To estimate the genetic susceptibility for childhood lymphoma, we conducted an association study for 23 cases and 148 controls. Total 1536 tag single nucleotide polymorphisms (SNPs) were selected in 138 candidate gene regions related to immune responses, apoptosis, the cell cycle, and DNA repair. Twelve SNPs were significantly associated with the risk of lymphoma (P(trend)<0.05) in six genes (IL1RN, IL2, IL12RB1, JAK3, TNFRSF13B, and XRCC3). The most significant association was seen for IL2 variant rs2069762 (OR(TG+GG) vs. TT=3.43 (1.29-9.11), P(trend)=0.002, minP=0.005). These findings suggest that common genetic variants in IL2 might play a role in the pathogenesis of childhood lymphoma.

Association of selected medical conditions with breast cancer risk in Korea.

Objectives To estimate the effect of medical conditions in the population of Korea on breast cancer risk in a case-control study. Methods The cases were 3242 women with incident, histologically confirmed breast cancer in two major hospitals interviewed between 2001 and 2007. The controls were 1818 women each admitted to either of those two hospitals for a variety of non-neoplastic conditions. Information on each disease was obtained from a standardized questionnaire by trained personnel. Odds ratios (ORs) for each disease were derived from multiple logistic regression adjusted for age, age of menarche, pregnancy, age of first pregnancy, and family history of breast cancer. Results Among all of the incident breast cancer patients, pre-existing diabetes (OR, 1.33; 95% confidence interval [CI], 0.99 to 1.78), hypertension (OR, 1.46; 95% CI, 1.18 to 1.83), thyroid diseases (OR, 1.26; 95% CI, 1.00 to 1.58), and ovarian diseases (OR, 1.70; 95% CI, 1.23 to 2.35) were associated with an increased risk of breast cancer when other factors were adjusted for. In a stratified analysis by menopausal status, pre-existing hypertension (pre-menopause OR, 0.80; 95% CI, 0.48 to 1.34 vs. post-menopause OR, 1.87; 95% CI, 1.44 to 2.43; p-heterogeneity <0.01) and ovarian disease (pre-menopause OR, 4.20; 95% CI, 1.91 to 9.24 vs. post-menopause OR, 1.39; 95% CI, 1.02 to 1.91; p-heterogeneity 0.01) showed significantly different risks of breast cancer. Conclusions Our results suggest the possibility that medical conditions such as hypertension affect breast cancer development, and that this can differ by menopausal status. Our study also indicates a possible correlation between ovarian diseases and breast cancer risk.

Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia

Current evidence suggests that apoptosis and the cell cycle system play an important role in cancer development. To identify susceptible genetic markers in these mechanisms, we did an association study in 63 patients and 148 controls. A total of 304 SNPs in 31 gene regions were selected. We evaluated an association at a gene region level by computing the minimum P-value (minP) and doing the false discovery rate (FDR) test. Both SNP and gene-based analyses presented associations with the risk of childhood leukemia for 5 genes: CASP7, CASP14, CASP8AP2, MYC, and RIPK1 (P(trend)<0.05). There were statistically significant associations for CASP7 (rs12416109 and rs3814231, P(trend) = 0.002 and 0.009, respectively, minP = 0.013, FDR = 0.042) and CASP14 (rs8110862, P(trend)<0.001, minP = 0.002, FDR = 0.027). This study suggests that genetic polymorphisms in apoptosis and cell cycle related genes might play a role in childhood leukemia development.

Prediction of Breast Cancer Survival Using Clinical and Genetic Markers by Tumor Subtypes

Purpose To identify the genetic variants associated with breast cancer survival, a genome-wide association study (GWAS) was conducted of Korean breast cancer patients. Methods From the Seoul Breast Cancer Study (SEBCS), 3,226 patients with breast cancer (1,732 in the discovery and 1,494 in the replication set) were included in a two-stage GWAS on disease-free survival (DFS) by tumor subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). The associations of the re-classified combined prognostic markers through recursive partitioning analysis (RPA) of DFS for breast cancer were assessed with the Cox proportional hazard model. The prognostic predictive values of the clinical and genetic models were evaluated by Harrell’s C. Results In the two-stage GWAS stratified by tumor subtypes, rs166870 and rs10825036 were consistently associated with DFS in the HR+ HER2- and HR- HER2- breast cancer subtypes, respectively (P rs166870=2.88×10-7 and P rs10825036=3.54×10-7 in the combined set). When patients were classified by the RPA in each subtype, genetic factors contributed significantly to differentiating the high risk group associated with DFS inbreast cancer, specifically the HR+ HER2- (P discovery=1.18×10-8 and P replication=2.08×10-5) and HR- HRE2- subtypes (P discovery=2.35×10-4 and P replication=2.60×10-2). The inclusion of the SNPs tended to improve the performance of the prognostic models consisting of age, TNM stage and tumor subtypes based on ER, PR, and HER2 status. Conclusion Combined prognostic markers that include clinical and genetic factors by tumor subtypes could improve the prediction of survival in breast cancer.

Tumor Subtype-Specific Associations of Hormone-Related Reproductive Factors on Breast Cancer Survival

Purpose It is inconclusive whether reproductive factors, which are known as risk factors of breast cancer, also influence survival. We investigated overall and subtype-specific associations between reproductive factors and breast cancer survival. Methods Among 3,430 incident breast cancer patients who enrolled in the Seoul Breast Cancer Study, 269 patients (7.8%) died and 528 patients (15.4%) recurred. The overall and subtype-specific associations of reproductive factors including age at menarche and menopause, duration of estrogen exposure, menstrual cycle, parity, age at first full-term pregnancy, number of children, age at last birth, time since the last birth, and duration of breastfeeding, on overall and disease-free survival (OS and DFS) were estimated by hazard ratios (HRs) and 95% confidence intervals (95% CIs) using a multivariate Cox proportional hazard model. Results An older age at menarche (HR for OS=1.10, 95% CI=1.03-1.19), a greater number of children (≥4 vs. 2, HR for DFS=1.58, 95% CI=1.11-2.26), and a shorter time since last birth (<5 vs. ≥20 years, HR for DFS=1.67, 95% CI=1.07-2.62) were associated with worse survival while longer duration of estrogen exposure with better survival (HR for DFS=0.97, 95% CI=0.96-0.99). In the stratified analyses by subtypes, those associations were more pronounced among women with hormone receptor and human epidermal growth factor 2 positive (HR+ HER2+) tumors. Conclusions It is suggested that reproductive factors, specifically age at menarche, number of children, time since last birth, and duration of estrogen exposure, could influence breast tumor progression, especially in the HR+ HER2+ subtype.

Heterogeneity of epidemiological factors by breast tumor subtypes in Korean women: A case-case study

Breast cancer is heterogeneous in clinical behavior by subtypes; however, it is unclear how this heterogeneity is related to epidemiological factors. To evaluate the differences in epidemiological factors by breast tumor subtypes, we investigated the associations of epidemiological factors between tumor subtypes in Korean women. From the Seoul Breast Cancer Study, a total of 3,058 patients with breast cancer were included in the analyses. Tumor subtypes were classified based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses. The epidemiological factors of each subtype were compared through case–case analyses using multivariate a polytomous logistic regression model adjusted for age and recruiting centers. The distribution of the subtypes was as follows: 1,714 HR+ HER2− (56.0%), 414 HR+ HER2+ (13.5%), 423 HR− HER2+ (13.9%) and 507 HR− HER2− (16.6%) patients with breast cancer. There were significant differences in age, menopausal status, age at menarche, number of children, age at first full‐term pregnancy (FFTP), duration of breastfeeding and duration of endogenous estrogen exposure between tumor subtypes (p < 0.05). Compared to HR+ HER2− patients, the other subtype patients showed more frequency in having more numbers of children and less frequency in having earlier menarche, later FFTP and longer endogenous estrogen exposure. Although HR− HER2+ patients were less obese, HR− HER2− patients were younger and more obese. In conclusion, age, body mass index and reproductive factors were differentially associated with breast tumor subtypes suggesting a possible distinct etiology for tumor progression.

The associations between immunity-related genes and breast cancer prognosis in Korean women.

We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell’s C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62–39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10–8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18–9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48–31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell’s C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women.

Abstract 4494: Preoperative serum levels of matrix metalloproteinase-2 (MMP-2) and survival of breast cancer among Korean women

Objective: We evaluated whether preoperative serum levels of matrix metalloproteinase-2 (MMP-2) work as a prognostic biomarker in breast cancer prognosis. Methods: Three hundred and three women with histologically confirmed breast cancer were recruited. The follow-up time for all patients was 4.24 years. The MMP-2 levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA) using the preoperative serum. The relationship of MMP-2 to survival was investigated using Cox9s proportional hazard model adjusted for the TNM stage and estrogen receptor (ER) status. Results: In the multivariate analysis, disease-free survival (DFS) was worse among patients with the third tertile of MMP-2 compared to the first tertile of MMP-2 (hazard ratio (HR)=1.80, 95% confidence interval (CI)=1.04-3.11, P=0.04). Furthermore, when the patients were stratified by histological grade and nuclear grade, the worse DFS was predicted by high levels of MMP-2 (HR=2.90 and 95% CI=1.42-5.92 in histological grade III vs. I-II and HR=2.61 and 95% CI=1.26-5.39 in nuclear grade III vs. I-II). In ER negative patients, high levels of MMP-2 also tended to have a worse prognosis (HR=2.75 and 95% CI=1.32-5.73). Conclusions: Our results suggest that the preoperative serum levels of MMP-2 were associated with the survival of breast cancer as a potential prognostic biomarker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4494. doi:1538-7445.AM2012-4494

Associations between genetic polymorphisms of membrane transporter genes and prognosis after chemotherapy: meta-analysis and finding from Seoul Breast Cancer Study (SEBCS)

Membrane transporters can be major determinants of the pharmacokinetic profiles of anticancer drugs. The associations between genetic variations of ATP-binding cassette (ABC) and solute carrier (SLC) genes and cancer survival were investigated through a meta-analysis and an association study in the Seoul Breast Cancer Study (SEBCS). Including the SEBCS, the meta-analysis was conducted among 38 studies of genetic variations of transporters on various cancer survivors. The population of SEBCS consisted of 1338 breast cancer patients who had been treated with adjuvant chemotherapy. A total of 7750 SNPs were selected from 453 ABC and/or SLC genes typed by an Affymetrix 6.0 chip. ABCB1 rs1045642 was associated with poor progression-free survival in a meta-analysis (HR = 1.33, 95% CI: 1.07–1.64). ABCB1, SLC8A1, and SLC12A8 were associated with breast cancer survival in SEBCS (Pgene < 0.05). ABCB1 rs1202172 was differentially associated with survival depending on the chemotherapy (Pinteraction = 0.035). Our finding provides suggestive associations of membrane transporters on cancer survival.